course 2 Flashcards

Question

Decarboxylation

Answer 1

removal of the carboxyl group in the form of CO2 - amino acids become biogenic amines o histidine -> histamine, hormone and neurotransmitter o glutamate -> GABA (gamma-Aminobutyric Acid), inhibitory neurotransmitter o tryptophan -> 5-hydroxytryptofan -> serotonin, one of the hormones of happiness

Answer 2

opposite of decarboxylation - CO2 is added - for example, in the synthesis of fatty acids

Answer 3

oxidation of single bond to double bond o -CH2-CH2- -> -CH=CH- + 2H+ + 2e- o very frequent reaction in metabolism - for example in β-oxidation of fatty acids, Krebs cycle and synthesis of unsaturated fatty acids

Answer 4

primary alcohols ▪ alcohol -> aldehyde -> carboxylic acids ● methanol -> formaldehyde -> formic acid ● ethanol -> acetaldehyde -> acetic acid ▪ methanol itself is completely harmless, only after its metabolism to formic acid it becomes extremely toxic all alcohols are metabolized by one enzyme (alcohol dehydrogenase), secondary alcohols ▪ alcohol -> ketone o tertiary alcohols – dehydrogenation does not occur

Answer 5

glucose could theoretically leave at the moment of entry into the cell, therefore in all cells immediately after entry it is esterified with phosphate to glucose-6-phosphate, which no longer crosses the membrane o Only hepatocytes have an enzyme that can separate the phosphate again

Answer 6

oxidation of glucose on 6th carbon -> glucuronic acid o oxidation of glucose on 1st carbon -> gluconic acid

Answer 7

fructose, mannose and galactose can be converted to one another though glucose

Answer 8

catalytically active RNA is not an enzyme but a ribozyme

Answer 9

– what substrate the enzyme works with ▪ absolute - the enzyme processes only one molecule (eg urease) ▪ relative - the enzyme processes one group of molecules (eg Hexokinase - phosphorylates all 6C sugars)

Answer 10

protein part of a complex enzyme is apoenzyme, non-protein part is cofactor o cofactors are ▪ organic – e.g. haeme ▪ inorganic - metal ion - Zn, Cu, Fe, Mn ● stabilize the active centre, aid redox reactions and polarize bonds o division of cofactors ▪ prosthetic groups - firmly bound to the enzyme, part of the stable structures ▪ coenzymes - only weakly bound to the enzyme, can completely detach

Answer 11

catalyze intermolecular oxidation-reduction reactions; transfer of hydrogen, electrons, or reaction with oxygen - types of enzymes - dehydrogenases, oxidases, peroxidases, oxygenases - eg alcohol dehydrogenase, lactate dehydrogenase (lactate <-> pyruvate), phenylalanine hydroxylase (phenylalanine -> tyrosine)

Answer 12

NAD (nicotinamidadenine dinucleotide) and NADP ((nicotinamidadenine dinucleotide phosphate) FAD a FADH2 - flavinadenine dinucleotide derived from riboflavin (vitamin B2) coenzyme Q - ubiquinone/ubiquinol ▪ part of the respiratory chain ▪ prosthetic group – haem

Answer 13

transfer groups (-CH 3, -NH 2, phosphate) from the donor to the acceptor - types of enzymes - C-transferases, glycosyltransferases, aminotransferases, phosphotransferases (or kinases)

Answer 14

ATP (adenosine triphosphate), GTP (guanosine triphosphate) ▪ carry phosphate groups CoA - Coenzyme A ▪ transmits acyls o TDP - thiamine diphosphate (also TPP - thiaminpyrophosphate) ▪ carries carbon groups ▪ precursor - thiamine (vitamin B1) o PALP - pyridoxal phosphate ▪ carries the NH2 group ▪ precursor - pyridoxine (vitamin B6) o THF - tetrahydrofolate ▪ carries single-carbon residues; precursor: folic acid

Answer 15

catalyse hydrolytic cleavage of the substrate = cleaves bonds with the help of water - we divide them into groups o Proteases - cleaves peptide bonds in protein and peptide molecules o glucosidases - cleaves glycosidic bonds o lipases - cleaves ester bonds in lipids o phosphatases - remove the phosphate group o amylases - cleaves bonds between glucose molecules in polysaccharides no coenzymes

Answer 16

enzymes catalyzing bond decomposition in a different way than hydrolysis or oxidation - double bonds or cyclic compounds are often formed - can cleave (or introduce) small molecules, e.g. H2O, CO2 or NH3 - coenzymes similar to transferases

Answer 17

catalyse reactions within a molecule of one substrate, move atoms (groups) from one carbon to another - e.g cis-trans-isomerase, ribose phosphate-isomerase, epimerase (changes the orientation of OH groups) - most often they do not contain coenzymes

Answer 18

they catalyse the synthesis of simple molecules to complex molecules - often energy-intensive bonds with simultaneous energy consumption (mostly ATP -> ADP + Pi) - often contain coenzymes of transferases o biotin (vitamin H) - carboxylation

Answer 19

Vitamin B1 - thiamine Vitamin B2 - riboflavin Vitamin B2 - riboflavin Vitamin B5 – pantothenic acid Vitamin B6 - pyridoxine Vitamin B7 = Vitamin H = coenzyme R = Biotin Vitamin B9 – Folic acid Vitamin B12 - cobalamin Vitamin C - Ascorbic acid

Answer 20

involved in carbohydrate metabolism - active form - coenzyme TPP (thiaminpyrophosphate) - metabolic function - transfer of hydroxy-alkyl residues = oxidative decarboxylation o eg, oxidative decarboxylation of pyruvate and α-ketoglutarate - symptoms of deficiency - fatigue, convulsions, digestive disorders, nerve disorders, beri-beri nerve disease - sources - cereals, yeast, lentils, offal, yolk, pork

Answer 21

components of flavoproteins, enzymes involved in oxidative reduction processes (respiratory chain) - active form – coenzyme FAD - symptoms of deficiency - inflammation of oral corners, lips, damage to mucous membranes and skin, growth arrest - sources - meat, milk, eggs, liver, yeast, beer

Answer 22

Also known as niacin form NIcotinic ACid vitamIN - Active form – nicotinamide nucleotides NAD and NADP - symptoms of deficiency - convulsions, nervous disorders, pellagra disease - sources - meat, fish, yeast, multigrain cereal, lentils

Answer 23

basis of coenzyme A, contribution to protein synthesis and oxidation reduction processes - symptoms of deficiency - nervous disorders, convulsions - sources - meat, cheese, eggs, liver, yeast, lentils

Answer 24

part of enzymes involved in amino acid metabolism (transaminases) o pyridoxal phosphate -> transamination and decarboxylation of AA - symptoms of deficiency - disorders of haemoglobin production, inflammation of skin and mucous membranes, epileptic inflammation - sources - liver, whole grain cereal products, egg yolk, yeast

Answer 25

significant coenzyme, promotes cell growth and division - symptoms of deficiency - skin diseases, anorexia, fatigue - sources - eggs, liver, vegetables, yeast, formed by intestinal bacteria

Answer 26

affects the amino acid metabolism necessary for the formation of red blood cells - active form - tetrahydrofolate(THF) - transfer of monocarbon residues o carries methyl residues and alters deoxyuridine phosphate - symptoms of deficiency: disorders of protein synthesis, anaemia - sources - eggs, leafy vegetables, yeast

Answer 27

does not occur in plants, it is formed only in animals - ensures normal haematopoiesis - consists of a tetrapyrrole skeleton (similar to haemoglobin) with a cobalt atom attached inside - metabolic function - transport of methyl groups - symptoms of deficiency - anaemia, degeneration of spinal nerves - sources - liver, meat, intestinal bacteria

Answer 28

Allows for iron absorption, formation of collagen and erythrocytes, promotes blood clotting, production of antibodies, is an antioxidant - oxidoreductase cofactor (electron donor) - symptoms of deficiency - gingivitis, bleeding, decreased resistance to infections, scurvy - the most severe stage of avitaminosis - sources - vegetables (Brussels sprouts, peppers), fruits (blackcurrants, strawberries), potatoes, internal organs of animals

Answer 29

Vitamin A - retinol Vitamin D – calciferol Vitamin E - tocopherol Vitamin K - phylloquinone

Answer 30

component of visual pigment, important for epithelial formation, antioxidant - active forms o retinal - vision, carbohydrate transport o retinoic acid - signalling molecule, ensures development, differentiation, growth - symptoms of deficiency - night blindness, drying of cornea and conjunctiva, rough skin, stopping growth - sources - liver, egg yolk, butter, cheese, sea fish fat, provitamin (β-carotene) in plant foods (carrots)

Answer 31

group of vitamins, most important - D3 (cholecalciferol) and D2 (ergocalciferol) - controls the metabolism of calcium and phosphorus, promotes their absorption from the small intestine and bone deposition - effective form - hormone calcitriol - hypervitaminosis - increase of calcium absorption, its deposition in tissues and formation of kidney stones - symptoms of deficiency - softening and deformation of bones - rickets (rachitis) - sources - fat of sea fish, butter, liver, egg yolk, also due to UV radiation of the skin

Answer 32

antioxidant, supports the activity of the gonads - protection of the organism against cancer (together with A and C) - symptoms of deficiency - muscle weakness, vascular system disorders - sources - vegetable oils, cereal sprouts

Answer 33

supports the process of blood clotting, promoting the synthesis of prothrombin in the liver - active form - phylohidroquinone - symptoms of deficiency - impaired blood clotting - sources - leafy vegetables, made up of intestinal bacteria

Answer 34

how fast the reaction will proceed is described by the Michaelis-Menten model - it suggests that the reaction rate depends on the substrate concentration (higher concentration = higher speed) Enzyme + Substrate <-> Enzyme-Substrate complex -> Enzyme + Product Maximum, speed is achieved when the enzyme is saturated - at an infinite substrate concentration o in practice this speed can be achieved, it is a real value

Answer 35

substrate concentration at which half of the maximum reaction rate is reached o the concentration of the enzyme does not matter, only the substrate concentration o we can imagine that the constant describes the affinity of the enzyme to the substrate - the lower the constant, the higher the affinity

Answer 36

competitive inhibitors “compete” with substrate molecules for the active site of the enzyme o Successful binding results in a dysfunctional enzyme-inhibitor complex o these inhibitors often resemble the substrate - they must fit in the same place as the substrate, so they must look similar o E + I <-> EI - it is a reversible action - by increasing the substrate concentration, it is possible to decrease the efficiency of inhibition- by increasing the substrate concentration we decrease the chance that the enzyme will pair with the inhibitor o Vmax will remain the same – at infinite concentration of substrate competitive inhibitors will not be effective - the action of a competitive inhibitor increases KM, because we need more substrate for the same reaction rate

Answer 37

the uncompetitive inhibitor is in all cases allosteric (= another binding site on the enzyme other than the active site) o binding of the inhibitor causes a conformational change in the enzyme which is then unable to bind its substrate - the inhibitor binds to the enzyme completely regardless of whether or not the substrate is bound to the enzyme= the concentration of the reactants does not affect the potency of the inhibition - vmax decreases - we have less functional enzyme molecules o the inhibitor does not look at the substrate concentration at all - even if we increase the substrate concentration, there will always be some of the enzyme molecules in the solution that will be inhibited - KM stays the same- the inhibitor only takes out several molecules of enzyme, it does not change its affinity to the substrate

Answer 38

Inhibitors that bind only to the enzyme-substrate complex o they are often allosteric o E + S + I -> ES + I <-> ESI - this inhibition is often observed with enzymes that bind multiple substrates - it works by binding the first substrate to the enzyme, causing a change in the conformation of the enzyme and revealing an additional binding site to which the inhibitor subsequently binds - the inhibitor is very poor at low substrate concentration - it does not have enough ES complexes to bind to o high substrate = lots of ES complexes= a lot of opportunities for the inhibitor to bind to an enzyme - substrate concentration does not affect the binding of the inhibitor to the enzyme-substrate complex - vmax and KM decrease (enzyme appears to have a higher affinity for substrate)

Answer 39

another binding site on the enzyme other than the active site

Answer 40

AChE is an enzyme responsible for the hydrolytic cleavage (degradation) of acetylcholine in the synaptic cleft between two neurons is a hydrolase and contains serine in its active site acetylcholine is a minor but very important neurotransmitter found on neuromuscular plates, in the CNS and in the PNS o It plays a role in maintaining consciousness, attention, memory formation and muscle signaling o it is an ester of acetic acid and choline

Answer 41

AChE causes cleavage of the ester bond between acetyl and choline - acetic acid and choline is formed - if the neuron is stimulated and the acetylcholine is released into the synaptic cleft, it must also be removed - acetylcholine cannot act permanently, it would cause hyperstimulation o for this reason, we directly breakdown acetylcholine via AChE ▪ the enzyme attacks the carbonyl carbon (C=O)

Answer 42

amplify signal on synapses that use acetylcholine as a neurotransmitter (cholinergic synapse) irreversible inhibitors= carbachol and sarin – nerve gas reversible inhibitors= edrophonium and donepezil

Answer 43

separate gland cells (technically it is a gland consisting of one cell) ▪ forms mucus mucin ▪ are in the GIT, the airway, the conjunctiva in the upper eyelid...

Answer 44

secretion is produced on the body surface either directly or through the duct o secretion exits the cell through its apical surface o sweat glands, mammary glands, sebaceous glands, salivary glands...

Answer 45

secretion remains in the body, most often goes from the cell to the surrounding connective tissue and then into the bloodstream o secretion from the cell via basal surface o pancreas, pituitary, adrenal gland, thyroid gland...

Answer 46

combination of exocrine and endocrine glands

Answer 47

secretory granules are excreted by exocytosis o secretion synthesis is continuous but its secretion is not - secretion is stored inside the cell o The merocrine cell has a lot of RER, GA and secretory granules

Answer 48

the cell secretes secretions by cleaving the portion of the apical cytoplasm in which the secretions are located o typical for the mammary gland - fat droplets accumulate at the apical pole and the whole piece of the cell breaks apart o frequent in lipid-secreting cells

Answer 49

the cell secretes secretion so in a way that it disintegrates completely and disappears by apoptosis o typical for sebaceous glands

Answer 50

secretion is secreted by individual molecules through the cell membrane (either by itself or via carriers) and is passively followed by water on the basis of osmosis o Hydrophilic and ionic secretion needs transporters to get through the cell membrane o the result of eccrine cell activity is mucus - solution of secrete, water and ions isotonic with cytoplasm ▪ from this solution, the ions are gradually pumped back into the cells

Answer 51

caused by a malfunction of the membrane transporter for Cl- ▪ the consequence of a higher concentration of chloride ions leads to excessive reabsorption of sodium from mucus ▪ because water follows sodium, mucus dehydrates and increases its viscosity ▪ too thick mucus explains the symptoms of cystic fibrosis - thin tubes (pulmonary alveoli, vas deferens) clog and excessive mucus density interferes with the ability of antimicrobial peptides, leading to frequent infections (mainly respiratory)

Answer 52

mucin mucus production; is oppressed by other cells, hence the shape of the cup ▪ have RER, large GA, apical cytoplasm filled with secretory granules o in some organs, the whole surface epithelium is composed of mucin-producing cells (stomach, uterus)

Answer 53

intraepithelial glands o are built directly into the epithelium o they do not have an outlet/ duct system- they open directly to the surface of the epithelium extraepithelial glands o are placed under the epithelium of origin o consist of a secretory section and a duct

Answer 54

tubular - tube shape, most common, mucinous glands (see below) o acinar -round shape, narrow lumen ▪ for these glands, serous secretion is typical - proteins, enzymes o alveolar - shape of a bladder, have a wide, well recognizable lumen - compound type of secretory portion o tuboacinous- the secretory compartment has the shape of a tube with a round end o e.g. submandibular and sublingual o tuboalveolar- there is a wide lumen at the end of the tube ▪ e.g. mammary glands in lactation, sweat glands

Answer 55

intralobular- surrounded by epithelial structures, inside the lobule, leads directly from acinus to interlobular duct ● intercalated duct – forms part of the intralobular duct ● striated- connects the intercalated duct to the interlobular duct. Also, part of the interlobular ducts ▪ interlobular- outlet between lobule ▪ main - connects to the interlobular ducts, it is the last duct before the secretion exits the gland

Answer 56

is produced by alveolar and acinous cells is basophilic - most often it is peptide hormones, proteins and enzymes o Serous secreting cell (aka serous cell) has round nucleus, RER, GA and secretory granules

Answer 57

is produced by tubular cells o goblet cell - Produces mucus rich in mucin o mucinous cell has an active nucleus, GER, GA, and a secretory granule o mucin secretory granules are well stainable by PAS dye, which is sensitive to polysaccharides

Answer 58

seromucinous o both types of secretory compartments occur side by side and also in direct combination - e.g. tuboalveolar o Serous semilumen - a cap from serous cells at the end of the mucinous tubule

Answer 59

something between smooth muscle and epithelium - contractile epithelial cells used to expel secretions from secretory compartments and into ducts - slender star-shaped cells (basket cells) which are found in glandular epithelium as a thin layer above the basement membrane but generally beneath the luminal cells - they contain cytokeratin’s as epithelial cells and actin and myosin as smooth muscle cells

Answer 60

reverse polarization - the cell secretes secretion towards the basalis lamina - construction of endocrine glands - always trabecula of cells, only in the thyroid gland we find follicles (due to storage of iodine)

Answer 61

- endocrine cells scattered everywhere along the GIT, secrete signalling molecules to regulate digestive system function - types of endocrine glands according to hormones produced o polypeptides and proteins - adenohypophysis, parathyroids, islets of Langerhans... o catecholamines - adrenal medulla o steroid hormones - adrenal cortex, testis, ovary o thyroxine – thyroid gland

Answer 62

Cuboidal epithelium arranged around the follicle - inside the follicle is colloid - thyroglobulin - a storage form of thyroid hormones

Answer 63

amphicrine character o Exocrine function - forms bile o endocrine function - involved in the metabolism and production of plasma proteins - the basic morphological unit of the liver is the lobule of the central vein - the hexagonal prism consists of the plates of hepatocytes o The central vein sits right in the middle of the whole prism o fenestrated capillaries and bile ducts lead from the central vein towards the periphery of the lobules - at the point of contact of the three adjacent lobules there is a triad - 1 vessel, 1 vein and 1 bile duct

Answer 64

contains many porins - channels that allow molecules to pass through the membrane o as a result, the outer membrane non-selectively permits all molecules smaller than 10 kDa - Bcl proteins - part of outer mitochondrial membrane - important proteins in the regulation of apoptosis - Contains a few enzymes of fatty acid metabolism and phospholipids - unlike the cell membrane, it contains almost no cholesterol

Answer 65

similar composition to cytosol (much less protein than matrix) - there are proapoptotic proteins, cytochrome C and a lot of protons

Answer 66

the original membrane of the former prokaryotic cell - almost impermeable and very selective - everything except for small uncharged molecules needs a carrier - it incorporates the respiratory chain complexes o ATP synthase forms elemental bodies on the inner mitochondrial membrane - folds (cristae) - sometimes they are modified and form tubules (in cells producing steroid hormones) - is composed of 75% proteins and 25% phospholipids o contains specific phospholipids cardiolipins that help with membrane elasticity

Answer 67

has a gel like consistency because of its high protein concentration (500 g protein per 1L matrix) - contains enzymes of Krebs cycle, β-oxidation of fatty acids and ornithine cycle, various nucleotide coenzymes, inorganic ions (Ca), mtDNA, relevant tRNA and mRNA, mitochondrial ribosomes, chaperones and chaperonins

Answer 68

most proteins are imported from the cytoplasm - they are synthesized on ribosomes in the cytosol - chaperones ensure that proteins remain unpacked so that they can be transported through the mitochondrial membrane - on the inner and outer membrane are translocators for proteins - Tom and Sam complexes external, Tim complexes internal o Tom (transporter of outer membrane) complex gets protein into intermembrane space o Sam complex is for proteins to remain integrated into the outer mitochondrial membrane o Tim (transporter of inner membrane) 23 complex pushes proteins from the intermembrane space into the matrix o Tim 22 complex integrates proteins from the intermembrane space into the inner mitochondrial membrane

Answer 69

small (16.5 kbp) circular double helix without introns - encodes 2 rRNA, 22 tRNA and 13 proteins o most of the genome has moved into the nucleus of the host cell, making the mitochondria nucleus dependent and unable to live independently - 600-1000 mitochondrial proteins are encoded by nuclear DNA - in the matrix of mitochondria there is also a proteosynthetic apparatus and 70S ribosomes that can produce molecules encoded by mitochondrial DNA o mitochondrial ribosomes resemble bacterial ribosomes, which means that some antibiotics targeting bacterial ribosomes may also affect mitochondria

Answer 70

production of ATP by oxidative phosphorylation - Krebs cycle, β-oxidation, ketogenesis, steroid synthesis, ornithine cycle, gluconeogenesis, iron and calcium metabolism (regulation of intracellular calcium, triggering of apoptosis or necrosis, synaptic plasticity and thermogenesis - basolateral labyrinth - transfer of water and ions using Na / K ATPase with high consumption of ATP o Insufficient activity of mitochondria leads to transmission disorders and thus to cell oedema

Answer 71

programmed cell death requiring gene expression, proteosynthesis, and ATP - triggers in response to apoptotic signal, stress, cell damage... - mitochondria contribute by releasing proapoptotic factors from the intermembrane space, interrupting the supply of energy to the rest of the cell, and overproducing ROS (reactive oxygen species)

Answer 72

membrane damage is one of the main causes of cell death - the initial phase of cell damage is disruption of the membranes - their ability to selectively permeability is impaired o this harms ATP production, leading to ATP deficiency, non-functional membrane pumps and cell swelling

Answer 73

mitochondria naturally form oxygen radicals that may damage mtDNA or host cell DNA - accumulation of mutations in mtDNA with age gradually decreases the function of mitochondria and respiratory complexes - mitochondrial function impairment affects long-lived cells - neurons, cardiomyocytes, muscle cells - consequence - heart failure, muscle weakness, diabetes mellitus, dementia, neurodegeneration...

Answer 74

maternal inheritance - inherited along the maternal line because paternal mitochondria are not passed on to the offspring - most variable - there are several tens of copies of mitochondrial DNA and at the same time we have tens of thousands of copies of mitochondrial DNA in the cell - DAD - diabetes and deafness o Mutated leucine gene synthesizes abnormal proteins o damage of hair cells and pancreatic β cells LHON - Leber's hereditary optical neuropathy o begins in middle age with optic nerve dying and ends with complete blindness o can be caused by multiple mutations in complex 1 - mitochondria do not work well and their production of ATP is not enough for powerful and energy-intensive nerves

Answer 75

onset of the disease in prenatal development or just after delivery - inherited by Mendelian inheritance, because the mutated genes are found in the nucleus and not in the mitochondria - Leigh syndrome - progressive degenerative brain disease

Answer 76

with the help of classic medicines very difficult, practically at all - possibility of so-called mitochondrial transplantation - the child then has 3 parents, from one egg, from the second sperm and from the third mitochondria o Legal only in UK - Unfortunately, the CRISPR method does not work on mitochondria because the DNA can no longer cross the membrane

Answer 77

there is a balance in the cell between fission and fusion mitochondria - fusion - content mixing, protein replenishment, mtDNA repair, distribution of metabolic intermediates - division - increase of mitochondria

Answer 78

mitochondria reproduce exclusively asexually - mtDNA is inherited maternally - all mitochondrial embryo genetic information comes from the egg and not from the sperm - mtDNA mutates faster than nuclear genome - more susceptible to mutation accidents o heart and nerve tissue (brain, retina) - most often mitochondrial diseases o the cell is able to recognize and destroy mitochondria with defective mtDNA or trigger apoptosis - mitochondria in the cell can exchange mtDNA but do not combine it

Answer 79

C6H12O6 + O2 -> H2O + CO2 + Energy during this time, the oxygen is reduced from 0 to -2, and carbon is oxidized from 0 to +4 o glucose degradation can conveniently be divided into two phases ▪ the first phase is the transfer of electrons to the transmitters (NAD, FAD) and the formation of CO2 – ie. glycolysis, Krebs cycle ▪ the second phase is the transfer of electrons to the final acceptor (oxygen) and the utilization of the energy we get ● Only in the second phase we need oxygen ● The process of the second phase of glucose metabolism is the so-called Respiratory Chain

Answer 80

„mitochondrial electron transport chain “ - is located in the inner mitochondrial membrane - consists of 4 large enzymes (complexes), coenzyme Q and cytochrome C

Answer 81

the last respiratory chain complex - takes electrons from cytochrome C and passes them to oxygen o oxygen is reduced from 0 to -2 = 4 electrons are needed for each O2 - cytochrome C - a relatively small protein containing one molecule of heme o heme contains an iron atom that can pass between Fe2+ and Fe3+ - this is how electron transfer functions o the whole cytochrome C can therefore carry only one electron at a time o is electrostatically attached to the inner membrane from outside (not part of the membrane) - complex IV is inhibited it cyanide

Answer 82

transfers electrons from coenzyme Q to cytochrome C - contains FeS (iron-sulphur) centre - an evolutionary ancient electron carrier - coenzyme Q (ubiquinone) - electron transporter inside the inner mitochondrial membrane o it's not a protein, it's just a small molecule (on picture) o has two forms - ubiquinone (oxidized form) and ubiquinol (reduced form) o there are many other types of coenzyme Q - mammals have coenzyme Q10 ▪ 10 because it contains 10 isoprene units o contains two oxygen in its structure, which can be reduced and then re-oxidized - it can carry two electrons at the same time ▪ these two electrons can be obtained from many different sources - complex I, complex II, ETF dehydrogenase...

Answer 83

a giant complex composed of 45 subunits - it is much larger than the membrane itself - oxidizes NADH + H+ to NAD+ o 2 electrons are released which travel to the coenzyme Q through complex I

Answer 84

embedded in the inner mitochondrial membrane, but not completely - partially communicating directly with the mitochondrial matrix - active also in Krebs cycle – oxidizes succinate to fumarate o In this reaction, 2 electrons are released and go through FAD to coenzyme Q o FAD (unlike NAD) is not a separate molecule, it is just a part of enzymes (like a human hand)

Answer 85

Complexes I, III and IV are large proteins that cross the entire inner membrane and pump protons from the mitochondria matrix into the intermembrane space during electron transfer, creating a strong proton gradient

Answer 86

serves mainly as an alternative pathway of electron transport to coenzyme Q - ETFDH (ETF dehydrogenase, electron-transferring-flavoprotein-dehydrogenase) o ETF dehydrogenase contains FAD in its structure, thanks to which it can take electrons from ETF (electron transfer flavoprotein) and then pass them on to coenzyme Q - GPDH (glycerol- phosphate dehydrogenase) o NADH, that is formed outside the mitochondria cannot spontaneously cross the mitochondrial membrane → it is transmitted by GPDH and subsequently reaches the respiratory chain where it donates its two electrons

Answer 87

an enzyme not part of the respiratory chain but also in the inner mitochondrial membrane - whole protein works like a turbine o has a proton channel that allows protons to pass from the intermembrane space to the matrix according to the concentration gradient o As it passes through the proton channel, it turns ATP synthase - like water flowing through a hydroelectric power station - rotation of ATP synthase connects ADP and Pi into ATP - oligomycin - bacterial product, ATP synthase inhibitor

Answer 88

occurs in the matrix of mitochondria

Answer 89

'crossroad of metabolic pathways' - the interconnection of carbohydrate, lipid, and protein metabolism - amphibolic pathway (ie anabolic and catabolic pathway) o catabolic function - energy source, ATP synthesis o Anabolic function - formation of precursors for the synthesis of glucose, lipids, amino acids, porphyrins - burns nutrients to the water, CO2 and reduced coenzymes that continue into the respiratory chain

Answer 90

1) synthesis of citrate (starting substance, hence citrate cycle)) - oxaloacetate + acetyl-coA -> citrate + CoA 2) dehydrogenation and hydrogenation -> formation of isocitrate (so called citrate activation) 3) dehydrogenation and decarboxylation -> formation of 2-oxoglutarate (or α-ketoglutarate) ▪ here CO2 is split off and NADH if formed 4) dehydrogenation, decarboxylation and binding of CoA -> formation of succinyl-CoA ▪ CO2 is slip off again and NADH is formed 5) cleavage of CoA -> formation of succinate ▪ GTP is formed 6) dehydrogenation -> formation of fumarate ▪ FADH is formed 7) hydration -> formation of malate 8) dehydrogenation -> formation of oxaloacetate ▪ NADH is formed - total yield from 1 acetyl-coA = 2 CO2, 1 GTP, 3 NADH and 1 FADH2 o the use of cofactors in the respiratory chain is about 10 ATP

Answer 91

citrate synthase, isocitrate dehydrogenase and α-ketoglutarate dehydrogenase They are enzymes that are inhibited by high concentrations of ATP, preventing excessive consumption of acetyl-CoA

Answer 92

an enzymatic complex that catalyzes the oxidative decarboxylation of pyruvate, which produces acetyl-CoA, which subsequently enters the Krebs cycle ● a number of coenzymes participate in this reaction along with the complex ▪ pyruvate + NAD+ + CoA -> acetyl-CoA + NADH + H+ + CO2 ▪ pyruvate dehydrogenase reaction is irreversible

Answer 93

catalyzes the first reaction of the Krebs cycle – condensation of oxaloacetate and acetyl CoA o ATP is not required for the condensation of oxaloacetate and acetyl-CoA under citrate synthase, on the contrary - if ATP is present, the Krebs cycle is generally inhibited (with sufficient energy, the cycle is not necessary)

Answer 94

converts citrate into cis-aconitate (dehydration) and then cis-aconitate to isocitrate (hydration)

Answer 95

dehydrogenates isocitrate to α-ketoglutarate (= 2-oxoglutarate) ▪ the rate of reaction depends on the concentration of ATP and NADH -> excess of ATP or NADH means that the reaction will proceed slowly (again the excess of ATP and NADH indicates enough energy and therefore no need to produce more) ▪ this reaction generates NADH + H

Answer 96

α-ketoglutarate -> succinyl-CoA + NADH + H+ ▪ catalyzes oxidative decarboxylation with simultaneous binding of α-keto carbon to CoA and formation of NADH + H + ▪ the same mechanism as the oxidative decarboxylation of pyruvate ▪ coenzyme thiamine pyrophosphate is required

Answer 97

cleaves attached CoA and at the same time generates GTP (GDP+Pi -> GTP) ▪ stupid nomenclature of the enzyme, because it does not synthesize succinyl-CoA, but breaks it down

Answer 98

Flavin enzyme with firmly bound zFAD and non-heme iron ▪ succinate dehydrogenase produces fumarate ▪ the reaction is carried out with simultaneous transfer of hydrogen to FAD, which is reduced to FADH2 ▪ succinate dehydrogenase is also complex II in the respiratory chain

Answer 99

hydrates fumarate into malate

Answer 100

dehydrogenates malate into oxaloacetate ▪ oxaloacetate and fumarate link the citrate cycle to the urea cycle ▪ oxaloacetate can also be used for glucose synthesis and aspartate (aspartic acid) synthesis

Answer 101

Coenzyme A is only a carrier of acetyl, it does not degrade during metabolism and can occur freely - source of acetyl-CoA may be, for example, glycolysis occurring in the cytoplasm o 1 glucose -> 2 pyruvates that enter the mitochondria and pyruvate dehydrogenase create acetyl-coA from them (see above) - β-oxidation of fatty acids occurring in mitochondria o carries much more energy than glycolysis - amino acids - degradation of some AA produces pyruvate, others produce directly Krebs cycle intermediates o alanine -> pyruvate; aspartate -> oxaloacetate...

Answer 102

these are reactions that deplete the Krebs cycle intermediates - if ATP is not needed, the Krebs cycle intermediates will begin to convert to other useful compounds o citrate - exits from mitochondria into the cytoplasm where it cleaves to acetyl-CoA + oxaloacetate ▪ acetyl-CoA is used for the synthesis of fatty acids and steroids ▪ oxaloacetate returns to mitochondria or is transaminated to aspartate o α-ketoglutarate -> its transamination forms glutamate (also the formation of glutamine, histidine ...etc.) o succinyl-CoA -> serves for porphyrin synthesis (=cyclic organic compound consisting of 4 pyrrole nuclei) o malate, oxaloacetate -> either converted to AA (aspartate), or gluconeogenesis produces glucose

Answer 103

anaplerotic reactions are reactions that produce citrate cycle intermediates o typical example is the synthesis of oxaloacetate from pyruvate - pyruvate + CO2 + ATP -> oxaloacetate + ADP + Pi ▪ catalyzed by the enzyme pyruvate carboxylase with the participation of biotin cofactor o metabolism of amino acids ▪ aspartic acid (Asp), asparagine (Asn) -> oxaloacetate ▪ glutamic acid (Glu), glutamine (Gln), histidine (His), proline (Pro), arginine (Arg) -> α-ketoglutarate ▪ valine (Val), threonine (Thr), methionine (Met) -> succinyl-CoA ▪ phenylalanine (Phe), tyrosine (Tyr) -> fumarate + acetylCoA ▪ alanine (Ala), serine (Ser), cysteine (Cys), glycine (Gly) -> pyruvate o Fatty acids with an odd number of carbons -> after β-oxidation remains propionyl-CoA, which is converted to succinyl-CoA

Answer 104

is closely related to the respiratory chain, the consumption of ATP and the consumption of reduced cofactors - activation - low ATP/ADP or NADH/NAD - inhibition - high ATP/ADP or NADH/NAD - Krebs cycle regulatory enzymes = citrate synthase, isocitrate dehydrogenase and α-ketoglutarate dehydrogenase

Answer 105

the outer membrane of mitochondria has a lot of pores, which makes it quite permeable o inner membrane tightly regulates the transport of substances and is almost impermeable -> carriers are used for the transport of larger molecules - matrix is charged negatively (OH groups), intermembrane space charged positively (proteins) ▪ the membrane potential ranges from 180 to 200 mV o molecules that can cross the membrane ▪ free diffusion - O2, CO2 a H2O ▪ antiport - pyruvate and H2PO4 for OH-, ATP for ADP, Ca2+ for 2H+

Answer 106

specific mechanism by which substances that would not normally pass through the inner mitochondrial membrane are transferred

Answer 107

ensures the transfer of NADH from the cytoplasm to the mitochondria 1) in the cytoplasm NADH transfers hydrogen to oxaloacetate, resulting in malate formation 2) malate enters the matrix by antiport with α-ketoglutarate 3) malate passes hydrogen to NAD, oxaloacetate is formed again 4) transamination → oxaloacetate becomes aspartate and glutamate becomes α-ketoglutarate 5) aspartate enters the cytoplasm with the glutamate antiport 6) second transamination → aspartate becomes oxaloacetate and α- ketoglutarate becomes glutamate - result = in the cytosol less NADH and in the matrix more NADH

Answer 108

the way by which cytosol rapidly regenerates NADH to NAD in glycolysis 1) NADH in cytoplasm converts dihydroxyacetone phosphate to glycerol-3-phosphate 2) glycerol-3-phosphate transfers hydrogen to mGPD (mitochondrial glycerol-3-phosphate dehydrogenase) o mGPDH has FAD as a prosthetic group, which then reduces coenzyme Q in the respiratory chain - result = oxidized NAD in the cytoplasm and reduced coenzyme Q in the respiratory chain

Answer 109

Predominantly cells over extracellular matrix o high adhesivety of cells o polarization of cells o avascular tissue - tissue nourishes by diffusion from the connective tissue under the basement membrane o Strong nerve innervation o high regenerative ability due to stem cells in the basement membrane o originates from all 3 germ layers - ectodermal epidermis, endodermal glands, mesodermal endothelium

Answer 110

one of the most important functions of the epithelium is to create compartments in the body and prevent free diffusion o examples - intestine, kidneys, exocrine glands, brain capillaries (haematoencephalic barrier), plexus choroideus (barrier blood-liquor), thymus, testes

Answer 111

zonula occludens (tight junction) cells leave no space between themselves o serves for compartmentalization of surface plasmalema in resorptive epithelial cells o zonula adherens (adhesive connection) - strong and mechanically resistant band connection using cell actin fibres o macula adherens (desmosome) - strong and mechanically resistant point connection using intermediate filament cells

Answer 112

proteins claudins and occludins via adapter proteins connected to actin filaments of neighboring cells o prevents the paracellular passage of substances => all substances must travel transcellularly o permeability varies among different epitheliums o impermeable - collecting ducts of kidneys, urothelium, capillaries in the brain o almost permeable - small intestine, proximal tubulus of the kidney

Answer 113

mediates interaction between cell and matrix o anchors cells o attached to connective tissue via anchor fibrils o consists of proteins and proteoglycans o lamina basalis ensures attachment of cells to the basement ▪ lamina rara (lucida) - transmembrane proteins syndecan or integrins connect cell and rara ▪ lamina densa - it consists of collagen IV, laminin, perlecan o lamina fibroreticularis - contains microfibrils and anchor fibers (fibrillin and collagen VI and VII), which fixate the basal lamina to the fibres of collagen III (connective tissue) under the basement membrane o special basement membranes are made of two basement membranes (kidneys, lungs)

Answer 114

simple diffusion - O2, CO2, NO o passive transport (facilitated diffusion) - carriers, ion channels, aquaporins (for water) o active transport - pumps (ATPases), the most important is Na / K ATPase o for larger molecules - endocytosis (pinocytosis, phagocytosis), transcytosis (transport of substances from the apical membrane to the basal or vice versa) and exocytosis o aquaporins - transmembrane proteins with a hydrophilic tunnel that facilitate diffusion of water o example in collecting duct in kidney, large intestine

Answer 115

impermeable junctions - ileum and colon, water and ions must pass transcellularly (or controlled) o permeable junctions - duodenum and jejunum, there is an absorption of ions and nutrients o water passes paracellularly according to the concentration gradient

Answer 116

runs through pinocytic vesicles -> the cytoplasmic membrane invaginates and then gets excised o some proteins trigger invagination of the plasmalema and the protein dynamin closes the sac o clathrin-mediated endocytosis o Clathrin coat - adapter protein o the ingested molecule (LDL, transferrin) binds to the receptor o Clathrin-independent endocytosis o caveola vesicles - numerous on endothelial cells o protein caveolin envelops the membrane o functions - endocytosis of viruses, transcytosis, start of signalling cascades (eg insulin)

Answer 117

transfer of macromolecules across barriers - endothelium o transmission of antibodies across the placenta into the fetus - transplacental transmission, passively from the mother's body o transmission of IgA antibodies through mucous membranes

Answer 118

vascular lining - barrier between blood and tissues o simple squamous epithelium o it has different permeability - from very permeable in bone marrow to impermeable in brain o endothelial function o gas exchange (diffusion), transport of substances, synthesis of vasoactive substances (mainly NO), vascular growth control, regulation of immune responses (facilitate the transfer of white blood cells to the site of inflammation) and participation in haemostasis

Answer 119

transcellular - blood-brain barrier o paracellular - intestinal epithelium o types of capillaries o continuous - almost or completely impermeable o fenestrated - the endothelium has proteins that create holes and allow selective passage of substances o sinusoid there are large holes in both the endothelium and its basement membrane that allow free passage of virtually all substances in the blood

Answer 120

glycoprotein and glycolipid layer, which covers the plasma membrane of some epithelium and other cells o prevents blood clotting and white blood cells sticking o allows cells of the immune system to pass to the sites of inflammation

Answer 121

on one side is a fenestrated endothelium o on the other hand, there are cytoplasmic processes of podocytes o basement membranes of both are pivoted and pressed together - one thick basement membrane is formed, which forms most of the barrier o there is a lot of heparan sulphate in this membrane, which is negatively charged, which repels proteins (as they are also negatively charged) and helps keep them in the blood o the gaps between the protuberances of the podocytes are quite small and the vast majority of proteins have no chance of getting through o albumin is just below the permeability limit - if the kidneys do not work as they should, albumin will get through and can be detected in the urine - albumin thus acts as an excellent marker of kidney function

Answer 122

thin-walled barrier - two epithelial cells (alveoli epithelium + endothelium) attached to each other, connected by basement membranes o alveoli epithelium - single-layered flat epithelium (type I pneumocytes) o continuous capillaries

Answer 123

BBB (Blood-Brain Barrier) - a barrier between the blood and the internal brain environment o several layers o endothelium- continuous capillary o basement membrane ▪ there may be pericytes in the basement membrane - a special cell type only for this occasion, helping to maintain BBB functionality and brain homeostasis o astrocyte processes- supporting glial cells, play a role in BBB and neuronal sheath formation o only water, a few gases and fat-soluble molecules can pass through the BBB, everything else needs carriers o is due to well-formed zonulae occludentes and a small number of caveol

Answer 124

multiple layers - basal, intermediate and superficial o gradual cell differentiation - in the basal layer there are stem cells that proliferate and differentiate towards the surface o tight junctions are present between the cells of the upper third of the epithelium (when they are up, they are not needed below) o thick basement membrane o the basal layer is of cubic or cylindrical cells o there is a fibrous layer under the basement membrane - either lamina propria or (in the skin) dermis

Answer 125

- epidermis skin o stratum corneum - lucidum - granulosum - spinosum - basale o keratin is insoluble in water -> prevents water loss -> only lipophilic substances pass through the skin ▪ in the stratum granulosum highest keratinization takes place and there is also a large number of zonulae occludentes ▪ cytokeratin filaments and profilaggrin are involved in the production of keratin

Answer 126

oral cavity, oesophagus, vagina, cornea, conjunctiva, larynx o stratum basale - parabasale - intermedium - superficiale o high glycogen content in superficial cells bacteria metabolize glucose anaerobically to lactate and ensure low pH

Answer 127

protects against damage from UV radiation by melanin synthesis o The melanocytes are present in the epidermis of the pars basalis o melanin-containing granules are passed to cells in the stratum spinosum in which the granules disintegrate, and the melanin is released into the cytoplasm o melanosomes (organelles) - from GER and GA - start of melanin formation o synthesis - dopa (enzyme tyrosinase) is synthesized from tyrosine, which polymerizes to melanin

Answer 128

location - urinary tract o lots of tight junctions o surface cells (umbrelocytes) are the largest cells in the urothelium, they have differently bent membrane o the rest of the epithelium - low cubic cells o Special protein in tight junctions - uroplakin - even increases their effectiveness o The surface of the cells (umbrelocytes) becomes more stained due to the presence of cytokeratin filaments o uroplakin - in the membrane o takes part in sealing as well

Answer 129

glucose - energy production (glycolysis) o energy supply - glycogenogenesis / fatty acid synthesis o conversion to other monosaccharides - pentose cycle (to ribose) o conversion to glucuronic acid by oxidation o fructose - conversion to glucose o galactose - conversion to glucose / lactose o synthesis of glycoproteins and proteoglycans

Answer 130

it is glucose with oxidized 6. carbon - was first isolated in urine, hence its name from Urine - biosynthesis proceeds by activation of glucose to UDP-glucose, followed by oxidation by enzyme UDP-glucose dehydrogenase to UDP-glucuronic acid - attaches to foreign hydrophobic substances in the liver to increase their solubility and to get out of the body via urine - it further forms glycosaminoglycans, proteoglycans and proteoglycan aggregates

Answer 131

These are long chains formed by alternating two molecules - uronic acid and hexosamine uronic acids are acids containing both aldehyde and carboxylic acid (glucuronic) hexosamines are hexoses with one OH group replaced by an amino group o hyaluronic acid, chondroin sulphate, keratan sulphate, heparan sulphate, dermatan sulphate

Answer 132

proteins (core proteins) to which all GAGs are perpendicularly bound (protein 5%, sugars 95%) o fill the extracellular space and determine some properties - resistance to pressure, return of tissue to its original shape, joint lubrication, articular cartilage hydration, water retention, bone component

Answer 133

hyaluronic acid to which proteoglycans are bound perpendicularly through binding proteins

Answer 134

alternative oxidative cleavage of glucose in the cell by NADP o no ATP, NADH or FADH2 is produced o the product of the pentose cycle is CO2, ribose-5-phosphate and 2 NADPH - the pentose cycle is the main source of NADPH o the pentose cycle can be divided into 2 phases - oxidation (irreversible) and monosaccharide mutual conversion (reversible) o cycle is regulated via NADPH - high NADPH / NADP ratio inhibits pentose cycle (NADPH is enough = no need to produce another) o enzymes for the pentose cycle are also present in erythrocytes, because NAPDH is used in defence against oxygen radicals, which are much in erythrocyte - hexokinase (Fru -> Fru-6-P) and fructokinase (Fru -> Fru-1-P)

Answer 135

at this stage, Glc-6-P is converted to ribulose-5-phosphate (Ru-5-P) and CO2 to form 2 NADPH o dehydrogenation - Glc-6-P -> 6-phosphogluconolactate, the enzyme glc-6-P dehydrogenase, results in NADPH o hydrolysis 6-phosphogluconolactate + water -> 6-phosphogluconate, enzyme 6-phosphogluconolactonase o decarboxylation - 6-fosfoglukonát 6-phosphogluconate -> Ru-5-P + CO2, enzyme 6-phosphogluconate dehydrogenase, NADHP is formed

Answer 136

source of fructose in food - sucrose (disaccharide, glucose-fructose) from fruit o fructose is activated by fructokinase (on Fru-1-P) or hexokinase (on Fru-6-P) o Defective fructokinase disease is essential fructosuria and is essentially asymptomatic o there is an aldolase B in the liver that can cleave Fru-1-P into glyceraldehyde (which is immediately phosphorylated to glyceraldehyde-3-P) and DHAP, thereby forming glycolysis intermediates while skipping the major limiting factor of glycolysis (a reaction catalyzed by phosphofructokinase 1) - fructose is thus metabolised much faster in the liver than glucose o defective aldolase B disease is hereditary fructose intolerance and is very dangerous o fructose does not increase insulin production, its entry into cells is independent of insulin (using GLUT 2 and 5 transporters)

Answer 137

a sugar alcohol produced by reducing the carbonyl group of fructose or glucose o artificial sweetener E420 o glucose is naturally metabolized by the enzyme aldose reductase to sorbitol (NADPH is needed) o important mainly in the liver, retina, lens, peripheral nerves and kidneys - sorbitol helps to maintain water o there is a problem in patients with hyperglycaemia - changing osmolarity causes cataracts, peripheral neuropathy, renal and retinal damage and vascular problems o sorbitol is further oxidized to fructose by the enzyme sorbitol dehydrogenase (NAD needed) o important in liver and sperm (sperms get energy from fructose)

Answer 138

dietary source - lactose (disaccharide, galactose-glucose) o non-insulin-dependent entry into cells o it is mainly metabolised to glucose in the liver o phosphorylation- galactose + ATP -> Gal-1-P + ADP, enzyme galactokinase o transfer UDP - Gal-1-P + UDP-Glc -> UDP-Gal + Glc-1-P, enzym uridyltransferáza o isomerization- UDP-Gal -> UDP-Glc, enzyme epimerase o galactokinase or uridyltransferase defect = galactosemia o use - glycoproteins, glycolipids, GAG, breast milk lactose

Answer 139

Central position in carbohydrate metabolism – all carbohydrates can be converted to glucose and vice versa - Energy can be obtained from it even in the absence of O2 - All of our cells are able to use it and some tissues are even strictly dependent on it o erythrocytes – because they do not have mitochondria they therefore do not use Krebs cycle or the respiratory chain o cells of CNS - however, during long-term starvation they adapt and 50% of their consumption is covered by ketone bodies

Answer 140

normal fasting value is 3,3-5,6 mmol/l o while after a meal it can be up to 7,1 mmol/l even in a healthy person - regulation of blood glucose o insulin – lowers glycaemia- glucose from blood enters cells ▪ cells use up glucose through glycolysis, pentose formation or glycogen storage o glucagon, adrenalin, growth hormone, cortisol – increase glycaemia – glucose goes from liver to blood ▪ in hepatocytes, glucose is formed de novo by gluconeogenesis or by degradation of glycogen storage - sources of glucose - exogenous (food), glycogen breakdown and gluconeogenesis (production of glucose from other metabolites)

Answer 141

two different mechanisms o secondary active transport using SGLT-1,2 (sodium-glucose transporter) ▪ glucose enters the cell by symport with sodium ▪ secondary active because the cell must expend energy to get rid of the sodium that came with glucose ▪ glucose is absorbed in the intestines and the proximal kidney tubule in this way o facilitated diffusion through GLUT 1-7 transporters ▪ used in the transfer of glucose between blood and cells

Answer 142

GLUT are channels in the cytoplasmic membrane that can open and allow glucose to pass freely across the membrane ▪ GLUT 1 - erythrocytes, blood-brain barrier ▪ GLUT 2 - liver, kidney, pancreatic β-cells, enterocytes ▪ GLUT 3 - brain ▪ GLUT 4 - adipose tissue, skeletal muscle, heart ● Insulin in the blood increases the amount of GLUT 4 transporters

Answer 143

as soon as glucose enters the cell, it is activated by enzymes and ATP through the phosphorylation from Glc to Glc-6-P - irreversible reaction - Activation of glucose is the first step in its metabolism, while ensuring that glucose does not flush out of the cell (phosphate cannot cross the membrane) - two isoenzymes phosphorylate glucose o glucokinase - in hepatocytes and pancreatic β-cells ▪ active at higher glycaemia (KM = 10 mM) ▪ β- cells respond to higher blood glucose levels via insulin secretion o hexokinase - everywhere except hepatocytes and pancreatic β-cells ▪ active at much lower concentrations than glucokinase (KM = 0.1 mM) ▪ is inhibited by its product (Glc-6-P)

Answer 144

converts Glc-6-P back to glucose by cleavage of inorganic phosphate - is present only in the liver, kidneys and enterocytes - is in smooth ER - Glc-6-P gets here via translocase o is in this cell compartment so that newly formed glucose does not immediately phosphorylate in the cytosol

Answer 145

catabolic reaction - conversion of glucose to 2 molecules of pyruvate (or lactate if we do not have enough oxygen) - occurs in the cytoplasm of all cells with inorganic phosphate - has two functions o energy production under anaerobic conditions - during glycolysis in addition to pyruvate, ATP is produced directly o source of acetylCoA - it can be used for everything possible

Answer 146

First phase - glucose will be converted to fructose-1,6-bisphosphate (Fru-1,6-PP) with the investment of two ATPs o 1. step – glucose activation - glucokinase or hexokinase enzyme, 1 ATP is consumed 2. step - isomerization - enzyme isomerase converts Glc-6-P to Fru-6-P 3. step - phosphorylation - 6-phosphofructo-1-kinase enzyme phosphorylates Fru-6-P to Fru-1,6-PP using 1 ATP

Answer 147

Fru-6-P breaks down into two identical three-carbon monosaccharides 4. step - cleavage - the enzyme aldolase A divides Fru-1,6-PP into glyceraldehyde-3-phosphate (Gra-3-P) and dihydroxyacetone phosphate (DHAP) DHAP is produced much more than Gra-3-P 5. step - isomerization - Triose phosphate isomerase enzyme converts DHAP to Gra-3-P

Answer 148

Gra-3-P is converted to pyruvate, from which the cell obtains 4 ATP and 1 NADH ▪ since we now have two Gra-3-P molecules, the following reactions will run twice each 6. step - phosphorylation - enzyme glyceraldehyde phosphate dehydrogenase phosphorylates Gra-3-P to 1,3-bisphosphoglycerate (1,3-PP-Gly), inorganic phosphate (Pi) enters the reaction and NAD is reduced to NADH 7. step - dephosphorylation - phosphoglycerate kinase enzyme cleaves one phosphate from 1,3-PP-Gly to form 3-phosphoglycerate (3-P-Gly) and one ATP 8. step - isomerization - phosphoglyceromutase enzyme converts 3-P-Gly to 2-P-Gly 9. step - dehydration - enzyme enolase from 2-P-Gly cleaves water, phosphoenolpyruvate (PEP) is formed 10. step - dephosphorylation - the pyruvate kinase enzyme cleaves the remaining phosphate, producing pyruvate and one ATP - total 1 NADH and 2 ATP are extracted from glycolysis - two ATPs were invested in the first stage and two ATPs were obtained from each glyceraldehyde-3-phosphate in the third stage = -2 + 2 * 2 = +2

Answer 149

branch point of glycolysis - fate of pyruvate depends on oxidative and redox state of the cell (sufficient O2 and NAD) o aerobic conditions - pyruvate enters the MIT matrix, where it is converted to acetylCoA o anaerobic conditions- pyruvate is converted to lactate (via enzyme lactate dehydrogenase) and released into the blood ▪ this happens because under aerobic conditions NADH is reduced in mitochondria, becomes NAD and can again help with glycolysis ▪ under anaerobic conditions, however, NADH accumulates until finally there is no NAD and glycolysis stops ▪ when pyruvate is converted to lactate, NADH is converted to NAD and can immediately return to glycolysis ● Pyruvate + NADH + H+ <-> Lactate + NAD+ ▪ there are no mitochondria in erythrocytes and so anaerobic glycolysis takes place there even under aerobic conditions

Answer 150

the regulatory points are 3 enzymes o glucokinase/hexokinase – activates glucose to Glc-6-P through using ATP o 6-fosfofrukto-1-kináza (PFK-1) - phosphorylatesFru-6-P to Fru-1,6-PP through using ATP ▪ the main regulatory enzyme ▪ allosteric enzyme - the activator is Fru-2,6-PP (this molecule is produced by insulin) ▪ is inhibited ● if the cell has enough energy = high concentration of ATP or citrate in the cytoplasm, acidic pH ● in the presence of counter-regulatory hormones o pyruvate kinase - dephosphorylates PEP to form pyruvate and ATP

Answer 151

apart of the regulatory points, gluconeogenesis is the same as glycolysis, but reverse o glycolysis regulatory points are irreversible - gluconeogenesis bypasses them (bypass 1, 2 and 3) - gluconeogenesis precursors - pyruvate, lactate, glycerol, oxaloacetate, propionate and glucogenic AMK (Ala, Gln...) - takes place in the kidneys, liver and a little in enterocytes - begins in mitochondria and then moves to the cytoplasm - energetically consuming o 2 Pyruvates + 4 ATP + 2 GTP + 2 NADH + 2 H+ + 4 H2O → glucose + 4 ADP + 2 GDP + 6 Pi + 2 NAD

Answer 152

bypasses pyruvate kinase catalysed reaction (10th step of glycolysis) - transport of pyruvate to mitochondria -> carboxylation of pyruvate (enzyme pyruvate carboxylase, cofactor biotin, consumption of one ATP) -> formation of oxaloacetate (OAA) -> transfer of OAA to cytosol -> conversion of OAA to PEP by PEP carboxykinase (consumption of GTP)

Answer 153

bypasses PFK-1 catalysed reaction (3rd step of glycolysis) - the enzyme fructose-1,6-bisphosphatase is used - simply phosphate cleavage, no ATP formed, only inorganic phosphates

Answer 154

bypasses the reaction catalysed by hexokinase (1st step of glycolysis) - enzyme Glc-6-phosphatase (not found in skeletal muscle) - Pi just breaks off again

Answer 155

Cori cycle o Method by which erythrocytes and muscles get rid of lactate - they send it to the liver to turn it back into glucose - alanine cycle o the way energy is supplied to the muscles while also removing toxic ammonia o Ammonia is linked to pyruvate by transamination, resulting in alanine that travels to the liver, where ammonia is detached and processed into urea o pyruvate is converted to glucose by gluconeogenesis and sent back to the blood - amino acids o all AA except Leu and Lys are able to degrade directly to pyruvate or Krebs cycle intermediates - glycerol o glycerol phosphorylation to glycerol-3-P - enzyme glycerol kinase o dehydrogenation of glycerol-3-P to DHAP - enzyme glycerol phosphate dehydrogenase

Answer 156

active in glucose deficiency (starvation) and in pathological conditions (sepsis, polytrauma, burns, tumors ...) - gluconeogenesis is activated by stress hormones (counter-hormone hormones), inhibited by insulin - major regulatory enzymes o pyruvate carboxylase - activated by AcetylCoA o PEP carboxykinase, Fru-1,6- bisphosphatase and Glc-6- phosphatase- regulated in the same way as glycolysis, except vice versa

Answer 157

o Lipids with energetic importance are called triacylglycerol = TAG - store much more chemical energy than sugars and proteins - fats are hydrophobic, i.e. they do not bind water and are not diluted by it (1g TAG is 100% fat, 1g glycogen is glucose + water is bound to it) o 1g TAG has 6 times more energy than 1g glycogen o supplies of glycogen and glucose are sufficient for one day, TAG for weeks - the total weight of TAG in a healthy person is around 15% of the body weight o the main site of TAG accumulation is the cytoplasm of adipocytes (fat cells)

Answer 158

hormone-sensitive lipase (HSL) releases fatty acids from stores o HSL performs complete lipolysis - 1 TAG -> 1 glycerol + 3 FA o is inhibited by insulin and activated by counter-regulatory hormones (glucagon, adrenaline, noradrenaline) - lipid utilization takes place in three steps o lipid mobilization - hydrolysis of TAG to FA and glycerol and their transport by blood o activation of FA in cytosol and their transport to MIT matrix o β-oxidation - degradation of FA to acetyl-CoA, which enters the Krebs cycle at the same time, reduced cofactors are produced, which are used directly in the respiratory chain

Answer 159

TAG is broken down into glycerol and FA and released from the cell into the blood o FA longer than 12C need to have a carrier in plasma (because they are hydrophobic) - they bind to albumin o glycerol is used in the liver (glycolysis / gluconeogenesis /...) - conversion of glycerol to glycolysis intermediates o Glycerol is the only component of TAG that can be converted to glucose through gluconeogenesis first phosphorylation on glycerol-3-P using ATP (enzyme glycerol kinase) then oxidation of glycerol-3-P to dihydroxyacetone phosphate using NAD + (enzyme glycerol-3-P dehydrogenase) - entrance of FA into cells o Short chain FA (<12C, do not need albumin) - they penetrate the membrane by simple diffusion o Longer-chain FA’s use different transport systems in the membrane - this is facilitated diffusion FATP - fatty acid transport protein FAT/CD36 - fatty acid translocase

Answer 160

involvement of FA in metabolism - in cytosol FA is activated by CoA to acylCoA (enzyme acyl-CoA synthetase) o FA + ATP + CoA -> acylCoA + AMP + 2Pi o the resulting bond is between the acid and the sulphur atom CoA = thioester bond

Answer 161

β-oxidation occurs in the matrix of mitochondria and is the most common fate of activated FA (the so-called majority pathway) - ER membranes contain enzymes that catalyse ω- (omega) and α- (alpha) oxidation o These oxidation pathways are called minority pathways, as they normally only consume about 5% of FA, but in pathological situations their importance massively increases o The Greek letters designate the carbon atom on which the reaction takes place o take place in HER hepatocytes and tubular kidney cells on FA with 10-12C - dicarboxylic acids are formed - short and medium FAs (below 12C) enter the mitochondria by simple diffusion - the long chain (12-18C) must be activated and transferred using the carnitine chain - very long (20C or more) enter the peroxisome where they are shortened

Answer 162

acyl-CoA passes through the outer membrane easily, inner membrane causes a little bit more trouble – carnitine and its translocases come into play here 1) FA leaves CoA and attaches to carnitine 2) carnitinacyltransferase I (CAT I) – on cytosolic side ofmitochondrial membrane o transfers acyl from CoA to carnitine, resulting in acylcarnitine 3) acylcarnitine translocase - in the inner mitochondrial membrane o Acylcarnitine is exchanged, via antiport, for carnitine 4) Carnitinacyltransferase II (CAT II) - in matrix mitochondria o transfers acyl from acylcarnitine back to CoA, produces acylCoA - free carnitine leaves matrix, via antiport, for acylcarnitine

Answer 163

a cyclical process, repeating itself - at each turn, the carbon chain is shortened by two carbons, which they release as acetyl-CoA - one cycle has four steps o dehydrogenation- acyl-CoA dehydrogenase enzyme o hydration- enoyl-CoA hydratase enzyme o dehydrogenation L-3-hydroxyacyl-CoA dehydrogenase enzyme o thiolysis- β-ketothiolase enzyme resulting reduced cofactors (NADH, FADH2) are used directly in the respiratory chain

Answer 164

works at the level of CAT I when FA enters MIT - is inhibited by malonyl-CoA (intermediate of FA synthesis) o so called cross regulation- an intermediate of one metabolic pathway inhibits another metabolic pathway o the principle of this regulation - in the synthesis of FA arises as an intermediate malonyl-CoA, which inhibits ß- oxidation = it prevents the opposite processes in one cell (degradation x synthesis)

Answer 165

FA are a rich source of energy for gluconeogenesis, but we do not get glucose from them (except for FAs with odd number of C) - AcetylCoA cannot be converted to pyruvate or oxalacetate - pyruvate dehydrogenase reaction is irreversible and both carbons from AcetylCoA are cleaved off as CO2 during the Krebs cycle - lants have another 2 enzymes in glyoxylate cycle - they can convert AcetylCoA to oxaloacetate

Answer 166

their β-oxidation is the same as in FA with even number of C, only two acetylCoA dont remain at the end, but one acetylCoA and one propionylCoA o PropionylCoA is converted to succinylCoA, which is involved in the Krebs cycle succinyl CoA can be converted to oxaloacetate from which gluconeogenesis can synthesize glucose - FA with an odd number of C is very little in the body

Answer 167

most unsaturated FA have a cis double bond configuration - enoyl-CoA-hydratase requires only trans isomers -> it is necessary to convert cis isomer to trans by isomerase - For the oxidation of unsaturated FAs, two additional enzymes are needed - isomerase and reductase

Answer 168

takes place on peroxisomes (contain catalase) o here is only a shortening -> then moving to mitochondria - the pathway is induced by a high fat diet and hypolipiemic drugs – clofibrate - oxidation ends with octanoyl-CoA, which is removed from peroxisomes by binding to carnitine - the first stage is catalyzed by flavoprotein dehydrogenase - electron transfer to O2 -> H2O2 o is not attached to the respiratory chain -> FADH2 from the first step of β-oxidation is not reoxidised in the respiratory chain, but in a reaction with O2 FADH2 + O2 -> FAD + H2O2 o peroxisomal catalase decomposes H2O2 2 H2O2 -> 2 H2O + O2 - reactions do not lead to the formation of ATP

Answer 169

there are 3 ketone compounds - acetoacetate, ß-hydroxybutyrate and acetone o the first are the most essential, acetone is a more of a waste product and is useless - can be completely degraded to CO2 and water - derived from AcetylCoA - ketones are essentially a blood-transportable version of acetyl - formed only in liver mitochondria

Answer 170

they replace glucose as the main energy substrate during starvation - glucose runs out, so the liver begins to produce ketone bodies and distributes them across the body to other tissues - ketones can nourish all organs except liver (no enzyme) and erythrocytes (no mitochondria) - AcetylCoA entry into KC depends on the availability of oxaloacetate - during fasting oxaloacetate is consumed for glucose synthesis o carbohydrate deficiency -> oxaloacetate deficiency -> KC slows down -> high AcetylCoA -> ketogenesis o carbohydrate deficiency -> low glycemia -> activated HSL -> TAG breakdown -> high FA -> β-oxidation -> high AcetylCoA -> ketogenesis

Answer 171

- condensation- enzyme ketothiolase - condensation- enzyme 3-hydroxy-3metylglutaryl-CoA synthase (HMG-CoA synthase) - breakdown - enzymeHMG-CoA lyase o HMG-CoA -> acetoacetate + AcetylCoA o produces acetoacetate, which is the first ketone in massive ketone formation β-hydroxybutyrate is quantitatively the most important ketone in the blood o diabetic ketoacidosis - a condition typical of type 1 diabetes mellitus

Answer 172

the liver produces them but does not use them – does not have CoA-transferase o It would be unnecessary to synthesize ketone bodies if they were to be degraded immediately - Once formed in the MIT matrix, ketone bodies enter the plasma - one of the Krebs cycle intermediates - succinyl-CoA - is used to activate ketone bodies - acetoacetate is activated by transfer of CoA from succinylCoA (using CoA-transferase) - succinate and acetoacetyl-CoA are formed - Acetoacetyl-CoA is then cleaved by β-ketothiolase to 2 acetyl-CoA - β-hydroxybutyrate will first give its two extra hydrogens to the nearest NAD, thereby forming NADH and acetoacetate

Answer 173

cardiac muscle and kidney cortex prefer acetoacetate over glucose - eventually the brain adapts to acetoacetate during starvation (up to 50% of energy can be taken from ketone bodies) - it also has a regulatory role - high levels of acetoacetate in the blood means the presence of a large amount of acetyl-CoA, which is a signal to reduce lipolysis (this means that the body has enough energy at that time)

Answer 174

There is storage for fat (TAG) and saccharides (glycogen) but none for proteins (muscle breakdown is the last resort) - TAG - convenient storage (because unlike glycogen it does not bind water)

Answer 175

carbohydrate storage in animals, in the cytosol (explains its violet colour), in almost all cells - in the liver (80-100g), skeletal muscle (300g) and in small quantities in each cell - women have more glycogen - vaginal mucosa o Liver glycogen - used to maintain stable blood glucose o Muscle glycogen – used during short-term strenuous muscle work o vaginal mucosa - glycogen -> lactate -> H + production -> acidic environment -> defence against microorganisms - PAS reactions in histological preparations brightly colours glycogen violet

Answer 176

branched homopolymer - Most glucose bound by α-1,4-O-glycosidic bonds - branching from the strain of glycogen is by α-1,6 bond - two groups of enzymes - one cleaves α-1,4 bonds, the other α-1,6 bonds - glycogen has 2 ends - elongation and shortening takes place at non-reducing ends containing terminal glucose (enzymes work with this end) - branching glycogen will provide more non-reducing ends - reducing end has a semi-acetyl hydroxyl – it is bound by the protein glycogenin, which forms the anchor at the beginning of the glycogen strain

Answer 177

all glycogen metabolism occurs in the cytosol - 1) phosphorylation- enzyme glucokinase in liver and hexokinase in muscle o glucose + ATP -> Glc-6-P + ADP - 2) isomerization- enzyme glucose phosphate isomerase o Glc-6-P -> Glc-1-P (= Cori ester) - 3 coupling of UDP - enzyme UDP-glucose pyrophosphorylase o Glc-1-P + UTP -> UDP-Glc -> formation of a macroergic compound - 4 connection of UDP-Glc to non-reducing end of glycogen- enzyme glycogen synthase o UDP is released and α-1,4 bond is formed - the chain of linked glucose grows until it reaches a certain length and branches - branching enzyme - branching enzyme - amylo-(1,4-1,6)-translocase o catalyzes glycogen branching - it forms α-1,6 bonds o new branches extended again by glycogen synthase

Answer 178

MAIN ENZYME: glycogen synthase regulation of glycogen synthase - phosphorylation (phosphorylated is inactive, dephosphorylated is active) o activated by insulin (trying to lower free glucose levels in blood), inhibited by glucagon (trying to get more free glucose into bloodi) and adrenaline - phosphorylation of glycogen synthase is done by proteinkinase and dephosphorylation by phosphoprotein phosphatase

Answer 179

- degradation of the glycogen molecule - again, in cytosol - 1. phosphorolytic cleavage - cleavage of α-1,4 bond and formation of Glc-1-P (= Cori ester) o Free inorganic P is used - linked to C1 glucose o enzyme glycogen phosphorylase- cleaves α-1,4 bond – attaches phosphate to it o ends 4 glucose molecules before branching - 2. isomerization Glc-1-P to Glc-6-P – enzyme phosphoglucomutase (glucose phosphate isomerase) - 3. Cleavage of branch – removal of α-1,6 bond

Answer 180

glycogen phosphorylase is active when phosphorylated - it is phosphorylated by phosphorylase kinase - insulin inhibits phosphorylase kinase (insulin does not want to have more free glucose in the blood wants to prevent glycogen breakdown) and counter-regulatory hormones activate it - again, signalling via PKA and CAMK

Answer 181

initial substance for the synthesis of FA is acetyl-CoA - carboxylation to malonyl-CoA o acetyl-CoA + ATP + HCO3 -> malonyl-CoA + ADP + Pi + H+ - enzyme acetyl-CoA carboxylase, biotin cofactor (or vitamin H / vitamin B7) o regulatory enzyme of the whole pathway - also affects β-oxidation of FA - CO2 removed during condensation with increasing FA

Answer 182

8 acetyl-CoA, 14 NADPH and 7 ATP - acetyl-CoA is transported from the mitochondria matrix using citrate - 8 NADPH is obtained by transporting citrate to the cytoplasm and the remaining 6 in the pentose cycle

Answer 183

sufficient substrates (carbohydrates / AMK) and energy are needed o the main regulatory enzyme acetyl-CoA- carboxylase (active in dephosphorylated form) o activated by – insulin and citrate – insulin and citrate - insulin activates glycolysis -> Acetyl-CoA, which is formed from pyruvate after glycolysis, is required for FA synthesis o inhibited by - glucagon, adrenalin, palmitoyl-CoA (if there is enough palmitoyl-CoA, there is no need to synthesize others) and AMP (in the absence of energy)

Answer 184

elongation, enzymes elongase, if we need over 16C long FA - formation of unsaturated FA is desaturation, enzymes desaturase - both occur on the SER membrane on the side facing the cytosol

Answer 185

final form of FA storage - starting with DHAP (dihydroxyacetone phosphate, intermediate of glycolysis) o reduction- enzyme DHAP dehydrogenase o addition of the first two FAs - enzyme acyltransferase glycerol-3-P + acylCoA -> monoacylglycerol-3-P + CoA monoacylglycerol-3-P + acylCoA -> phosphate acid = diacylglycerol phosphate o hydrolytic separation of phosphate from phosphate acid - enzyme phosphatidic acid phosphatase phosphatidic acid + H2O -> 1,2-diacylglycerol + Pi o connection of the last FA – again the enzyme acyltransferase 1,2-diacylglycerol + acylCoA -> TAG + CoA

Answer 186

tissue characterized by excitability, contraction and relaxation - due to myofilaments (actin and myosin II) - Mechanocytes - cells capable of movement, have a high amount of actin and myosin - types of muscles - smooth, striated skeletal and striated heart

Answer 187

sarcolema - cytoplasmic membrane of muscle cells o sarcoplasma - cytoplasm of muscle cells o sarcomer - interval between two Z lines in muscle o sarcoma - a tumour derived from muscle cells

Answer 188

myocyte - muscle cell o myofilaments - actin and myosin o myofibril - a thin fibre inside muscle cells; it is a sarcomere chain attached at both ends to the sarcolemma o myotoma - a block of embryonic cells from which muscles develop o myocardium - muscle of the heart

Answer 189

skeletal and cardiac muscle - five strips - A, I, M, H a Z o A band indicates the presence of myosin o I band indicates the absence of myosin, the presence of actin o M band indicates the centre of myosin fibers o H band indicates gaps between actin fibers o Z band indicates anchoring of actin fibers - H and I strips shorten during contraction - the sarcomere is the section between two Z strips

Answer 190

skeletal and cardiac muscle has large reserves of Ca2+ and is, therefore, less dependent on plasma calcium o Ca2+ is released from the sarcoplasmic reticulum (that is a form of modified SER) into the cytoplasm where it binds to troponin C and activates myosin phosphatase - triggers myosin dephosphorylation (one of the contraction steps)

Answer 191

Ca2+ binds to the calmodulin, which then activates myosin light chain phosphorylating kinase o Phosphorylation of light chain is required in smooth muscle for its binding to actin in the dephosphorylated state, myosin is rolled up

Answer 192

contraction is not controllable by will - it is ensured by autonomous nerve - consists of thin, spindle-like cells o nucleus is centrally placed, long and narrow o are full of actin, myosin, and intermediate filaments (desmin and vimentin) o dense bodies (desmin) similar to Z lines; they are thickened sites where the filaments connect to each other or to the plasma membrane - smooth muscle cells have cellular connections via hemidesmosomes and nex o they transfer substances by pinocytic invagination - occurrence - walls of hollow organs (thickness is about 150-200μm), blood vessels (15-20μm), skin, prostate eye - smooth muscle contraction is induced by the mediator being spilled into the environment, transmitted through the nexes, automatically or stretched

Answer 193

the basic building unit is a cylindrical cell - cardiomyocyte (85-100μm) o lengthened cells, nucleus in the middle of the cell, a lot of mitochondria, a large supply of glycogen and lipids o contain a lot of myoglobin - similar to haemoglobin but have only one binding site; is only in muscle cells o diads - at the Z line level; it is formed by T-tubule (invagination of sarcolemma) and cistern of sarcoplasmic ER

Answer 194

cardiomyocyte junction which contains several intercellular junctions o fascie adherens - anchoring actin filaments o desmosomes - anchorage of intermediate filaments o nexes - they ensure the transfer of information between cells and serve to coordinate contraction

Answer 195

an independent system that maintains the regularity and autonomy of heartbeat o conduction system: sinoatrial (SA) node, internodal atrial connections, atrioventricular (AV) node, His bundle, Tawar arms, Purkinje fibres

Answer 196

Purkinje fibres - contain much less myofibrils and mitochondria, lack of intercalated discs, have only nexes and local adhesive bonds; they contain a lot of glycogen - cardiomyocytes have a very low ability to regenerate - in the case of cell death, a ligament is formed which is not capable of conducting electrical excitement and cannot even contract o this ligament can rupture under high pressure and blood starts to escape from the heart to the pericardium cavity, where it accumulates and prevents heartbeat, which very quickly leads to death

Answer 197

the basic unit of skeletal muscle is the fiber-multinucleated syncytium – (fusion of a large number of cells in one) with a diameter of 60-100μm - the skeletal fiber nuclei are oval and are located just below the sarcolemma - muscle development - mesenchymal cells develop into myoblasts (which migrate and divide), which gradually begin to connect to myotubules and to the final muscle fibers skeletal muscles are covered by fascia (a string) on the surface, which is a cover of dense collagen ligament

Answer 198

Satellites cells (belong to stem cells) serve for muscle growth and repair - they are able to divide and fuse to prolong or repair an already existing muscle fiber o their abilities are not unlimited, in case of too much damage the muscle dies and is replaced by connective tissue - the sarcolemma in the skeletal muscle clings in and forms tubulous invaginations - so-called T-tubules

Answer 199

sarcoplasmic reticulum (SER) - highly developed, modified ER full calcium forming a network around each myofibril o together with invaginations of sarcolemma form so-called triads (SER-T tubules) at the A and I strip level

Answer 200

White fibre - larger; more actin, myosin and glycogen; fewer mitochondria, lipids and myoglobin predominantly anaerobic metabolism - rapid contraction of muscles, but quickly tired suitable for sprints o red fibre smaller; multiple mitochondria, lipids and myoglobin; less actin, myosin and glycogen mainly aerobic metabolism - slow muscle contraction, but lasts for a very long time suitable for marathons

Answer 201

collagen connective tissue that clamps the muscle into the bone

Answer 202

endomysium - envelops one muscle fiber o perimysium - envelops several bundles of fibers o epimysium - envelops the entire muscle

Answer 203

protein dystrophin - inside stabilizes plasma membrane and connects it with actin (in Z bands) o There may be many mutations in the dystrophin gene - mutations that damage the function of dystrophin (or its auxiliary proteins) give rise to various diseases collectively called muscular dystrophy o Duchenne muscular dystrophy - X-linked genetic disease where part of the dystrophin gene is deleted Gradually laterally striated muscle breaks up, which eventually leads to death around the age of 20 due to respiratory failure

Answer 204

Cellular movements are usually based on the interaction of motor proteins (molecular motors) with cytoskeletal structures – proteins move along cytoskeletal structures while using up ATP

Answer 205

Kinesins: interact with microtubules Dyneins: interact with microtubules Myosins: interact with microfilaments

Answer 206

structure - 2 globular ATP binding heads (which interact with microtubules), stalk and tail (made of light chains which bind cargo) o movement uses up ATP - function - transport of material into + end of microtubules (from centre to periphery) - occurrence – mitotic spindle

Answer 207

structure - 2 globular ATP binding heads (which interact with microtubules) and stalk (which binds cargo) o head formed from 7 domains - movement of dynein is quite chaotic and can be described as the walk of a drunk sailor – movement forward follows is accompanied with wobbling from side to side - function - transport of material to – end of microtubule (from periphery to centre) - occurrence – mitotic spindle, flagella, cilia

Answer 208

structure - globular ATP binding head (which interacts with actin microfilaments) and tail (which may bind cargo or bind to other myosins and form myosin filaments) - types of myosin o myosin-I – found in nearly all types of cells, monomer (1 head + 1 tail) transport of vesicles inside the cell o myosin-II – in muscles, dimers (2 heads + 1 tail in helix) movement of the whole cell – contractile ring, muscle movement - function of myosin – movement to + end of actin microfilaments o transport of vesicle, movement of plasmatic membranes and muscle movement

Answer 209

3 types of microtubules o kinetochore which reach from centrosomes to kinetochores ( kinetochores are sites on centrosomes where microtubules anchor) o polar – bind with polar microtubules of opposing centrosome and push centrosomes apart o astral – reach out into all sides from centrosome, bind to surrounding structures and anchor the centrosome

Answer 210

flagella – allows for cellular movement - cilia – allows for cell to manipulate/move its surrounding - flagella and cilia appear the same on the inside - 9 doublets of microtubules with a central pair of microtubules o anchored by - end in basal body - both structures move via the help of dynein – microtubule pairs are connected by dynein, which is anchored to one microtubule and “walks” towards the other o when microtubules are not tightly connected – one microtubule moves o when microtubules and tightly connected – both microtubules bend towards the same direction

Answer 211

transport of organelles (along microtubules) is mediated by kinesin and dynein - transport of vesicles (along actin microfilaments) is mediated by myosin I

Answer 212

D – contractile ring - during cytokinesis at the equatorial line “strangle” the cell - B - contractile bundles - „muscle “of cells, attached to the plasmatic membrane, can change shape of cell - Myosin II helps with contraction

Answer 213

Used for example by macrophages - Lamellipodia, filopodia, pseudopodia – projections of plasmatic membrane filled with actin filaments - growth of actin filaments and myosin II Æ growth of actin filament Æ elongation of membrane Æ attachment of growth/projection to the surface through focal adhesions Æ butt contraction (using myosin II) - for amoeboid movement, you always need a stable surface

Answer 214

structure – mainly myofibrils (actin microfilaments + myosin II) - muscle contraction - myosin II drags actin filaments towards itself o resting state – myosin bound to actin o binding of ATP onto myosin causes actin to move away o breakdown of ATP to ADP and Pi releases energy and myosin moves gently backward o in its new location, myosin weakly binds to actin (onto a different monomer than before) o Pi is released from myosin and the bound between myosin –actin becomes stronger o in the last step, ADP is released which causes the movement of myosin forwards which cause the movement of the whole actin fiber

Answer 215

structure – mainly myofibrils (actin microfilaments + myosin II) - muscle contraction - myosin II drags actin filaments towards itself o resting state – myosin bound to actin o binding of ATP onto myosin causes actin to move away o breakdown of ATP to ADP and Pi releases energy and myosin moves gently backward o in its new location, myosin weakly binds to actin (onto a different monomer than before) o Pi is released from myosin and the bound between myosin –actin becomes stronger o in the last step, ADP is released which causes the movement of myosin forwards which cause the movement of the whole actin fiber

Answer 216

Lack long-term stability, they constantly degrade and rebuild - Protein daily turnover varies by tissue type- skeletal muscle 10%, liver 40%, small intestinal mucosa 80% - Recommended daily intake (for 70kg male) – 100g o Oxidation of 100g of protein will cover 10-20% of the bodies energy needs

Answer 217

Sources of AAs – diet, degradation of body of body proteins, synthesis de novo - Protein turnover is strictly regulated - AA pool – amino acids, which are freely available in the body to be used, about 100g o Highest level of AA in the body is glutamine and alanine – transport ammonia in blood - Use of AA – proteosynthesis, degradation (to energy/ glucose/ FA), production of nitrogenous substances o Excess AA cannot be stored (there is no storage protein) so it is burned as energy

Answer 218

Expresses the balance between the intake of nitrogen in the diet and loss of nitrogen (mostly through urine) - in adulthood, we have a balanced nitrogen equilibrium - N accepted = N excluded - Higher protein intake triggers catabolism of excess AA and urea or NH3 excretion - Positive nitrogen balance o Protein intake exceeds losses o for example, during recovery from illness (we replenish our losses), in periods of growth, or by administration of proteoanabolic hormones (insulin, testosterone, growth hormone) - negative nitrogen balance o losses of nitrogen exceed its intake o e.g during starvation, severe illnesses or administration of catabolic hormones (glucagon, cortisol) o 1g of nitrogen comes from approximately 6.25g of proteins

Answer 219

cellular proteins have different half-lives o ornithine decarboxylase - lasts 11 minutes o haemoglobin - lasts 120 days, just like erythrocyte o Y-Crystalline (eye lens protein) - lasts a lifetime

Answer 220

protein ubiquitin (= ubiquitin) o serves as a label – when several ubiquitins are bound to a protein it is labelled for destruction- so called polyubiquitination - the degradation of polyubiquitinated proteins itself takes place in proteasomes - a large compound of proteolytic enzymes

Answer 221

branched - Val, Leu, Ile o aromatic - Phe, Trp o basic - Lys o contain sulphur - Met o with a hydroxyl group - Thr

Answer 222

Gly, Ala, Ser, Pro, Cys, Tyr, Asn, Gln, Asp, Glu

Answer 223

COO- cleaves from AAs during decarboxylation o histidine -> histamine

Answer 224

alanine -> pyruvate o runs simultaneously with transamination in the opposite direction - AMK1 + KK2 -> KK1 + AMK2 alanine + α-ketoglutarate -> pyruvate + glutamate

Answer 225

glutamate -> α-ketoglutarate o NH group is released in the form of ammonia

Answer 226

freely reversible reactions - exchange between the amino group on the amino acid with a keto group on the α-keto acid o the amino acid becomes an α-keto acid and α-keto acid becomes an amino acid - enzyme - transaminase (aminotransferases) o ALT – alanine aminotransferases o AST – aspartate aminotransferases - Cofactor is pyridoxal pyrophosphate (derivative of vit. B6)

Answer 227

conversion of the carboxyl group of glutamate (in the side chain) to the amide group of glutamine o Glu + NH3 + ATP -> Gln + ADP + Pi - enzyme glutamine synthetase (in cytosol) - glutamine is the most transporter of nitrogen (ammonia) in the blood - glutamine enters the liver and the mitochondria, where glutaminase converts glutamine to glutamate o Gln + H2O -> Glu + NH4 + - This results in nitrogen getting out of the periphery directly into the liver mitochondria, where it is converted into urea and eliminated from the body = detoxification function

Answer 228

glutamate dehydrogenase enzyme - occurs in mitochondria, mainly liver - glutamate was most likely formed by transamination of α-ketoglutarate - it is the removal of NH2 group from glutamate and formation of α-ketoglutarate from glutamate o Glu + NAD -> α-ketoglutarate + NADH - - the ammonia goes back into the ornithine cycle - - it is mostly linked to glutaminase, which produces glutamate from glutamine

Answer 229

extrahepatically attempt to bind ammonia to carriers and send them to the liver for urea formation o transamination most often to pyruvate, alanine or α-ketoglutarate is formed, glutamate is formed o amidation - Glu + NH3 -> Gln - in the liver – what occurred extrahepatically + oxidative deamination of glutamate

Answer 230

most terrestrial vertebrates convert ammonia into urea - concentration of ammonia in blood is 35μmol/l - is toxic for the brain – is non-polar and therefore freely crosses the blood-brain barrier o merges with α-ketoglutarate in the brain, forms glutamate and blocks Krebs cycle

Answer 231

urea forms from NH3, CO2 and NH2 groups, that have been donated by aspartate - occurs mainly in the liver, but urea is excreted by the kidneys - urea cycle begins in the mitochondrial matrix, the rest in the cytosol 1) formation of carbamoyl phosphate 2) formation of citrulline 3) formation of arginosuccinate 4) breakdown of arginosuccinate 5) formation of urea

Answer 232

regulatory enzyme carbamoylphosphate synthetase I o activation of N-acetylglutamate which is formed by the reaction of acetyl-CoA and Glu o enzyme N-acetylglutamate synthetase activates arginine - urea cycle is a proton production reaction, therefore during acidosis (excess of H+) the reaction is stopped - during high levels of protein in the diet there is \increased transcription of all enzymes of the urea cycle

Answer 233

it is the active exchange of intermediates - occurs through aspartate and fumarate - each degraded amino acid donates its amino group onto α-ketoglutarate, which forms glutamate - enzyme AST (aspartate aminotransferase) switches the amino group from glutamate to oxaloacetate, to form aspartate - aspartate enters the urea cycle, fumarate exits - fumarate is then recycled to oxaloacetate in the Krebs cycle, waiting for the next amino group

Answer 234

carbon skeleton of each amino acid is metabolized by its own specific pathway - eventually, however, 7 intermediates are formed KETOGENIC o acetoacetyl-CoA - Lys, Leu, Phe, Tyr, Trp o acetyl-CoA - Ile, Leu GLUCOGENIC o fumarate - Phe, Tyr o oxaloacetate - Asp, Asn o succinyl-CoA - Val, Ile, Met, Thr o α-ketoglutarate - Glu, Gln, Pro, Arg, His o pyruvate - Gly, Ala, Ser, Thr, Cys, Trp

Answer 235

amino acids that break down into acetyl-CoA or acetoacetyl-CoA are so called ketogenic (because glucose can’t be synthesized from them, but ketone bodies can) and others are so called glycogenic (because glucose can be synthesized from them - division of amino acids o ketogenic - lysine a leucine (begin with L) o glycogenic - serine, threonine, cysteine, methionine, aspartate, glutamate, asparagine, glutamine, glycine, alanine, valine, proline, histidine, arginine o ketogenic and glycogenic - isoleucine, phenylalanine, tyrosine a tryptophan (aromatic AA) o some are quite easy to derive/remember 4C amino acids - aspartate and asparagine transaminate to oxaloacetate 5C amino acids - glutamine and glutamate transaminate to α-ketoglutarate alanine transaminates to pyruvate lysine and leucine (both branched AAs begin with L) are ketogenic glycine, serine a cysteine – all small amino acids as well as alanine, turn into pyruvate

Answer 236

valine, leucine, isoleucine - it occurs not only in the liver but also, to a significant extent, in skeletal muscles and the heart - used in those with hepatic failure and athletes to provide quick energy 1) transamination - specific transaminase o greater activity in skeletal muscle and heart, less activity in liver o products are 2-keto acids, which are washed out of the muscle into blood and taken up by the liver 2) decarboxylation 3) dehydrogenation - product is acyl-CoA

Answer 237

essential - Phe, Trp, Val, Leu, Ile, Met, Thr, Lys - conditionally essential - Arg, His - non-essential o oxaloacetate -> Asp, Asn o 2-ketoglutarate -> Glu, Gln, Pro, (Arg) o pyruvate -> Ala o 3-phosphoglycerate -> Ser, Cys, Gly o Phe -> Tyr

Answer 238

Phe and Tyr differ by one OH group - The enzyme phenylalanine hydroxylase and cofactor biopterin (H4) can bind OH to Phe and produce Tyrosine - Enzyme dihydropyridine reductase recycle biopterin - from Tyr, for example, melanin and thyroid hormones are synthesized

Answer 239

AR disease due to the absence or decreased activity of enzyme phenylalanine hydroxylase - The body begins to accumulate and alternatively breaks down Phe - Alternative degradation of Phe may produce (inter alia) phenylethylamine, which damages the brain - Phenylketonuria is resolved by strict withdrawal of phenylalanine from the diet and artificial administration of tyrosine

Answer 240

Group of amines formed by the decarboxylation of amino acids - (Phe ->) Tyr -> catecholamine’s (adrenaline, noradrenaline, dopamine; hormones and neurotransmitters) - Trp -> serotonin (5-hydroxytryptamine; neurotransmitter) - His -> histamine (immune system signalling agent, neurotransmitter) - Ser -> ethanolamine -> choline -> acetylcholine (neurotransmitter in neuromuscular plates) - Cys -> cysteamine (component of Coenzyme A) - Asp -> β-alanine (component of Coenzyme A) - Glu -> γ-aminobutyrate (GABA; neurotransmitter)

Answer 241

Small molecule, short half-life in our body - Precursor is arginine – produced No and citrulline - enzyme NO-synthase - isoenzyme, has several forms o NOS I - brain - neurotransmission (helps neurotransmission of other transmitters) o NOS II - macrophage – killing of bacteria o NOS III - endothelial - NO causes vascular dilation – vasodilation (relaxes smooth muscle) - Clinical significance of NO – nitrates in the treatment of angina pectoris (restriction of blood flow to the heart, pre-infraction) o Hypotension accompanying septic shock

Answer 242

thyroxine (T4) a triiodothyronine (T3) – from tyrosine, they are not biogenic amines (they still have COO-)

Answer 243

tyrosine derived pigment (produced by its oxidation and polymerization) - we recognize two types o occult – melanocytes in skin o neuromelanin – mainly in the substantia nigra of the middle brain

Answer 244

SAM is a very common methyl donor in methylation reactions - Formed by the fusion of methionine and ATP, during which ATP loses all its phosphates o enzyme methionine adenosyltransferase - after methyl donation, SAM is regenerated with N5-methyl-THF

Answer 245

provides a very fast energy reserve for muscle tissue - arginine + glycine -> guanidinoacetate + ornithine o enzyme glycinamide transferase o occurs in the kidneys - guanidinoacetate + SAM -> creatine + S-adenosyl-homocysteine (recycled back to SAM) o enzyme guanidinoacetate methyltransferase o takes place in the liver - creatine -> creatinine + H2O

Answer 246

histidine - histamine - tryptophan - serotonin, melatonin - phenylalanine, tyrosine - adrenalin a noradrenalin, thyroid hormones - glutamate - GABA - glycine - heme, purine, bile acid conjugation, creatine - ornithine and arginine - creatine, polyamines (spermidine, spermine) - glycine, glutamine, aspartate - purines and pyrimidines - arginine - NO - cysteine - taurine - serine –phospholipid base

Answer 247

the concentration of amino acids in plasma - 2,3-4,0 mM o glutamine (0,6 mmol/l has the highest amount; the main form of transport of ammonia) and alanine (0,3 mmol/l; main component of glucose-alanine cycle) - ammonia - 6-35 μmol/l, when it exceeds 50 μmol/l its toxicity starts to appear and damages the CNS - urea - 2,5-8,3 mmol/l - creatinine - 50-120 μmol/l

Answer 248

major organ of amino acid metabolism o removal of amino groups from amino acids o ammonia detoxification - 95% is excreted in the urea cycle, glutamine is produced from the rest and sent to the kidneys o conversion of the C-skeleton to glucose, fatty acids or ketone bodies o formation of non-essential amino acids

Answer 249

all the amino acids we take in the diet must pass into the blood through enterocytes - enterocytes regulate the entry of individual amino acids into the body - glutamine is the basic energy substrate of rapidly dividing cells (e.g. enterocytes or immune cells) o amino group of glutamines enters the purine formation, and oxidation of the C-skeleton yields energy o during starvation and stress, the main source of glutamine is skeletal muscle

Answer 250

main ‘reservoir’ of proteins – used during stress and/or starvation - even muscle cells alter the spectrum of amino acids released into blood o what they gain by proteolysis of their own proteins does not correspond to what they secrete into the blood - branched amino acids can be transaminated in muscle – their α-keto analogues are released into the blood (or oxidized to gain energy), the amino groups are transferred to glutamine or alanine – they go back to the blood

Answer 251

are the major site of N-catabolite excretion (urea, ammonia, creatinine, uric acid etc.) o = nitrogen catabolites begin to accumulate in during kidney damage - tubular cells are able to convert glutamine to glutamate into α-ketoglutarate - ammonia is released - glycogenesis also occurs in the kidneys - about 10 - 15% - conversion of citrulline -> arginine

Answer 252

- marasmus – starvation due to insufficient energy and protein intake o proportional reduction of both fat and non-fatty matter - kwashiorkor – inadequate intake of protein with adequate intake of energy and vitamins o retarded growth, loss of pigmentation on skin and hair, ascites, mental apathy

Answer 253

muscle contraction is a mechanism for converting potential energy into mechanical energy o two contractile proteins – actin and myosin (myosin type II) are responsible for this

Answer 254

creates dimers, which then stack on top of each other to form one long filament o one monomer consists of 1 heavy chain (globular head and long fibrillary tail) and 2 light chains (adjacent to the globular head and have an important regulatory function)

Answer 255

universal stimulus to muscle contraction in all types of muscle tissue is- increased calcium concentration in the cytosol - muscle contraction is a cyclic process, at its end/beginning myosin is strongly (ionically) bound to actin o at this stage, the muscle is contracted - release of contraction – binding ATP to myosin -hydrolysis of ATP -again, the binding of myosin onto actin -moving the head back to its original state -removal of ADP from the myosin head

Answer 256

increased calcium concentration in skeletal muscle occurs during membrane depolarization stimulus for membrane depolarization comes from neuromuscular plate - binding of acetylcholine to membrane ion channels opens them and releases sodium ions into the cell, thereby depolarization of membrane - acetylcholine channels would not be enough, therefore they are supported by voltage-controlled sodium channels o depolarization gradually spread across the membrane and activates voltage- controlled calcium channels these channels are called dihydropyridine receptors o dihydropyridine receptors are mechanically linked to calcium channels in the sarcoplasmic reticulum through which calcium leaks into the cytosol calcium channels in the sarcoplasmic reticulum are called ryanodine receptors o all the calcium required for muscle contraction comes from sarcoplasmic reticulum

Answer 257

a protein that sits on the actin-myosin complex and prevents the binding of myosin to actin without sufficient calcium in its surroundings

Answer 258

tropomyosin is a protein that periodically blocks binding sites on actin (= blocks myosin binding) troponins are globular proteins whose function is to monitor Ca2 + levels

Answer 259

breakdown of acetylcholine in the neuromuscular plate and membrane repolarization o Ca2+ pump in the sarcoplasmic reticulum membrane (SERCA) returns calcium to SER SERCA is automatically activated at high cytoplasmic Ca2+ concentration

Answer 260

in rough outlines, depolarization is similar to skeletal muscle (although it has a different stimulus) o does not acquire a stimulus to contract the neuromuscular plate, such as skeletal muscle, - however, there is a big difference in the mechanism of calcium channel opening in the sarcoplasmic reticulum o dihydropyridine and ryanodine receptors are not linked - instead, ryanodine receptors open in response to Ca2+ molecules that have entered the cytosol through open dihydropyridine receptors o the heart muscle thus requires calcium from the extracellular environment o dihydropyridine receptors therefore allow a few calcium ions to enter the cytosol, which then open up the ryanodine receptors

Answer 261

- dihydropyridines - drugs called calcium blockers o affect the heart contraction (make it more difficult) without affecting the skeletal muscles - i.e. drugs against hypertension and arrhythmia

Answer 262

contraction is regulated through hormonal signalling - different structure - smooth muscle has single cells with one nucleus, that are connected together - the main difference is the duration of the contraction - the contraction has a much longer onset and a much longer duration - for smooth muscle, much of the calcium required to contract comes from outside o thus, calcium channel blockers are very effective in blocking smooth muscle contraction smooth muscle has no tropinotropomyosin complex o instead the calcium sensor is myosin light chain kinase - MLCK o MLCK is activated by the calmodulin-calcium complex - Smooth muscle needs to phosphorylate one myosin to contract (without it no contraction will occur) o phosphorylation is catalyzed by MLCK, which is activated by the calmodulin-calcium complex, which is the calcium regulating factor - when there is no calcium, there is no calmodulin-calcium complex, no MLCK is active, no phosphorylation, no muscle contraction - muscle relaxation is regulated by myosin light chain phosphatase o cuts off phosphate groups as soon as the calcium level is reduced

Answer 263

skeletal muscle - at rest gains most of the energy from fatty acids, with increasing level of effort carbohydrate utilization increases - has two types of fibres that differ in their substrate orientation white fibre - glycolytic (primary substrate is glucose), very fast pulling ability, can work well even without oxygen, produce lactate red fibre - rely on aerobic metabolism (mitochondria, oxygen, fatty acids)

Answer 264

cardiac muscle - can work only aerobically o It primarily processes fatty acids, but can also metabolize glucose and lactate - smooth muscle - not very energy intensive

Answer 265

- a small molecule composed of three pieces of amino acids (arginine, glycine, methionine), which acts as an ATP buffer o is able to be phosphorylated from creatine to creatine phosphate so far from equilibrium that it has the character of ATP ATP + Cr <-> ADP + Cr-P is a reversible reaction with no energy loss o creatine and creatine phosphate are spontaneously converted to a degradation product called creatinine creatinine acts as a marker of kidney function (more creatinine in blood and less in urine means trouble)

Answer 266

an enzyme that cleaves phosphate from ATP and passes it on to creatine, creating creatine phosphate o it can catalyze the same vice versa, without any loss of energy - energy to contract o ATP, which is stored in the muscles, is sufficient for about 5 seconds o Cr-P reserves are consumed for a further 15 seconds o then energy needs to be met by the metabolism of sugars or fatty acids

Answer 267

metabolic pathways are constantly monitored and adjusted - the synthesis and degradation of metabolites meet the requirements of both cells and the organism o it is never possible to satisfy everyone - most cells or the most important organs are prioritized

Answer 268

compartmentation of metabolic processes o change in the concentration of the active regulatory enzyme change in absolute enzyme concentration modulating the activity of an existing regulatory enzyme x Covalent modification of the enzyme molecule x interventions that alter enzyme kinetics

Answer 269

eukaryotic cell is divided into compartments - only certain metabolic pathways take place in each compartment o there is a different representation of enzymes in each compartment - Specific transmitters in membranes ensure proper distribution of substrates and products o allow the cell to affect several metabolic pathways at once - e.g. transport of Acetyl-CoA from mitochondria to the cytoplasm promotes the Krebs cycle (takes product) and FA synthesis (adds substrate) - compartmentation facilitates the regulation of contradictory events o For example, FA synthesis occurs in the cytoplasm, whereas MT degradation occurs in mitochondria - subsequent processes take place close to each other – e.g. Krebs cycle and respiratory chain - both pathways take place in the matrix of mitochondria

Answer 270

it proceeds through the induction (activation) or repression (inhibition) of the expression of the gene which encodes the enzyme - mostly transcription factor (TF) is involved o the effect of TF is usually reversible and often dependent on ligand binding (or ligand-dependent TF) o Ligands are signalling molecules or various metabolites - the effect lasts longer (hours, days) than the regulation of the activity of an existing enzyme (seconds, minutes) - examples of this regulation o glucocorticoids induce the expression of genes encoding gluconeogenesis enzymes o enzymes of the monooxygenase system are induced by xenobiotics (foreign substances that have nothing to do in the body) o heme inhibits the synthesis of δ-aminolevulate synthase

Answer 271

formation of active enzymes from inactive precursors - irreversible activation o converting an inactive proenzyme into an active enzyme by partial proteolysis part of the inactive precursor is cut off -> what remains is the active enzyme o examples include digestive enzymes, caspases or coagulation factors o rapid increase in the concentration of active enzyme o via proteolytic breakdown we can inactivate an enzyme

Answer 272

enzyme interconversion (between active and inactive form) - reversible activation o Fast switching of the enzyme to active and inactive form (activation/inhibition) due to another enzyme o mechanism of enzyme interconversion is reversible ATP-dependent phosphorylation and dephosphorylation of enzymes Enzymes that provide interconversion are protein kinases (phosphorylate) and protein phosphatases (dephosphorylate) o phosphorylation activates or inhibits, depending on the particular enzyme o often response to a hormonal signal

Answer 273

effect of substrate and product concentration and KM, pH, temperature, etc. the more substrate or less product, the faster the reaction will proceed effect of the presence of activity modulators (activators or inhibitors) o The accumulation of an intermediate or end product of pathway metabolism leads to inhibition so-called feedback control e.g. acetylCoA inhibits its own synthesis o The intermediate (or product) of one metabolic pathway affects the rate of the other (often contradictory) metabolic pathway so-called cross regulation e.g. malonylCoA (an intermediate of FA synthesis) inhibits the degradation of FA o The intermediate affects one of the following enzymes in its metabolic pathway so-called step-forward regulation e.g. nucleotide synthesis

Answer 274

availability of O2 - ratio of cofactors NADH / NAD+ - availability of ADP for ATP synthesis - UCP (uncoupling proteins, viz. 2.7.2)

Answer 275

availability of substrates (acetyl-CoA and oxaloacetate) = substrate control - a collection of products (NADH, FADH) by subsequent reactions (respiratory chain) = respiratory control - ratio ATP / ADP = energetic control o A high ratio (much ATP, little ADP) indicates enough energy in the cell and will slow the Krebs cycle o low ratio (low ATP, much ADP) indicates a lack of cell energy and will accelerate the Krebs cycle - regulatory enzymes - citrate synthase, isocitrate dehydrogenase (the main regulatory enzyme), 2-ketoglutarate dehydrogenase

Answer 276

Interconversion pyruvate dehydrogenase (PDH) complex - phosphorylation (inactive) / dephosphorylation (active) o insulin activates dephosphorylation - the main regulatory mechanism o glucagon activates phosphorylation - wants to increase blood sugar concentration = must prevent processing of sugar in cells - competitive inhibition by product (acetyl-CoA) - inhibition by increased NADH / NAD+ - at a high ratio, the cell has enough energy and may not produce additional

Answer 277

hexokinase / glucokinase - 6-phosphofructo-1-kinase (PFK) - the main regulatory enzyme o activation increased AMP / ATP ratio Presence of Fru-2,6-bisP (occurs when insulin / glucagon ratio increases) insulin o inhibition increased ATP / AMP ratio presence of citrate in the cytosol (citrate in the cytosol means that there is so much in mitochondria that it is already climbing out)) acidic pH - pyruvate kinase

Answer 278

pyruvate carboxylase o activation- cortisol, glucagon, excess Acetyl-Co o inhibition- insulin - phosphoenolpyruvate carboxykinase - Fru-1,6-bisphosphatase- the main regulatory enzyme o the regulation of Fru-1,6-bisphosphatase is exactly the opposite of that of PFK - glucose-6-phosphatase- activation by cortisol and glucagon, inhibition by insulin

Answer 279

degradation of glycogen- glycogen phosphorylase - main regulatory enzyme o activation - glucagon, adrenaline (phosphorylation), increased AMP / ATP ratio, Ca2+ (in muscle) o inhibition- insulin - glycogen synthesis - glycogen synthase o activation- insulin o inhibition- glucagon, adrenaline (phosphorylation)

Answer 280

the regulatory enzyme is glucose-6-phosphate dehydrogenase (G6P DH), which requires NADP+ for its activity o inhibition- increased NADPH / NADP+ ratio o activation- insulin

Answer 281

hormone sensitive lipase an important regulatory enzyme in fat cells, it is activated in stressful situations o Activation - catecholamines (adrenaline, noradrenaline), glucagon (phosphorylation) o inhibition - insulin

Answer 282

Initiation of β-oxidation requires the supply of FA - the rate of β-oxidation is regulated more or less by the rate of transport of FA into mitochondria o Carnitine-acyl transferase I (CAT I) - inhibited by malonyl-CoA and increased insulin / glucagon ratio - Acetyl-CoA, FADH2 and NADH must also be collected by subsequent reactions, otherwise, β-oxidation will slow down

Answer 283

regulation at the level of substrate availability - Acetyl-CoA o is closely related to lipolysis and beta-oxidation

Answer 284

Acetyl-CoA carboxylase - the main regulatory enzyme, in ER o the first enzyme of the entire metabolic pathway - ensures the transport of long fatty acids into the mitochondria o inhibition - palmitoyl-CoA (generally acyl-CoA = when we have enough FA, we do not have to make new ones), glucagon (phosphorylation, repression) and AMP o activation - citrate, insulin, low-fat, high-energy, high-carbohydrate diet

Answer 285

the ornithine cycle enzymes are activated by a protein-rich diet or by metabolic changes during fasting - urea synthesis is a proton productive reaction = it is inhibited by acidosis - regulatory enzyme - carbamoyl phosphate synthetase I o activation - N-acetylglutamate N-acetylglutamate is formed by the enzyme N-acetylglutamate synthetase, which is activated by arginine

Answer 286

metabolism is a set of catabolic and anabolic reactions - intermediates are part of metabolic pathways o e.g. pyruvate can be converted to lactate (lacking in oxygen), or can provide the amino acid alanine, participate in glucose production or be converted to acetyl-CoA - types of metabolic reactions o catabolic (Greek kata = Down) - fission, degradation, exergonic reactions - e.g. sugar-> CO2 a H20 o anabolic (Greek ana = Up) - synthetic, endergonic reactions - e.g. glycogen synthesis, urea formation o amphibolic (Greek amphi = both sides) - sequence of reactions, some of which are catabolic and some anabolic

Answer 287

glycolysis- degradation of carbohydrates to pyruvate / lactate - glycogenolysis- degradation of glycogen to glucose - lipolysis- degradation of triglycerides to glycerol + fatty acids - beta-oxidation- degradation of fatty acids to acetyl-CoA - ketone bodies breakdown - in case of liver starvation they produce so-called ketone bodies which send other tissues for degradation - degradation of proteins and amino acids

Answer 288

gluconeogenesis- glucose synthesis - glycogenesis- glucose synthesis - fatty acid synthesis - lipogenesis synthesis of TAG from fatty acids and glycerol - ketogenesis- production of ketone bodies in the liver - proteosynthesis- protein synthesis - ornithine cycle- urea formation

Answer 289

pyruvate dehydrogenase reaction- converts pyruvate to Acetyl-CoA - Krebs cycle - uses Acetyl-CoA to produce CO2, NADH (NADH should be correctly written as NADH + H+) and FADH2 o important- Krebs cycle has a second name - Citrate cycle - respiratory chain- consumes NADH and FADH2 to produce ATP and H2O

Answer 290

arises from glycolysis, degradation of some amino acids, transamination of alanine... o Acetyl-CoA (energy production), alanine (photosynthesis), lactate (anaerobic glycolysis), oxaloacetate (gluconeogenesis) or ethanol (alcoholic fermentation, thus producing beer and wine)

Answer 291

arises from sugars (glycolysis through pyruvate), fats (β-oxidation), ketone bodies and some amino acids o may enter the Krebs cycle (energy production) of fatty acid / ketone / cholesterol synthesis

Answer 292

NAD is an uncharged (oxidized) state, NADH is a charged (reduced) state o In some reactions, it is necessary to supply / remove electrons, in which case the appropriate electron transmitter is needed e.g. in glycolysis we need to remove electrons - therefore we need free NAD and in case of lack of glycolysis it stops o there is also a phosphorylated version - NADP and NADPH- NADP a NADPH (NADP+ a NADPH + H+

Answer 293

1. extracellularly, complex nutrients break down into smaller ones - proteins into amino acids, polysaccharides to monosaccharides... 2. The individual TAGs, amino acids and monosaccharides reach the cell 3. they are processed into components of the Krebs cycle (mostly Acetyl-CoA) in the cell 4. CO2, small amount of energy and reduced cofactors NADH and FADH2 remain from Acetyl-CoA citrate cycle 5. Reduced cofactors continue into the respiratory chain, where oxidative phosphorylation produces ATP

Answer 294

monosaccharides are absorbed by the intestinal wall into the bloodstream and transported to the liver o they are degraded or transformed into glucose in the liver - glucose is leached back to the blood in a controlled way, excess glucose forms glycogen or storage fat in the liver o cells can take glucose from blood and use it for energy, fatty acid synthesis, ribose... o Once glucose enters the cell, it will never leave it (liver cells are the exception) o Glucose is stored in the liver and muscle cells in the form of glycogen

Answer 295

glycolysis- a process in which glucose in a cell is degraded to pyruvate to release energy in the form of ATP o in the cytoplasm, NAD is needed, 2 pyruvates, 2 ATP and 2 NADH are produced from one glucose - pentose phosphate cycle - it does not serve as an energy source but provides pentoses (ribose) for nucleotide formation and NADPH + H+

Answer 296

autotrophic organisms - have the ability to synthesize carbohydrates from inorganic substances during photosynthesis - heterotrophic organisms - if necessary, they form glucose from simple organic substances (from pyruvate, glycerol...) o this process is called gluconeogenesis, occurs in the liver after glycogen exhaustion o gluconeogenesis is identical to glycolysis except for a few reactions, just running in the opposite direction

Answer 297

TAG is first broken down into glycerol and fatty acids o glycerol is phosphorylated to the glycolysis metabolite (glycerol -> glycerol-3-P -> dihydroxyacetone-P) o fatty acids undergo β-oxidation, resulting in a lot of Acetyl-CoA, NADH and FADH2 β-oxidation occurs in mitochondria

Answer 298

the synthesis of TAG is based on Acetyl-CoA - it gradually builds up fatty acids of the required length, which are then connected one after the other to glycerol until the whole TAG is formed o this is done in the cytoplasm, and NADPH is needed

Answer 299

proteins in the intestine hydrolytically cleave enzymes up to amino acids - when AA is used as an energy source, the amino group is first removed by deamination, the resulting carbon skeleton is metabolized to various products, which sooner or later travel to the Krebs cycle o Each AMK has its own path of degradation - ammonia enters the ornithine cycle where it is converted into urea, which is then expelled from the body o the ornithine cycle is linked to the Krebs cycle via a couple of intermediates

Answer 300

non-essential AAs can be synthesized in the liver - each cell can produce proteins from the AMK it already has (which it receives from the blood)

Answer 301

it is a sequence of reactions in which Acetyl-CoA degrades to CO2, ATP and reduced coenzymes NADH a FADH2 - occurs in the matrix of mitochondria - always released during the Krebs cycle: 2x CO2, 1x ATP, 3x NADH and 1x FADH2

Answer 302

hydrogen bound in NADH and FADH2 is oxidized by oxygen to form water and ATP - occurs on the inner membrane of mitochondria - the main suppliers of reduced cofactors are the Krebs cycle and β-oxidation of fatty acids - hydrogen is not directly combined with oxygen, oxidation is carried out gradually through several stages (redox systems) - the hydrogen atoms are split into protons and electrons, which are then transferred through several proteins until they finally join with oxygen at the end to form water

Answer 303

they have an incredible number of functions (in terms of metabolism) and so it is so difficult to create an artificial substitute for them - play a vital role in maintaining homeostasis, the synthesis and conversion of nutrients, and the regulation of storage and release of energy

Answer 304

glucostatic function- the liver regulates blood glucose (blood glucose) o high post-meal glucose = glucose uptake and glycogen production o Low fasting blood glucose = breakdown of glycogen and release of glucose into the blood - the supply of glycogen in the liver is about 80-100 g - enough for about 24 hours - Gluconeogenesis begins when the glycogen stores are depleted - glucose synthesis from non-sugar substrates

Answer 305

the deamination, transamination and subsequent conversion of the carbon skeleton of all AAs takes place in the liver - ensures removal of ammonia from the body by urea synthesis in the ornithine cycle (ammonia is toxic) - non-essential amino acids are synthesized and most plasma proteins are produced

Answer 306

high energy consumption - concentration of urine and transport of substances is not easy - during prolonged fasting, gluconeogenesis may produce glucose - have enzymes of amino acid metabolism

Answer 307

muscle contraction requires a lot of ATP - ATP sources o creatine phosphate - phosphorylates ADP to ATP, waste product is creatinine o anaerobic glycolysis o aerobic glycolysis + oxidative phosphorylation o muscle glycogen - 300-1000g of glycogen is standard in the muscles) o nutrients from circulation - glucose and fatty acids

Answer 308

BCAA (Branched-Chain Amino Acids; Leucine, Isoleucine and Valine) - can be transaminated and used directly in muscles, o carbon skeletons are used in energy metabolism (Krebs cycle) o Ammonia is incorporated into Ala, Glu and Gln and released into the blood - the liver catches, deaminates and forms urea

Answer 309

Storage of TAG (postprandial - after meal) - lipoprotein lipase (endothelial) - catalyzes the degradation of TAG - de novo lipogenesis (= from the beginning) - from glucose - lipolysis - release of fatty acids (FA = Fatty Acids) and glycerol (during fasting) - hormone sensitive lipase - enzyme catalysing the breakdown of TAG, activated by glucagon

Answer 310

egoist- 2% body weight, 20% energy, 25% total oxygen - glucose is the main source of energy for the brain - it has a daily consumption of 120g o neuroglycopenia - a state of sugar deficiency in the brain, leading to unconsciousness, brain damage and death - in the adapted starvation (3 weeks) also the oxidation of ketone bodies, which cover up to 50% of energy needs

Answer 311

there are many inter-organ connections within energy metabolism - two examples - the Cori cycle and the Glucose-alanine cycle

Answer 312

the way in which erythrocytes and muscles are dehydrated - Lactate is sent to the liver, processed into glucose and sent back

Answer 313

the way in which muscles are supplied with energy while also extracting toxic ammonia - ammonia is attached to pyruvate, alanine is produced, which travels to the liver, where ammonia is disconnected and processed into urea - pyruvate is converted to glucose by gluconeogenesis and sent back to the blood

Answer 314

the effect of insulin and counter-regulatory hormones on energy metabolism on the one hand - insulin - on the other hand - counter-hormones glucagon, cortisol, adrenaline, growth hormone

Answer 315

All this leads to a reduction in blood glucose - increases glucose storage (mainly in the liver) - activates glycolysis and blocks gluconeogenesis - activates glycogen production - activates the conversion of carbohydrates into fatty acids - promotes the transport of TAG into adipose tissue - blocks lipolysis and ketogenesis - promotes protein production and tissue growth - insulin is therefore technically an anabolic hormone

Answer 316

antagonize the effect of insulin (through cAMP) - all leads to increased blood glucose - the point is to maintain blood glucose between meals and during increased glucose consumption o Decomposition of hepatic glycogen and glucose excretion o stimulation of gluconeogenesis o ketogenesis - an alternative fuel for cells

Answer 317

Insulin rises after a meal food gets into the intestines -> glucose is absorbed -> blood glucose rises -> we need to get it down -> pancreas releases insulin into the blood

Answer 318

Glucagon rises while starving man has not eaten for a long time -> glycemia is low -> need to get it up -> pancreas eliminates glucagon into the blood

Answer 319

Volume - around 5,5l o hematocrit - percentage of erythrocytes 35-45 in women, 40-50 in men o leukocytes and thrombocytes forming a white, cloudy layer are found in the space between plasma and erythrocytes this layer is about 1% of blood volume, it is made of leukocytes and thrombocytes and it is called buffy coat o rest of blood is plasma water, inorganic salts and organic compounds (proteins - albumins, globulins...)

Answer 320

liquid separated from clotted blood. o composition similar to blood plasma, but unlike plasma it does not contain fibrinogen and other blood clotting factors

Answer 321

examination of peripheral venous blood o We determine the differential white blood cell count and information about the blood cell morphology o Nowadays we often use machine for differentiation and evaluation o however, some abnormal cells are not recognized by the machine, so if a disease that could affect blood cells is suspected, the blood count is examined manually under a microscope - manual differentiation o Blood smear staining is standardly performed according to Pappenheim

Answer 322

nuclear-free biconcave cells - size - 7,5 x 2,6 μm o biconcave shape means larger surface area and better gas exchange - contain a 33% haemoglobin solution - number - 3,9 - 5,5 million in 1μm o the number is dependent on gender, race, geography and many other factors,

Answer 323

important protein - spectrin - together with actin form the characteristic shape of erythrocyte - a network of spectrin and actin is bound to the membrane via ankyrin proteins - erythrocytes do not have mitochondria (so they wouldn’t consume the oxygen they carry) o are reliant on anaerobic metabolism, which means glucose - its entry into the cell is facilitated by insulin non-dependent diffusion o a small portion of glucose enters the pentose cycle, by which the RBC gains NADPH, which the cell needs to protect against free radicals and keep iron in Fe2 + form

Answer 324

lifespan in circulation is 120 days - gradually become less elastic, deforming - they are destroyed in the spleen by macrophages - 0.5-1.5% of red blood cells in the blood may be reticulocytes, which are immature erythrocytes that mature over time - erythrocytes carry oligosaccharides on their membranes that determine the AB0 system

Answer 325

anaemia - decreased haemoglobin concentration in the blood, often associated with decreased haematocrit and increased bleeding - polycythaemia- increased erythrocyte count and haemoglobin concentration, increasing blood viscosity and risk of thrombosis o caused by either adaptation or hemoblastosis (tumour growth from erythrocyte precursors) - anisocytosis- higher size variability - macrocytes- larger erythrocytes, often means a lack of Vitamin B12 - microcytes- smaller erythrocytes (Fe deficiency) - sickle cell anaemia - point mutation in the haemoglobin β-chain gene

Answer 326

6.000 - 10.000 in 1μl - twice as many at birth than in adulthood - granulocyte and agranulocyte differential count o not counting them from the whole blood volume but only by smearing a small blood sample o granulocytes neutrophils 60 - 70% eosinophils 2 - 4% basophils 0 - 1% o Agranulocytes lymphocytes 20 - 30% monocytes 3 - 8%

Answer 327

size 12-15 μm - contains two types of granules o specific with a specific function for the given type of leukocyte o azurophilic - lysosomes - all granulocytes in peripheral blood are terminal stages of development - they no longer divide and they survive in the blood for only a few days - the last step of granulocyte maturation is nuclear segmentation - left shift - terminology, means the presence of a greater number of less mature granulocytes in peripheral blood

Answer 328

nucleus divided into 2-3 lobes connected through chromatin bridge o Barr's body may be visible on the neutrophil as it peeks from the lobe (blue arrow) o Immature granulocytes do not have a segmented nucleus and are called band neutrophils. - anaerobic metabolism - energy source glucose - they are present in the bloodstream for 1 day, in tissues for 1 to 2 days, after which they become apoptotic

Answer 329

content of their granules: o specific - modified lysosomes, contains alkaline phosphatase, collagenases and basic proteins o azurophilic – many hydrolytic enzymes The aim of neutrophils is to phagocytize the Foreign organism

Answer 330

a rapid release of white blood cells, after phagocytosis of pathogens, they utilize a lot of oxygen to produce hypochlorite, which destroys pathogens. They are able to form this molecule with the help of the enzyme myeloperoxidase

Answer 331

typically has a two-lobed nucleus - specific granules o crystalline medulla (internum) – main basic protein o matrix (externum) - lighter - play a role in allergies and parasitic infections - eosinophilia occurs o eosinophilia is a state of increased eosinophils in the blood - modulation of inflammation (inactivation of leukotrienes and histamine)

Answer 332

the core is divided into irregular lobes, but it is not visible because it is covered by granules - contains specific metachromatic granules, which contain histamines and heparin o these granules are degranulated after binding of certain antigens o severe degranulation may lead to the development of anaphylactic shock - function - regulation of immune response

Answer 333

do not contain specific granules, only azurophilic granules - the nucleus is round – kidney shaped - typical of acute inflammation (they work fast), have a short lifespan - accumulation of dead agranulocytes produces pus - includes lymphocytes & monocytes

Answer 334

sorted by size into small (6-8μm), medium (9-18μm) and large (over 18μm) - have basophilic cytoplasm and isolated azurophilic granules - contain a large spherical nucleus, condensed chromatin, a distinct nucleolus, a thin band of cytoplasm, ribosomes, and azurophilic granules - small B and T lymphocytes - the so-called memory cells, which provide specific immunity - predominate in the blood o 65-75 of which are T lymphocytes o we do not recognize them in common observation, we need cytogenetic methods

Answer 335

oB-lymphocytes differentiate in the bone marrow into plasma cells and produce immunoglobulins Provide antibody (humoral) immunity o T-lymphocytes provide cellular immunity - they differentiate in the thymus and learn to recognize their own antigens oNK (natural killers) - provide non-specific cellular immunity by inducing apoptosis roughly like macrophages destroy tumor cells and cells infected with viruses developmentally closer to T lymphocytes than B lymphocytes

Answer 336

-TH-lymphocytes (helper) - CD4, they allow cooperation of APC (antigen-presenting cells) and B-lymphocytes, they stimulate antibody production -TC- lymphocytes (cytotoxic) - CD8, they clear common cells, they can induce apoptosis in target cells -TSUP- lymphocytes (suppressor) - CD8 control activity of other lymphocytes - induce apoptosis

Answer 337

12-20μm - oval, kidney-shaped eccentric nucleus - have basophilic cytoplasm, azurophilic granules, RER, polyribosomes, mitochondria, Golgi complex - circulating monocytes are precursors of macrophages - after a short period of time in circulation, they leave the blood and enter into the connective tissue and differentiate into macrophages (eg Langerhans cells in the skin)) - they are phagocytes and antigen-presenting cells- they are able to phagocytose a pathogen, distinguish it and send on its membrane an antigen that tells B and T lymphocytes what pathogen is found inside the monocyte

Answer 338

leukocytes leaving the blood o rolling of leukocytes over on endothelium due to the presence of selectins (P a E) o adhesion - leukocytes attach to the endothelium via integrin o diapedesis (transmigration) - leukocytes pass through the endothelium

Answer 339

they are nuclear-free biconvex particles, dropped from the cytoplasm of megakaryocytes in the bone marrow - 200.000 - 400.000 per 1μl - break down in the liver and spleen - the center is called the granulomere and the lighter peripheral area is the hyalomer

Answer 340

granulomere - contains mitochondria, glycogen and granules δ (delta) granule - dense bodies, containing ATP and serotonin α (alfa) granule-specific platelet clotting factors (fibrinogen, PDGF, FGF, von Willebrant factor, platelet factor IV) λ (lambda) granule - lysosomes

Answer 341

open system of channels, surface plasmalema is invaginated contains a marginal bundle of microtubules actin and myosin allow contraction

Answer 342

function- hemostasis o Contact with the extracellular matrix induces thrombocyte adhesion o after injury of a small blood vessel, a platelet plug (primary hemostasis) is formed from aggregated platelets within a few minutes, followed by a mechanically stable blood clot (secondary hemostasis) from a ball of insoluble fibrin fibers o fibrin fibers are formed from soluble fibrinogen protein by a chain reaction - coagulation cascade

Answer 343

hemopoiesis and hematopoiesis are exactly the same, they are synonyms and freely interchangeable words

Answer 344

the baby in the uterus also needs blood cells, but at the beginning of the development he/she does not have bone marrow yet, so they have to produce it differently - prenatal haemopoiesis occurs in several periods, which overlap partially o mesoblast period – yolk sac o hepato-lienal period - liver and spleen o medullary period - bone marrow

Answer 345

haemopoiesis is the result of simultaneous proliferation and differentiation from haemopoietic stem cells - pluripotent stem cells = hemocytoblasts - self-renewable, low mitotic activity - multipotent stem cells come from pluripotent, have 2 strains - lymphoid and myeloid o unlimited direction of differentiation, but only a slight ability of self-renewal - unipotent stem cells (progenitor cells) - intended only for one cell type, self-renewal ability, high mitotic activity

Answer 346

soft tissue formed by reticular connective tissue in the bodies of long bones and in the spaces between the trabeculae

Answer 347

it consists of modified fibroblasts, reticular fibres (collagen III) and an inorganic component (fibronectin, laminin, proteoglycans) o vascular niche - blood supply, it is a place of maturation of blood cells and the appearance of helper cells sinusoids - they provide blood supply, they are capillaries with discontinuous endothelium o endosteal niche - at the marrow margins, it contains stem cells, osteoblasts (building bone) and osteoclasts (bone breaking) - according to the colour of the pulp we distinguish red (haemopoietically active), yellow (inactive) and grey (typical for late age)

Answer 348

red bone marrow’s reticular cells influence Hemopoesis by their cytokines o contains in addition to ligament also ropes, mesenchymal cells, fat cells and macrophages, sinusoids mesenchymal cells adipose cells macrophages o at older age, hematopoiesis occurs only in flat bones

Answer 349

arises from red bone marrow- haematopoiesis decreases in the pulp of long bones during growth, reticular connective tissue is replaced by fat cells and red pulp turns yellow o is capable of reactivating to red bone marrow - cytological examination of bone marrow smear is performed after collection (for example) from sternum and stained similarly as a blood smear

Answer 350

Some cytokines, which mostly originate from bone marrow stromal cells or from kidney and liver, act to maintain the equilibrium between the need for individual cell types and their overproduction. - growth factors colony stimulating factors (CSF) are glycoproteins that promote stem cell proliferation o Erythropoietin (EPO) - in kidneys, doping substance, promotes the production of red blood cells o thrombopoietin- from kidneys and liver, promotes the formation of platelets

Answer 351

in the context of hematopoietic stem cells, colony-forming units (CFUs) are stages where the stem cell is already partially differentiated and only a certain cell line can develop from it

Answer 352

- CFU-E erythropoiesis involves five stages of nuclear cell maturation, including four mitoses - differentiation leads to an increase in hemoglobin, a decrease in ribosomes, cell shrinkage, condensation and loss of nucleus o pycnose means increased density and condensation of chromatin of the cell nucleus observable by light microscopy - lasts about 8 days -> 5 days proliferation + differentiation and 3 days differentiation without further division - is stimulated by the cytokine erythropoietin (glycoprotein), which is produced in the kidney mainly during hypoxia - for normal erythropoiesis cyanocobalamin (Vitamin B12), folic acid and iron are also required

Answer 353

- erythropoiesis occurs in so-called erythropoietic islets - groups of immature erythrocytes around the macrophage o The macrophage provides them with a favourable microenvironment - eg it removes secreted cell nuclei o islets are formed during the mesoblastic period of hemopoiesis o iron deficiency -> erythrocytes light and small because they have haemoglobin deficiency o lack of folic acid or B12 -> large erythrocytes because there are few of them and everybody tries to carry as much haemoglobin as possible

Answer 354

proerythroblast- large oval cell with basophilic cytoplasm o nucleus – loose chromatin, large in comparison to plasma, has a nucleolus - basophilic erythroblast - condensed nucleus, basophilic cytoplasm (polyribosomes) - polychromatophilic erythroblast - decrease in the number of ribosomes, haemoglobin occurs - orthochromatophilic erythroblast- maximum condensed dark nucleus, eosinophilic cytoplasm (due to haemoglobin) o ejection of nucleus (modified apoptosis) - normoblast - reticulocyte - nuclear-free cell with ribosome residues and mitochondria (=substantia reticulo-filamentosa) o after three days of maturation, it is released into the circulating blood as mature erythrocyte

Answer 355

granulocytes and monocytes are derived from a common progenitor cell CFU-GM - promyelocytes have extensive GER and GA, due to the formation of azurophilic granules and later specific granules - elements of granulopoiesis are more frequent in bone marrow than elements of erythropoiesis (due to the short lifetime of granules) - differentiation may include core change (segmentation) and the appearance of specific granules - the whole development (from myeloblast to mature granulocyte) takes about 11 days

Answer 356

- myeloblast - the youngest cell, contains no granules, finely dispersed chromatin - B/N/E promyelocyte- basophilic cytoplasm, RER, GA, large violet azurophilic granule (functionally corresponding to lysosomes) o Nucleus is eccentric and flattened - B/N/E myelocyte nucleus condensation, specific granules increase, azurophilic granules decrease - B/N/E metamyelocyte - diminished nucleus o at this stage, the cells stop dividing - B/N/E granulocyte -mast cells - development proceeds differently o the precursor is released into the peripheral blood it travels until it settles in some tissue where it matures o has an IgE receptor - the whole development takes place in the bone marrow, where they are also stored

Answer 357

monoblast -> promonocyte -> monocyte -> macrophage -> activated macrophage - monoblast is identical to myeloblast - promonocyte large cell, basophilic cytoplasm, large lightly inverted nucleus, abundant GER, large GA - monocytes form azurophilic granules - lysosomes (peroxidase, acid phosphatase) - they live in the blood for about 8 hours and then on the periphery for several months as macrophages, which are antigen-presenting cells - mainly acts in tissues, not in blood; they function as osteoclasts

Answer 358

there are no specific morphological differences between T and B lymphocytes - the progenitors differentiate in the bone marrow - lymphocytic progenitor cells give rise to precursor stages of lymphocytes (lymphoblasts, prolymphocytes), which are functionally competent after maturation o maturation processes occur in primary lymphatic organs of bone marrow (B-lymphocytes) or thymus (T-lymphocytes) - is also divided into periphery in secondary lymphatic organs (spleen, lymph node, tonsila

Answer 359

the precursor cell is a lymphoblast, which differentiates into prolymphocytes, which no longer divide and mature into lymphocytes - Prolymphocyte can differentiate into NK cell, or naïve B / T-lymphocyte o naive lymphocyte - have not yet encountered antigen travel through the blood to peripheral lymphatic organs, where 95% of them disappear by apoptosis o activated B-lymphocyte differentiates into plasma cell - condition of survival and successful differentiation o generation of surface receptors capable of recognizing and binding foreign antigen o not to have affinity for self-tolerance antigens (self-tolerance)

Answer 360

formation of thrombocytes (blood platelets) in the bone marrow megakaryocyte development is based on CFU-Meg via immature intermediate stages of megakaryoblast and promegakaryocytes - huge nucleus size is caused by repeated DNA duplication without nucleus separation (so-called endomitosis) - cell development, polyploidy (several sets of chromosomes) and platelet cleavage during development - thrombopoietin a cytokine controlling the development of megakaryocytes, produced by osteoblasts of endosteal niche, liver and kidney

Answer 361

- megakaryoblast -> promegakaryocyte -> megakaryocyte - megakaryocyte- huge polyploid cell (up to 64 sets of chromosomes) o irregular lobed nucleus, numerous mitochondria, abundant RER, GA o formation of granules in the cytoplasm (later platelet granules) o plasmalema invagination = system of demarcation membranes - invagination delimits the cytoplasm region to platelets o creates long protuberances into the vessel, gradually constricts them o after the cytoplasm breaks down into platelets, the cell is destroyed by apoptosis remaining megakaryocyte’s nucleus with a narrow margin of the cytoplasm removes macrophages - Platelets are produced by the fragmentation of megakaryocyte processes, referred to as proplatelets

Answer 362

erythrocytes- 4-6*106 o Haematocrit - the ratio between the volume of red blood cells and the volume of whole blood men - 42-52% women - 37-47% - thrombocytes - 150-400*103 - leukocytes - 4-9*103

Answer 363

- 2 million new erythrocytes enter the circulation per second - among the new erythrocytes are so-called reticulocytes - young erythrocytes, which still contain ribosomes and ER components o increased representation of reticulocytes in the blood is a sign of haemolytic anaemia (haemolysis is increased) - there are antigens on the surface of the erythrocytes that are responsible for determining the blood type - erythrocyte production is stimulated by erythropoietin (EPO) - hormone synthesized in the kidney - erythrocytes have large and elastic surface (for better gas diffusion)

Answer 364

o Na+/K+-ATPase o GLUT 1 - non-insulin dependent consists of 12 transmembrane helical segments o Anionic transporters – e.g. Cl-/HCO3

Answer 365

o erythrocyte recovers all energy from glucose o 90% anaerobic glycolysis o 10% from the pentose cycle - NADPH is also created to protect against oxidative stress - erythrocytes participate in the Cori cycle - 2,3-bisphosphoglycerate(2,3-BPG) - produced by isomerization of 1,3-BPG (intermediate glycolysis) o 2,3-BPG is formed in the erythrocyte when blood enters the oxygen-deficient tissue -> at that time 2,3-BPG binds to hemoglobin and decreases its affinity to oxygen, releasing O2 from hemoglobin into the surrounding tissue

Answer 366

- erythrocyte has only the minimum necessary organelles and cytosol for survival, the rest of the cell is packed with hemoglobin, which ensures the transport of various substances through the blood - oxygen transport (O2) - reactive oxygen species (ROS) are formed which are dangerous and erythrocytes prevent them from producing NADPH - transport of carbon dioxide (CO2) - transport of hydrogen (H+) - has significant buffering properties (35% buffering capacity of blood)

Answer 367

- SOD - superoxide dismutase - CAT - catalase - GPx - glutathione peroxidase - GR - glutathione reductase

Answer 368

- in erythrocytes, it ensures a backward reduction of methaemoglobin to haemoglobin, or "the return of haemoglobin to life" - Hb-Fe3+ + e- -> Hb-Fe2+ (coenzyme NADH or NADPH)

Answer 369

- Glc-6-P is the first pentose cycle enzyme (conversion of Glc-6-P to 6-P-gluconolactone) - its malfunction or lack means absence of reducing cofactors NADPH, which serves as a glutathione reductase coenzyme in GSH regeneration - consequently, GSSG is not reduced to GSH, resulting in increased sensitivity to oxidative damage -> resulting in haemolytic anaemia due to excessive oxidative damage to erythrocytes

Answer 370

- a pyruvate kinase defect causes phosphoenolpyruvate not to convert to pyruvate - this defect may be the cause of haemolytic anaemia

Answer 371

it leads to a damage to the erythrocyte membrane which further leads to impaired molecule exchange and haemolysis

Answer 372

- hemoglobin is a hemoprotein composed of the globin protein and the prosthetic group of heme o has a quaternary structure (4 subunits - 2α and 2β) and each subunit contains one prosthetic group (heme) - myoglobin is something different than hemoglobin - myoglobin has only one globin chain and one heme, it is found only in muscles (stores oxygen for the muscle) and binds oxygen more firmly than hemoglobin (it has a higher affinity for oxygen)

Answer 373

- due to the quaternary structure, the affinity of oxygen to haemoglobin is allosterically modified o saturation curve shows sigmoidal dependence - once one oxygen molecule binds, the affinity of haemoglobin to oxygen increases (e.g. the other oxygen is easier to bind) - Oxygen-free haemoglobin is in the T-conformation and has a low affinity for oxygen o once one oxygen molecule connects to heme on one subunit, the affinity of heme for oxygen on all other subunits increases o the more oxygen attached to the heme, the greater the affinity of heme between heme and oxygen o haemoglobin, which is fully saturated with oxygen, is in the so-called R-conformation

Answer 374

- adult haemoglobin - HbA o HbA1 - α2β2 o HbA2 - α2σ2 - this is much less frequent (about 2% of total Hb adults) - Fetal haemoglobin - HbF o HbF - α2γ2 o HbF has a higher affinity for O2 than HbA - therefore the fetus is able to receive oxygen from the mother's blood even at lower partial pressure o physiologically occurs in the child's body up to 6 months of age

Answer 375

- occurs in bone marrow in erythrocyte precursors (not in erythrocytes themselves) - The 4 separate subunits are joined by non-covalent bonds to form the tetramer hemoglobin

Answer 376

o thalassemia - a hereditary disease with impaired formation of one of the type of Hb chains (both α and β- thalassemia exist) o Anaemia - anemia indicates a reduced ability of blood to carry O2 sideropenic anemia - lack of haemoglobin due to formation of abnormal haemoglobin HbS, point exchange of one amino acid (glutamic acid) for another (valine) - physiological concentration of Hb in the blood o women 120-162 g/l, men 135-172 g/l

Answer 377

- carries O2 and part of CO2 o partial pressure O2 - 100mmHg in arterial blood and 40mmHg in venous blood - partial CO2 pressure - 40mmHg in arterial blood and 46mmHg in venous blood - buffering blood - histidine residues in hemoglobin can take up free H + to form deoxyhemoglobin (HHb)

Answer 378

- as bicarbonate HCO3 - 70% - bound to hemoglobin - 23% o HCO3 reaction may take place, whereby bicarbonate then leaves the cell and instead closes (to maintain pH) Cl- o if CO2 is bound to haemoglobin, the whole molecule is called carbaminohemoglobin - loosely dissolved - 7%

Answer 379

Exchange of HCO3- and Cl- between plasma and erythrocyte in the lungs due to the Hamburger effect, HCO3 from plasma enters erythrocyte and Cl- from erythrocyte enters plasma

Answer 380

- CO2 escapes in the lungs, so there will be a more alkaline environment (pH7.6) -> alkaline environment together with increased pO2 stabilizes R- conformation thus increasing the affinity of hemoglobin for oxygen and enabling oxygen binding O2 - on the arrival of bicarbonate to the periphery releases H+ -> more acidic environment (pH 7.2) -> acidic pH together with higher temperature and increased pCO2 stabilize T-conformation, thus decreasing affinity of hemoglobin to oxygen and enable CO2 binding

Answer 381

a shift of the saturation curve to the right (lower affinity of hemoglobin to oxygen) at lower pH

Answer 382

- metHb - methaemoglobin- has Fe3 + instead of Fe2 + and therefore cannot transport oxygen - HbA1C - glycated haemoglobin - glucose-linked haemoglobin - COHb - carbonylhemoglobin/ carboxyhaemoglobin- in carbon monoxide poisoning - sulfhaemoglobin, cyanhemoglobin- occurs in poisoning with sulphate, hydrogen cyanide or cyanides

Answer 383

- CO has a 200x higher affinity for Hb than O2 - maximum allowed concentration in air is 0,003% - Consequences - Reduction of oxygen transfer capacity Hb, reduced oxygen supply of cells - the degree of CO intoxication depends on the pCO in the air and the duration of exposure

Answer 384

- heme is one of the iron-containing coenzymes (mainly reactive Fe2+ ion) o Fe2+ is extremely reactive, Fe3+ is poorly soluble at a neutral pH - Heme is a cyclic tetrapyrole – consists of 4 pyrrole nuclei, which are connected by methine bridges o various substituents are attached to the pyrrole rings o there is a system of conjugated double bonds in the heme, giving the molecule its red color o If we remove iron from the heme, it becomes porphyrin o If the iron in the heme is substituted with magnesium, the heme becomes chlorophyll

Answer 385

- the main components are glycine and succinyl-CoA - the first reaction takes place in the matrix, then the synthesis moves to the cytosol and returns to the last two reactions in the matrix

Answer 386

1. Step: glycine + succinyl-CoA -> 5-aminolevulinic acid (5-ALA) + CO2 + CoA o enzyme - ALAS (ALA Synthase) o cofactor – pyridoxal phosphate o It is a regulatory step of the synthesis 2. Step: condensation: 2x 5-aminolevulinic acid -> porfobilinogen + 2 H2O o enzyme - ALAD (ALA Dehydrogenase) 3. Step: deamination: 4 molecules of porfobilinogen join together to form hydroxymethylbilan the enzyme is porfobilinogen-deaminase 4. Step: cyclization: hydroxymethylbilan -> uroporphyrinogen 5. Step: Two step decarboxylation of substituents 6. Step: dehydrogenation: protoporphyrinogen -> protoporphyrin + H2 7. Step: Add iron: protoporphyrin + Fe2+ -> heme o enzyme - ferrochelatase

Answer 387

- a relatively short process o 1. Step: cleavage of the ring: heme -> CO + Fe3+ + biliverdin (linear tetrapyrrole) enzyme - heme oxygenase o 2. Step: reduction: biliverdin -> bilirubin - In the spleen, we form bilirubin by the degradation of heme -> it is an unconjugated (indirect) bilirubin, which is transferred via albumin into the liver, where it is conjugated with glucuronic acid, resulting in a conjugated (direct) bilirubin, which is soluble in water and excreted by bile out of the body

Answer 388

- Jaundice – symptom caused by a higher level of bilirubin in the blood o Prehepatic jaundice – the cause of jaundice is before/in front of the liver E.g. in conditions that cause an increased degradation of heme In the blood, there will be an increased concentration of indirect bilirubin o Hepatic jaundice – the cause of jaundice is in the liver E.g liver damage, typically cirrhosis In the blood, there will be increased concentrations both types of bilirubin o Post hepatic jaundice – the cause of jaundice is beyond the liver E.g. if the biliary tract is blocked In the blood, there will be an increased concentration of direct bilirubin

Answer 389

- porphyria o a common symptom of porphyria is photosensitivity - ALA Dehydrogenase – second enzyme in the synthesis of heme

Answer 390

- in nature, it mostly occurs in the form of Fe3+, but it is insoluble in water and therefore difficult to obtain o for life, we need Fe2+ which is very reactive and almost absent in organisms - in humans, iron intake is very closely regulated – it enters the body in the form of food in two forms o hemic iron – much easier to use o free iron (Fe3+) – must undergo treatment in the stomach

Answer 391

- for iron to enter enterocytes, it must be reduced from Fe3+ to Fe2+ o many things help with reduction, such as reducing agents (typically Vitamin C) and low pH o directly in the membranes we find DcytB (duodenal cytochrome B), which also reduces Fe3+ to Fe2+ - absorption into enterocytes occurs in the vast majority of the duodenum via using DMT1 transporters - in the enterocytes, iron becomes one of three things a) enterocyte uses this iron for its own metabolism b) iron is stored in a Fe3+ crystal form and the whole crystal is encapsulated by a ferritin protein c) is exported to the blood using ferroportin transporter - as soon as iron exports from the enterocyte into the blood, it is captured by its transporting molecule – transferrin o transferrin however transports iron in the form Fe3+, therefore it is necessary for Fe2+ to be oxidized, before it is bound to trasnferrin this oxidation is ensured by haphaestin directly during the excretion of iron from the enterocyte o transferrin has a great affinity for iron – at normal pH, transferrin and iron cannot be separated o each molecule of transferrin binds 2 iron molecules

Answer 392

- if the cell wants iron, it exposes the transferrin receptor on its surface - the receptor captures the transferrin that carries the iron, and the entire receptor-transferrin-iron complex is endocytosed - the resulting endocytic vesicle has proton pumps in the membrane that pump protons inside and drastically lower the pH - inside the endocytic vesicle, the pH drops to such an extent that iron from transferrin simply falls off and is transported from the vesicle to the cytosol, again using the DMT1 transporter o during this step, iron is simultaneously reduced back to Fe2+ - the receptor-transferrin complex is recycled back to the membrane, the transferrin is released without iron and travels through the blood again

Answer 393

- because of the effort required in nature to obtain iron, our body is set up to eliminate as little iron as possible - The only two ways to get rid of iron are by bleeding and through getting rid of cells (intestinal, skin) - There can also be too much of iron - for example, in multiple blood transfusions o In this case, chemical chelators come into play

Answer 394

- Takes place at the level of ferroportin - enterocyte can get stuffed with iron, but that does not mean that it is released into the blood - the frequency of ferroportins is influenced by the hepatic hormone hepcidin (hepcidin promotes the degradation of ferroportins) o The liver produces hepcidin in response to iron levels in the body o hepcidin production is impaired in hereditary hemochromatosis - degradation of ferroportins does not work and over time toxic amounts of iron accumulate in the body

Answer 395

- takes place at the level of post-translation adjustments - IRP (iron response element binding protein) - protein, which binds to iron response element IRE o IRP1 - as FeS cluster, where iron is bound, if there is a lot of iron in the vicinity (and therefore if there is little iron in the surroundings, iron will not be bound to FeS cluster) when iron falls off the FeS cluster, a conformational change will occur allowing IRP to bind to IRE - the effect of IRP binding to IRE depends on the location of the IRE on the mRNA o if the IRE is upstream of the coding sequence an IRP that sits on the IRE would block the translation of that mRNA strand and thus the presence of IRP on the IRE would have an inhibitory effect o if the IRE is downstream of the coding sequence , an IRP that sits on the IRE would block degradation of this mRNA strand and hence the presence of IRP on IRE has a stimulating effect

Answer 396

- Stopping bleeding - it is a protective mechanism to heal damage in the blood circulation - the fluidity of the blood and the intact and (unwettable) endothelium are prerequisites for continuous circulation - haemostasis, however, also has negative effects - blood clots can form on the surface of atheroma plaques (atheroma or atherosclerotic plaque is the deposition of fat on the inside of blood vessels), which can even completely clog the vessel - sepsis or tumors may cause haemostasis

Answer 397

- haemostasis is a broader term and encompasses all stages of haemostasis 1) reflex vasoconstriction - blood vessels immediately contract when breached to reduce bleeding rate 2) platelet activation and aggregation - a precursor of blood clotting, enough to cover small defects 3) haemocoagulation- soluble fibrinogen is converted to fibrous insoluble fibrin and with platelets forms a network o The result is a blood clot on the wound surface o Thrombin catalyzed o This is where the coagulation cascade takes place 4) blood plasma proteins break down by platelets and fibrin fibres = thrombolysis

Answer 398

- they are nuclear-free fragments of megakaryocytes (biconvex disks) without their own proteosynthetic apparatus - everything they have in them is prepared in advance - the central zone with granules is the granulomere, the peripheral lighter zone is the hyalomer o granulomer contains mitochondria, glycogen and granules δ (delta) granules dense bodies, containing ATP and serotonin α (alfa) granules - specific platelet clotting factors (fibrinogen, PDGF, FGF, von Willebrant factor, factor IV) λ (lambda) granules - lysosomes in general, substances contained in granules are used in vasoconstriction, haemocoagulation and repair o hyalomer-is formed by membrane invagination and forms a system of channels that are important for the secretion of signaling molecules contains, for example, enzymes for the formation of eicosanoids

Answer 399

- platelets are nuclear-free = no proteosynthesis - aerobic metabolism - through their mitochondria, they process their reserves of glycogen - the cytoplasm contains o microtubules, actin and myosin - a contractile apparatus that allows platelet contraction and granule release o phospholipids - necessary for activation of some coagulation factors o glycoproteins - allow platelets to attach to a damaged vessel wall and prevent attachment to a healthy wall

Answer 400

- participates in the whole course of haemostasis, but play a crucial role in the so-called primary haemostasis 1. Adhesion - binding to injured subendothelial collagen o GP binding (platelet glycoprotein receptor) and vWF (von Willebrand factor) 2. Activation - Platelets activate exposed collagen, thrombin, ADP, PAF and TXA2 o positive feedback - activated platelets produce TXA2, activating additional platelets o expression of GP IIb / IIIa receptors, which allow platelets to interact well with each other o Plate shape change - contractile proteins and cytoskeleton ensure a shape that best covers the wound space 3. Aggregation - through thrombin and other substances it connects through fibrinogen o primary (reversible) aggregation - necessary for ever-forming gaps in the endothelium and healing of small defect o secondary (irreversible) aggregation - associated with a release reaction (degranulation) 4. Degranulation (secretion reaction) - secretion of granule content 5. Formation of white (platelet) thrombus- such a temporary haemostatic plug o the breakdown and fusion of platelets occurs (viscous metamorphosis) 6. Connection with coagulation - platelet phospholipids are expressed on the surface, which promotes coagulation 7. Wound healing - platelets secrete substances with proliferative effects, eg Platelet Derived Growth Factor (PDGF)

Answer 401

- old model is more suitable for in vitro measurements (in laboratories) - the new (revised) model is valid in vivo

Answer 402

- Most are produced in the liver - according to their different function in the process of blood clotting we can divide them into 5 basic groups o 1. Serine proteases, that catalyze partial proteolysis of coagulation factors o 2 proteins serving as cofactors of enzymes o 3. Ca2+ (factor IV) - helps to bind some coagulation factors to membrane phospholipids o 4. fibrinogen (factor I) precursor of the fibrin network o 5. transglutaminase (factor XIII) - stabilizes the fibrin network

Answer 403

- Vitamin K enables posttranslational carboxylation of glutamate residues in γ-carbon to form γ-carboxyglutamates (Gla) - some blood thinners work as non-functional vitamin K analogues – e.g. Warfarin

Answer 404

- haemocoagulation occurs when platelet-mediated primary hemostasis is not sufficient - has two phases - activation of factor II (internal or external, that is one) and formation and stabilization of insoluble fibrin o internal and external phases meet at the site of coagulation factor X

Answer 405

- initiated by tissue thromboplastin (factor III; tissue factor) o thromboplastin - a mixture of proteins and phospholipids released from damaged cells or released by activated endothelial cells and leukocytes - the external pathway is important for the onset of blood clotting - the internal pathway is important for the amplification of haemocoagulation

Answer 406

- initiated by contact phase - negatively charged surface (injured exposed collagen and platelets membranes) activate f. XII to XIIa

Answer 407

- substrate - prothrombin (f. II) - the product of the prothrombinase complex is thrombin (IIa)

Answer 408

- central position in the whole haemostasis - ensures coagulation, anticoagulation, regulation of fibrinolysis and activation of cellular components - cleaves fibrinogen into fibrin - activates o platelets and endothelium o Neutrophils and monocytes - they express tissue factor on them o factor XIII that provides stabilization of the fibrin network o factors V, VIII and XI that amplify coagulation o and with the help of thrombomodulin, thrombin also activates protein C -> anticoagulation

Answer 409

- tissue factor (TF) and VIIa ((so the extrinsic pathway) starts coagulation

Answer 410

- thrombin activates platelets and leukocytes that express negatively charged phospholipids on the surface - the result of amplification is o more thrombin o the creation of reaction surfaces with bound activated factor molecules for complementing the internal tenase and prothrombinase complexes

Answer 411

- consists of 3 globular domains (two peripheral D domains and one central E domain) o domains are connected to each other by 2 rods (triple helix α, β, γ) o there are 2 peptide tails on the central domain - fibrinopeptides A and B (from α, β helix) Thrombin cleaves both fibrinopeptides, to form fibrin monomer, which spontaneously polymerizes to form fibrinpolymer

Answer 412

- there is a need to maintain a balance of procoagulation and anticoagulation processes - major anticoagulant factors o blood flow- makes it difficult to concentrate coagulation factors in one place o endothelial cells - produce prostacyclin, NO and thrombomodulin o antithrombinIII o protein C a protein S

Answer 413

it is an α2-globulin, the most important inhibitor of coagulation - belongs to serpins - acts as an inhibitor of serine proteases - binds and inactivates thrombin and factors IXa, Xa, XIa and XIIa o heparin (sulphatedGAG) increases the ability of AT III to bind factors - congenital AT III deficiency - thrombophilic condition

Answer 414

- slows the blood clotting process by eliminating non-enzymatic coagulation factors Va and VIIIa - vitamin K dependent - protein S is a cofactor of protein C - protein C is activated by thrombin-thrombomodulin complex to activated protein C (APC) o APC cleaves non-enzymatic factors Va and VIIIa upon binding to phospholipids o without Va and VIIIa is a dysfunctional inner tenas and prothrombinase complex

Answer 415

- AD hereditary mutation, manifested by increased blood clotting - by this mutation one of the cleavage sites disappears from the Va - this leads to the APC cleaving Va much more slowly - the most common congenital thrombophilic condition - people with this mutation are at risk if combined with other procoagulant factors such as hormonal contraceptives or cigarettes

Answer 416

- removal of free Ca2 + ions by means of citrate, EDTA or oxalate - this principle is used eg for collecting non-coagulated blood for laboratory processing - heparin strengthens AT III - binds thrombin - vitamin K analogues - coumarin preparations (warfarin, pelentan) block posttranslational modifications dependent on vitamin K

Answer 417

- blood plug cannot stay in the body forever - therefore there are mechanisms by which the body removes the coagulum – fibrinolysis - the principle is the cleavage of the insoluble fibrin network into soluble fibrin-degradation products by the action of the enzyme plasmin o plasmin is derived from plasminogen and, when activated, acts as a serine protease specific for fibrin and fibrinogen

Answer 418

- their job is to eat a foreign organism, kill it and then die o that is why, neutrophils are equipped with hydrolytic enzymes within their numerous lysosomes - have few mitochondria - are glucose dependent due to NADPH production o NADPH is used to produce reactive oxygen species for more reliable killing of bacteria - respiratory burst- such enrage of neutrophils, when with increased consumption of O2 and glucose, neutrophils start to produce huge amounts of free radicals to annihilate anything they have just engulfed - in addition, nitrous oxide is also produced in neutrophils to kill bacteria o arginine-> citrulline+ NO enzyme - nitric oxide synthase o this can be dangerous in large infections - neutrophils can produce up to toxic amounts of NO, leading to septic shock

Answer 419

o Proteases- serve as a homing beacon for neutrophils, produced by phagocytic cells elastase, collagenase, cathepsin G o Protease inhibitors- they are plasma proteins α1-antitrypsin, α1-antichymotrypsin, α2-makroglobulin o The protease / anti-protease ratio affects the rate of inflammation

Answer 420

- forms 55 - 60% of body mass - women have less water than men (because they have more fat) - small children and pregnant women have a higher WBW - in older people, total body water decreases - we distinguish between two components of WBW o intracellular fluid (ICF) - forms 2/3 WBW o extracellular fluid (ECF) - forms 1/3 WBW intravascular fluid (IVF) – found in vessels (plasma and lymph) and forms 1/4 ECF interstitial fluid (ISF) – tissue fluid, forms 3/4 ECT

Answer 421

- plasma is blood after the removal of cells o anticoagulants (calcium binding agents e.g. citrate) and centrifugation is used to separate blood elements from the plasma o we can conduct blood clotting tests on plasma (as it contains coagulation factors) o examination of blood plasma is used in emergency/urgent medicine o „-aemia" = concentration of something in the plasma/blood - serum is a liquid without clotting factors o serum is suitable for most biochemical tests; therefore, it is most often used compared to plasma o „-rrhachia“ = concentration of something in cerebrospinal fluid

Answer 422

- water (up to 92%) – free or hydrating (bound to molecules) - low molecular weight components - ions (minerals), energy substrates, metabolites - high molecular weight components - proteins, lipoproteins

Answer 423

osmolarity is usually not measured, but it is calculated from an imperfect formula, which assumes that osmolarity is mainly influenced by low molecular weight (LMW) components o from each group of low molecular weight components (ions, nutrients, metabolites) we take the main one and form a formula o 2 * Na+ (twice because ions are positive and negative) + urea (most common metabolite) + Glc (most common nutrient) o osmolarity is regulated mainly by the pituitary gland via antidiuretic hormone (ADH)

Answer 424

difference between measured and calculated osmolarity o calculated osmolarity is not accurate, most often it comes with discrepancies o physiological value of the osmolar window is 4 - 12 mmol/l o high OG means there is an unfamiliar, osmotically active substance in the blood, which is interfering with our balance - helps us determine if a patient underwent poisoning - headaches when drunk - firstly hyperosmolarity, then hypoosmolarity

Answer 425

- Water and urea pass freely between cells and blood. The problem lays in other substances. - e.g. glucose and Na+ are trapped inside cells, therefore their concentration in blood does not reflect their situation/concentration inside cells.

Answer 426

- isotonic solutions have approximately the same osmolarity as plasma o balanced solutions – Ringer or Hartman solutions – their compositions resemble that of plasma in all aspects - it is important to respect the tonicity of solutions administered to patients, because the water content in blood interferes with the water content in cells o hypotonic environment (high amount of water in blood) – water enters cells, which then bulk up o hypertonic environment (low levels of water in blood) – water exits cells, which then shrinks

Answer 427

o rapidly receiving a large number of cells leads to: swelling of brain bad blood flow into the brain o rapidly decreasing the osmolarity leads to decrease in cell volume – typical is the damage to myelin sheath in the pontine region of the brain (so-called pontine demyelination) o motor and sensory problems

Answer 428

- cations - Na+, K+, Ca2+ - anions – mainly Cl-, HCO3 - and in lower concentrations also HPO42-, HSO4- - metabolites - urea, creatinine, uric acid, bilirubin - nutrients – glucose, fatty acids, ketone bodies - others - vitamins, hormones, xenobiotics... - law of electroneutrality: there must be a balance between anions and cations - anion gap (AG) = other anions which are not Cl- or HCO3- o AG = (Na+ + K+) - (Cl- + HCO3-) o Increases during the overproduction of ketone bodies in the body

Answer 429

- Main cation of ECF (135 mM - 145 mM) - Along with Cl-, it is responsible for 80% of the osmolarity of the plasma Æ binds water Æ determines the volume of plasma - sodium + water Æ blood pressure - hormones regulating natremia (concentration of sodium in blood) o aldosterone – increases the reabsorption of sodium in kidneys o atrial natriuretic polypeptide (ANP) – decreases the reabsorption of sodium in kidneys produced by the heart (heart produces hormones) increases the secretion of Na+ and water into urine, thus reducing the total blood volume decreases blood pressure

Answer 430

- main anion of ECF (97 - 108 mM) - accompanies sodium – maintains osmolarity and decreases pH - important for maintaining acido-basic balance (ABR) - chloride anion co-forms gastric juice (hydrochloric Acid - HCL) - neutrophil granulocytes produce hydrochloric acid during respiratory bursts from free blood Cl- and H+

Answer 431

- typical ICF cation - 98% in ICF (c = 155mM), only 2% v ECF (c= 3.8 - 5.2 mM) o this gradient is extremely important due to the role it plays in the membrane potential o together with magnesium it is one of the main ICF cations - potassium is important especially in excitatory tissues, especially the heart, where hyperkalaemia is more dangerous than hypokalaemia

Answer 432

- largest gradient – its level in ECG is 10 000x higher than in ICF o ECF (2.25 - 2.75 mM) - In plasma occurs in free (ionized) and bound fractions o ~46% Ca2+ binds to plasma proteins (albumin) o ~6% Ca2+ form complexes with small anions (HCO3-, citrate, lactate...) o ~48% Ca2+ forms free (ionized fractions) which are the only physiologically active ones - fractions ratio (during constant total calceamia) affects o pH – increase in pH (e.g during hyperventilation) leads to the decrease of free (ionised) Ca2+ Æ convulsions o proteinemia - loss of proteins Æ decrease in bound fraction

Answer 433

- regulation of Ca2+ o to increase calcaemia: parathormone and calcitriol o to decrease calcaemia: calcitonin - significance of Ca2+ o stabilization of membranes of excitatory tissues o muscle contraction (no muscles contract in the absence of calcium) o haemocoagulation – activates coagulation factors o necessary for lactation o part of inorganic bone matrix (hydroxyapatite)

Answer 434

- concentration in blood ( 22 - 26 mM ) - bicarbonate is an important blood buffer - it forms half of the blood buffer capacity - its concentration decreases during the increase of ketone bodies

Answer 435

- glucose = 3.3 - 5.6 mM - fatty acids = 0.6 - 1.7 mM o the longer the chain, the more albumin is needed for transport in blood o the high molecular weight molecules “lipoproteins” transport other lipids - ketone bodies o similar to glucose, so they are water soluble and transport freely in blood o concentration of 3-hydroxybutyrate < 0.5 mM o when concentration of 3-hydroxybutyrate > 3 mM Æ KETOACIDOSIS - amino acids = 2.3 - 4.0 mM o Mainly: Glutamine (Gln = 0.6 mM) because it carries ammonia in blood o and Alanine ( Ala = 0.3 mM)

Answer 436

- ammonia (12-50 μM) o most of ammonia comes from deamination of AA - urea (2,5-8,3 mM ) o occurs in the body in high concentrations, is formed in the liver - creatinine (50-120 μM) o it is a waste product from muscle metabolism o itself is not harmful o high creatinine is a sign that something is wrong in the body o if it is in excess “gout” is formed, at higher concentrations it starts to crystalize Æ arthropathy - bilirubin (17 μM) o waste product of haemoglobin metabolism o during bilirubinaemia above 40μM there is jaundice o bilirubin depletes albumin binding capacity and begins to diffuse into tissue

Answer 437

Lipoproteins and proteins

Answer 438

- fatty acids with short chains (up to 12C) can freely move in plasma, longer fatty acids need to be bound to a transporter protein albumin - other lipids need to be distributed by lipoproteins - lipoproteins are composed of lipids and proteins o In the core of lipoproteins are non-polar substances triacylglycerol’s (TAG) and cholesterol esters (CE) o Surface of lipoproteins consists of Phospholipids Apoproteins Cholesterol

Answer 439

- The total plasma concentration ("total proteins") ranges from 60 - 80 g/l - Plasma proteins are synthesized in the liver (except for immunoglobulins, which are formed by plasma cells) - Function of plasma proteins: o maintaining oncotic pressure at around 25 mmHg or 2.2 kPa) o taking part in hemocoagulation and fibrinolysis o immunity: antibodies, complement cascade, and acute phase reactants o transporting poorly water-soluble substances o buffer of blood o are antioxidants o diagnosis of diseases (enzymes- creatinine kinase, markers) - plasma proteins are divided based on serum electrophoresis ( which is separation according to mobility in an electric field) o using agarose gel as a medium yields 5 to 6 fractions 1) albumin 2) alpha-1 fraction 3) alpha-2 fraction 4) beta fraction (sometimes divided into beta-1 and beta-2 fractions) 5) gamma fractions

Answer 440

o Sits on the border of permeability of glomerular filtration membranes. o During the destruction of the membrane, albumin is the first plasma protein to filtrate into the urine - forms 60% of all plasma proteins - 35 - 53 g/l - function of albumin o maintaining oncotic pressure of plasma (oncotic pressure is the osmotic pressure caused by proteins) albumin forms up to 75% of its value hypalbuminaemia= leakage of fluid into the intestine, causing swelling “storage” of proteins half-life is 21 days (takes a while before changes in its level take effect) buffer transport of substances albumin is the most important transporter of substances in the plasma it takes part in the transport of unconjugated bilirubin, fatty acids, thyroid hormones, Ca, Mg, Zn, drugs...

Answer 441

- α1-antitrypsin o protease inhibitor o belong to APPs/RAF (acute phased reactants) - α1-fetoprotein (AFP) o used in prenatal diagnostics o in adults with carcinoma of liver, there are high levels of it

Answer 442

- haptoglobin – binds free haemoglobin, APPs - ceruloplasmin – main transporter protein of Cu, Fe2+ -> Fe3+ - α2-makroglobulin – protease inhibitor

Answer 443

- protein transferrin o transmits Fe3+ o without a bound iron o acts as an antioxidant - C-reactive protein (CRP) o APP – normal concentration is below 10 mg/l, during acute bacterial inflammation its level increases rapidly o Binds substance C of Streptococcus pneumonia - fibrinogen o belongs to coagulation factors (factor I o APP - hemopexin o secure binding o transport of free heme

Answer 444

- produced by plasma cells (the only plasma proteins that are not synthesized in the liver) - their structure consists of two pairs of heavy and two pairs of light chains interconnected by S-S bridges - we differentiate between 5 classes of gamaglobulins, based on their heavy chains – IgG, IgA, IgM, IgD and IgE

Answer 445

during the damage and breakdown of cells, intercellular enzymes are released into the ECF and these enzymes can be found in the plasma - we determine the activity [μkat/l], which is the measure of tissue damage – the more IC proteins in ECF, the higher the damage - the problems lay in the specificity – the same enzyme is released from multiple tissues, but some are tissue-specific o liver tests ALT – alanine-aminotransferase, from cytoplasm ASP – aspartate-aminotransferase, from mitochondria GMT a ALP - gama-glutamyltransferase and alkaline phosphatase, mainly from cells around the gallbladder o Heart examination - CK (creatine kinase) and isoenzyme CK-MB (myocardial specific creatine kinase) AST, LDH (lactase dehydrogenase)- only historical significance o Pancreatic examination – pancreatic amylase and lipase o muscles - CK (creatine kinase)

Answer 446

Connective tissue is composed of cells and a significant amount of intercellular matter, which is divided into interstitial fluid and extracellular matrix - each type of connective tissue has different proportions of these components

Answer 447

- Different connective tissue – connective tissue proper / cartilage / bone / adipose tissue - functions o supporting (support and connection) and nourishing (some tissues do not contain blood vessels, they obtain nutrients by diffusion from connective tissue) o storage of metabolites - fats, minerals (calcium in bone) o defence- immune and inflammatory response o Reparation after damage - Characteristics o large amounts of extracellular matrix and few cells o Presence of blood vessels and good regeneration (except for cartilage) o origin from embryonic connective tissue = mesenchyme

Answer 448

cells- contain Vimentin protein in their intermediate filaments o fixed- fibroblasts, reticular cells, fat cells Fibroblasts are cells that produce reticular fibers o mobile - macrophages, plasma cells, mast cells, white blood cells - extracellular matrix = ECM o fibrillar component- made up of fibers - collagen / reticular / elastic fibers Collagen and reticular fibers are both collagen but stain differently o amorphous component- glycoproteins (thin fibers), proteoglycans (huge molecules, bind water) and tissue tissue

Answer 449

- a bundle of parallel collagen fibrils - one collagen fibril is a triple helix of 3 peptide chains - the individual fibrils are secreted separately into the extracellular mass and joined together there - the most common types of collagen are I, II and III, but there are about 28 of them - strong when pulled on (like a steel wire) - used to attach or form a net

Answer 450

- composed of thin bundles of collagen fibrils (mainly type III) - form networks around cells of parenchyma organs, capillaries, fat cells, muscle fibers, - are part of the basal lamina (specifically lamina fibroreticularis) - staining- AgNO3 - reticular fibers are called argyrophils because of their affinity for silver

Answer 451

- formed by elastin surrounded by microfibrils - staining- resorcin-fuchsin, orcein -> turns brown-violet - unlike collagen fibers, they have a rubber-like function -> they can be reversibly stretched and normally return to their original state after deformation - elastin has specific amino acids - desmosin and isodesmosin, which form cross bridges between elastic fibers - elastin synthesizes fibroblasts on their ribosomes as a globular tropoelastin consisting of two secondary structures (β- spiral and α-chain) and is subsequently secreted from the cell o immature elastic fibers arise after interaction of elastin and microfibrils (which are made up of fibrilin protein), which form mature elastic fibers by aggregation fibrilin can also occur independently to elastic fibres, for example, in the eye apparatus

Answer 452

spindle cell with oval nucleus (only the nucleus is often seen in the specimen) - fibroblast is active cell, fibrocyte is inactive cell (in G0 phase, easy to activate and divide) - produces both fibrous and amorphous matter o proteosynthetically active - light nucleus with nucleoli, basophilic cytoplasm, GER and GA - collagen, elastin, proteoglycans and glycoproteins - myofibroblast- modified fibroblast, actively forms extracellular matrix and shows similarities to smooth muscle cells (has a lot of actin fibres) = tissue with myofibroblasts is capable of long-term contraction

Answer 453

- contains hydroxyproline, hydroxylysine, glycine -> characteristic of collagen 1. The mRNA, after leaving the nucleus, associates with a ribosome and translation occurs 2 A preprocollagen protein is synthesized, which carries a signal sequence that sends the entire protein to RER immediately after generation 3 In RER, the pre-collagen will become a procollagen by post-translation modifications o cleavage of the signal sequence o hydroxylation of proline and lysine amino acids to hydroxyproline and hydroxylysine (cofactor Vitamin C) o glycosylation of hydroxylysines formed in the previous step (glucose or galactose attached) o after glycosylation, the 3 chains are joined together to form a left-handed triple helix of procollagen 4. procollagen continues to Golgi apparatus, where it adds an oligosaccharide to it, envelops it with a vesicle and sends it out of the cell 5 Once the procollagen is outside the cell, the membrane enzymes of the procollagen peptidases capture the procollagen and cleave its free globular ends (shortening it) - what remains is called tropocollagen 6. enzyme lysyl oxidase ((extracellular copper-dependent enzyme) mediates bonds between several tropocollagen o polymer of tropocollagen is collagen

Answer 454

- collagen I. – done, tendon, teeth, skin - collagen II. - hyaline and elastic cartilage - collagen III. - reticular lamina and reticular fibers - collagen IV. - basal lamina - collagen V. - chorion and amnion - descending by size - collagen I. is the thickest, each next is thinner than the previous one

Answer 455

- vitamin C - necessary for hydroxylation of collagen, a problem in scurvy - Ehlers-Danlos syndrome skin hyperelasticity and joint hypermobility due to lack of procollagen peptidase or lysyl hydroxylase (no cross-bridges and therefore no collagen polymerization) - Marfan syndrome - autosomal dominant defect of fibrilin, myopia (nearsightedness), ectopia (occurrence beyond its usual site) lenses, skeletal defects, arachnodactyly, mitral valve prolapse, dilatation of the aorta ascendens

Answer 456

- also, known as amorphous matrix - fills the spaces between the fibers - glycoproteins- fibronectin, chondronectin, laminin... - glycosaminoglycans (GAG) - chondroitin sulfate, heparan sulfate, dermatan sulfate, keratan sulfate o Hyaluronic acid - forms a skeleton to which other components bind - proteoglycans- aggrecan, perlecan, versican, syndecan - core protein and GAG

Answer 457

- long chains from disaccharide units - consist of alternating hexosamine and uronic acid - sulfonated, attached by covalent bonds to the protein - chondroitin sulphate (cartilage), dermatan sulphate (dermis), keratan sulphate (cornea), heparan sulphate (liver)

Answer 458

- abbreviation HA (hyaluronic acid) - consists of 250 - 50 000 disaccharide subunits - it is neither sulfonated nor bound to a protein - has a huge volume in aqueous solution, forming a viscous gel - function o viscous gel - water supply, turgor retention, joint lubricant o connects proteoglycan molecules into proteoglycan aggregates o interacts with cell surface receptors, thereby stimulating migration and proliferation - biosynthesis - formed by the enzyme HA synthase, which is fixed on the inner surface of the cell membrane

Answer 459

- Linear polysaccharide composed of a core protein to which glycosaminoglycans (GAGs) bind - attaching a lot of proteoglycans to hyaluronic acid creates a proteoglycan aggregate - proteoglycans have the appearance of bottle-washing brushes - binds water and growth factors - they are components of the basal lamina

Answer 460

- the extracellular matrix is attached to the cells by integrins - integrins- receptors for extracellular matrix molecules, components of hemidesmosomes, and focal adhesions - inside the cell integrins are attached to cytoskeletal fibres (paxillin, vinculin, talin, β-catenin))

Answer 461

- is not completely stable and must be adjusted - degradation and remodelling of ECM is done by Metalloproteinases (MMP) collagenase, cathepsin, stomelysin, gelatinase o Metalloproteinases are lysosomal enzymes produced by various types of cells, including macrophages - Importance- invasion of microorganisms (streptococci) - enzymes enable crossing through extracellular matrix o in the invasion of tumors, the basement membrane will be degraded (cells lose integrins) and thus the attachment of cells to the basal laminate will be lost

Answer 462

- occurs after tissue damage or trauma - healing and scar formation o a blood clot is formed immediately after injury, platelets release growth factors and cytokines o the first neutrophils and macrophages enter the wound to kill bacteria and tissue debris o The process of granulation - proliferation of fibroblasts and blood capillaries through damaged wound sites o some fibroblasts turn into contractile myofibroblasts, bringing the wound edges closer o At the same time, re-epithelialization occurs - the epithelial cells travel from the wound edges towards the center until the entire wound area is covered and a new basement membrane is formed (which takes about 5 days) o finally, myofibroblasts disappear by apoptosis - scar retraction - scar reduction / retraction - pathological but commonly occurring phenomenon (myofibroblasts remained functional for too long)

Answer 463

- phagocytic cells - contain lysosomes and phagosomes (vacuoles) - accumulate vital dyes - trypan blue, ink (dark blue) - function - break down fibres and other components of intercellular matter o they are part of the immune system - they are among the antigen presenting cells (MHC II, more in the 3rd course) o produce signalling molecules (cytokines) - interleukin 1, TNF-α - macrophages are formed by conversion from monocytes o monocytes are formed in the bone marrow and are washed out into the bloodstream, after about 8 hours they enter the tissues and there they turn into macrophages o tissue macrophages then show numerous heterogeneity depending on the tissue and are therefore called differently in each tissue histiocyte in connective tissue, osteoclast in bone, microglia in nerve tissue, Kupffer cells in liver, Langerhans cells in skin

Answer 464

- arise from bone marrow - have an oval shape and an oval core, are basophilic - contain a large number of granules, by which they gain their basophilicity - their granules contain vasoactive mediators - histamine, heparin and leukotrienes (chemotactic mediators of inflammation) - metachromatic granule - characteristic of some basic dyes, dye changes its colour after binding to some biological tissue (eg blue dye binds to metachromatic granule and turns black) o granules are metachromatic due to the high content of acid residues in heparin glycosaminoglycan - responsible for the immune response and early allergic response - mast cell types o mucosal mast cells (lungs and intestine) - smaller, containing chondroitin sulphate o connective mast cells - functions- they are mostly negative, but there are exceptions (for example, they can inactivate snake poisons) o histamine secretion (causes itching in the swelling) & heparin ((prevents the formation of thrombus in the swelling) o produce cytokines, growth factors and arachidonic acid derivatives - activation- antigen binding to IgE receptor - allergic reaction -> effector cells of early type allergic reaction - synthesis of inflammatory mediators - prostaglandins and leukotrienes

Answer 465

- nucleus is placed eccentrically (wheel/kernel shaped nucleus, imagine a 300-year-old wheel on a car) - striking nucleus, lumps of heterochromatin sit on a nuclear envelope - arises from activated B-lymphocyte – immunoblasts - they have almost no cytoplasm, but after activation they turn into large cells by immunoblasts - photosynthetically active - GER a GA - production of antibodies - ach plasma cell has its own antigen against which it produces antibodies - in mucosal tissue, in immune organs

Answer 466

- embryonic - mesenchyme, jelly-like tissue (Warton’s jelly) - adult - collagenous connective tissue (dense / thin), reticular connective tissue, elastic connective tissue - specific - brown and white adipose tissue

Answer 467

- mesenchyme- embryonic tissue with star cells and a small amount of extracellular matrix o consists of glycoproteins and hyaluronic acid, which allows easy cell migration o is the basis for the development of all types of binders, blood elements and blood vessels (blood and lymphatic) - Wharton jelly- fetal connective tissue, collagen V, hyaluronic acid o mostly amorphous matter, less fibres, almost no cells o occurs in all fetal tissues - placenta, chorion, umbilical cord, ...

Answer 468

loose - cells and less fibres - occurrence eg in lamina propria, perimysium in muscles, etc. - dense - more fibers and fewer cells o regular - tendons (connection of muscle and bone), fascia ((connective tissue muscle), aponeurosis (flat tendon) o irregular - dermis - tendons - transfer of tension between muscles and bones o matrix - collagen fibres, less elastic fibres and proteoglycans o between the fibres there are rows of spread fibroblasts and tendinocytes (tendon cells) that are interconnected by gap junction o tendons are wrapped with a layer of thin ligament (epitenonium), from which extend into the septum from the thin ligament (peritenonium), which divides the tendon into bundles of fibres Nerves and blood vessels enter the tendon through the septum

Answer 469

- bundles of branched elastic fibers accompanied by small amounts of collagen fibres and fibroblasts - there is less collagen in the elastic ligament and there are thinner types of collagen

Answer 470

- three-dimensional mesh made up of fibroblasts (called reticular cells) and fibers (collagen III) o suitable environment for haemopoesis and lymphatic organs (red bone marrow, spleen, lymph nodes) - reticular connective tissue is sparse at the blood site, dense at the accumulation of cells - the reticular fibers themselves may also be present outside the connective tissue - for example in the basalis laminate

Answer 471

- low intercellular matter, fat cells predominate, separated by fibrous septa White adipose tissue and brown adipose tissue

Answer 472

- consists of adipocytes - the nucleus is flattened and placed eccentrically (off centre); - the connective tissue is richly vascular - hormonal control - insulin, catecholamines, prostaglandins - adrenaline stimulates lipolysis - can deactivate perilipine - insulin stimulates fat storage - function- energy supply, insulation against heat loss (not important in humans), filling free spaces (organ fixation), mechanical pressure absorption (structural fat) and synthesis of signalling molecules and hormones

Answer 473

- adipocytes are multivacular - they contain many fat droplets - inside the cell, the core is stored in the middle of the MIT - present in foetuses and newborns - between shoulder blades, back of neck o in small quantities, even in adults - rich vascular supply and sympathetic noradrenergic innervation - function - thermogenesis - thermoregulation in newborns o uncoupling protein 1 - uncovering protein thermogenin - heat is generated in MIT instead of ATP o animals have a lot of brown fat just because of thermogenesis - mainly bears and others who resort to winter sleep

Answer 474

- Forms and maintains shape of body - forms an extracellular matrix that connects and binds cells and organs o The extracellular matrix is the major component of connective tissue o Has fibrillar (fibrous) component, amorphous (glycosaminoglycans) component and tissue fluid (water) o the connective cells are embedded in it - connective tissue thus contains cells (connective cells, fibroblasts ...), fibers and amorphous matter in different proportions, which creates differences between individual types of connective tissue (e.g. bone, adipose tissue, cartilage, vitreous gel...) - a large part of the tissue is always ECM and the cells are scattered in it

Answer 475

- structural - creates capsules enveloping organs, tendons, ligaments and thin ligament o Bone, adipose tissue and cartilage are specialized types of connective tissue - immune - phagocytic and immunocompetent cells, antibody producing plasma cells - nutritional - environment for metabolite exchange between cells and blood circulation, - animal connective tissues are highly variable o tendon and skin range are firm and elastic, bone is hard and dense, cartilage absorbs impacts and is elastic,eye jelly is soft and transparent - in all these cases a large part of the tissue is made up of the extracellular matrix (ECM) and the cells are scattered in it

Answer 476

- in other tissues the amount of ECM is insignificant, but in connective tissue the ECM is the most important part of the whole tissue o e.g. ECM is responsible for kidney filtration properties - it creates a glomerular membrane that is negatively charged and repels positive charges o ECM also minimizes joint friction and allows cell movement - variability is determined by the type of collagen, its amount and the presence of other molecules

Answer 477

- determines the shape of the tissues by binding the cells and filling the space between them - some embryonic cells must migrate through the ECM - Biochemical changes in ECM occur during inflammation and aging - ECM also plays a role in metastasis - allows cancer cells to migrate into blood and lymphatic circulation - ECM molecules are involved in rheumatoid arthritis and osteoarthritis

Answer 478

- Structural proteins - collagen (tensile strenght) - specialized proteins (adhesive proteins) - fibronectin, laminin and elastin (fibrous protein) - proteoglycans- consist of GAGs attached to protein core - proteoglycans can bind in bulk to hyaluronic acid and thus form a proteoglycan aggregate

Answer 479

- Structural proteins - collagen (tensile strenght) - specialized proteins (adhesive proteins) - fibronectin, laminin and elastin (fibrous protein) - proteoglycans- consist of GAGs attached to protein core - proteoglycans can bind in bulk to hyaluronic acid and thus form a proteoglycan aggregate

Answer 480

Collagen fibers - accounts for about 25% of all mammalian proteins - the most abundant protein in our body - is present in discontinuous connective tissue, bones, tendons, skin, veins and opaque sclera o contains 33 % glycine ,21 % proline and hydroxyproline as well as lysine and hydroxylysine - Mammals have many different types of collagen - are produced by different cell types, but most by fibroblasts - the structure of one molecule of collagen (tropocollagen) is in the form of a right-handed triple helix and consists of smaller molecules - three left-handed peptide helixes - 1 tropocollagen consists of about 1,000 amino acids - every third amino acid is glycine o the other two important molecules of collagen are 4-hydroxyproline (or 3-hydroxyproline - both containing an amino group = an amino group in the ring) and 5-hydroxylysine

Answer 481

collagen is synthesized on ribosomes as a precursor preprocollagen - the signal sequence introduces it to GER, where preprocollagen is changed to procollagen by posttranslational modifications o cleavage of the signal sequence o hydroxylation of proline and lysine amino acids to hydroxyproline and hydroxylysine enzymes lysyl hydroxylase and prolyl hydroxylase with cofactor Vitamin C o glycosylation of hydroxylysines formed in the previous step (glucose or galactose attached) o after glycosylation, the 3 chains join and together form a left-handed triple helix of procollagen by creating disulphide bridges between individual molecules - thanks to SH groups of cysteines o At this point, procollagen is long and has untangled ends rich in cysteine - procollagen continues to Golgi apparatus, which adds oligosaccharides to it, envelops it with a vesicle and sends it out of the cell - once the procollagen is out of the cell, the membrane enzymes capture it and cleave its free globular ends (thus shortening it) - what remains is called tropocollagen or collagen fibres and what is cleaved is called the propeptide o Tropocollagen is stabilized by inter and intra-chain cross-links - the enzyme lysyloxidase extracellular enzyme dependent on copper) mediates the bonds between several tropocollagen, thus forming the finished collagen (collagen is therefore a polymer of tropocollagen)) o the formation of bonds between tropocollagen occurs via aldehydes, their condensation, schiff base formation etc...

Answer 482

- collagen I. - skin, tendons, bones, dentin - collagen II. - cartilage, vitreous humour - collagen III. - fetal skin, uterus, blood vessels - collagen IV. - glomeruli, kidneys, capsule lenses, basement membranes o Type IV does not form striated fibers - unlike for others, it has a globular structure

Answer 483

- defects at the level of triple helix folding and stabilization - Ehlers-Danlos syndromes- it is a group of about 10 clinically and genetically distinguishable diseases that are associated with manifestations of structural weakening of connective tissue (joint hypermobility, translucent fragile skin ...) o type VI - lysylhydroxylase deficiency (EDS type VI) - transverse bonds are less stable, the clinical picture is hyperextensibility of the skin and joints, poorly treatable injuries and deformities of muscles and bones - scurvy- lack of vitamin C in the diet for proline hydroxylation, manifestations are subcutaneous and other bleeding, muscle weakness

Answer 484

- during tissue development, the cells (fibroblasts) move along the already formed collagen fibers, stretch and stretch it into the ropes, affecting the arrangement of the collagen fibers and at the same time the collagen fibers affect the distribution of fibroblasts - fibronectin is responsible for the ability of cells to attach to the collagen fibers - it is an adhesive protein (glycoprotein) - a fibrous dimer found in both ECM and blood o fibronectin molecules are divided into several domains and form bonds with cell membrane (via integrins), collagen, fibrin and various proteoglycans - A sudden drop in fibronectin concentration may indicate cancerous growth - fibronectin is secreted by the same cells as collagen

Answer 485

- binding to the cell surface is realized by receptors for fibronectin which are integrins - integrins are heterodimers, have different types of α and β polypeptide chains - fibronectin interacts indirectly with actin microfilaments present in the cytosol, contacting the intra-cellular space - also participates in cell migration by providing a binding site

Answer 486

- a protein conferring extensibility and shrinkage in tissues - found in the lungs, large arteries, elastic ligaments, skin .. - contains a large amount of proline and Gly, little OH-proline, no OH-lysine, is not glycosylated - prolyl hydroxylase hydroxylates some prolines (Vitamin C is the cofactor) - produced by fibroblasts, after secretion from the cell oxidative deamination of lysyl residues (enzyme lysyloxidase) - he main cross-links are desmosins (condensation of 3 lysine-derived aldehydes and one normal lysine) - formed mainly during embryonic development - later minimal metabolism (elastase inhibited) - cross-linked form of elastin is insoluble, very stable and resistant (with low metabolic turnover) - elastin contains repeating sequences (pentapeptide Val-Pro-Gly-Val-Gly and hexapeptide Val-Ala-Pro-Gly-Val-Gly)

Answer 487

- is an adhesive protein, a large glycoprotein that is a structural component of microfibrils - fibroblasts secrete it into the ECM where it is incorporated into insoluble microfibrils o they create a kind of scaffold that stores tropoelastin, which matures here into elastin - fibrilin defect results in a decrease in elasticity and strength of the elastic ligament - Marfan syndrome is caused by mutation of the fibrillin gene (15th chromosome)) o Eyes are effected (ectopia lentis – dislocation of lens), skeletal and cardiovascular system are effected as well (weakened aorta)

Answer 488

- after collagen IV, laminin is the most common protein in the basement membrane, a specialized type of ECM - laminin has the ability to bind to other ECM components - entactin (nidogen), a glycoprotein that is the major factor connecting cells to the lamin, binds to laminin - is composed of 3 different peptide chains linked to a cross structure

Answer 489

- has 3 layers o epithelium o basement membrane - its primary components are 3 proteins - laminin, entactin and collagen IV o endothelium - reduces the penetration of large molecules by the glomerulus into the renal tubule (small molecules pass) - larger molecules such as albumin (greater than 8nm) do not pass due to negative charge in the laminate or pass only in very small quantities o Negative charge repels mostly plasma proteins and is caused by heparan sulphate - when the membrane is damaged (e.g. by glomerulonephritis), the pore size changes, and the charge is distributed differently -> passes albumin and other plasma proteins (albuminuria), which we can easily test

Answer 490

- 40-120nm thick layer of specialized ECM o supports epithelial cells, separating them from the connective tissue o surrounds muscle, endothelial and fat cells - two layers of epithelia are adjacent to each other in the kidney glomeruli and in the alveoli - the basement membrane is made of 2 basal laminations - determines cell polarity, affects metabolism and organizes proteins in the plasma membrane

Answer 491

glycoproteins and proteoglycans

Answer 492

- prevent compression and serve as a filler - contain up to 95% carbohydrates and 5% protein (lots of carbohydrates, the rest protein) they are proteins containing covalently linked glycosaminoglycans (GAG) o GAG - hyaluronic acid, chondroitin sulphate, keratan sulphate, heparin, heparan sulphate and dermatan sulphate o an unbranched polysaccharide consisting of repeating dimers o have negative charges o they are long polymers of dimers of amino sugar (D-glucosamine or D-galactosamine) and uronic acid o with the exception of hyaluronic acid, they contain sulphate groups - found in synovial fluid, vitreous humour, artery walls, bones, cartilage and cornea - often have the group -SO3- and thus carry a negative charge (also COO- group) - are hydrated and act as lubricants because they bind large amounts of water and sodium - they are secreted from the cells to the ECM after synthesis - Negatively charged GAG chains repel each other, thus taking up a lot of space and acting as molecular sieves that determine which substance enters or leaves the cell - degradation (both glycoproteins and glycolipids) occurs in the cell after endocytosis by lysosomal fusion of the endocytes - Chondroitin sulphates in proteoglycans are an important component of cartilage

Answer 493

- proteins that have covalently linked oligosaccharide (glycan) chains to the central protein chain) - almost all human plasma proteins are glycoproteins (except albumin)) - glycoproteins may contain more than 50% carbohydrates, but generally the protein component should predominate - 7 monosaccharides predominate in human glycoproteins - Glc, Man, Gal, NeuAc, Fuc, GalNAc, GlcNAc

Answer 494

o chondroblast – young cell, differentiates from the mesenchymal cell, produce the extracellular matrix o chondroclast – degrade the cartilage (macrophages)

Answer 495

o collagen type II - hyaline and elastic cartilage o collagen type I - fibrocartilage

Answer 496

inorganic part of ECM – from glycoproteins (chondronectin, hyaluronic acid, chondroitin sulphate) and proteoglycans - it is an avascular tissue nourished by the diffusion from the perichondria - bad regeneration – extensive damage heals through collagen scars - basic degenerative process of cartilage is calcification, but sometimes it may be physiological (e.g. during ossification) - high compression elasticity, as 80% is water - the arrangement of collagen fibres can be visualized under a polarized microscope

Answer 497

round cells with a light nucleus and a prominent nucleolus - chondrocytes are responsible for the synthesis of everything in the extracellular matrix o has a proteosynthetic apparatus - GER, GA, vesicles - anaerobic metabolism – storage of energy through glycogen stores and lipid droplets - lacunae – in histology a lacuna is a small cavity in which chondrocytes (in cartilage) or osteocytes (in bone) sit. o chondrocytes fill up the whole lacunae – on a slide, there if often free space, but that is only an artefact

Answer 498

- chondrocytes in cartilage are surrounded by a thin layer called pericellular matrix, which chemically and mechanically differs from the extracellular matrix (for example contains a soft network of collagen type VI) - divided into o territorial matrix – thin layer, basophilic, a lot of proteoglycans, neighbors with chondrocytes o interterritorial matrix – further from chondrocytes, lighter, more extracellular matrix

Answer 499

- formed by collagen, proteoglycans, glycoproteins and water (binds to proteoglycans, forms up to 80% of total volume) o proteoglycans - chondroitin-4-sulphate, chondroitin-6-supltate a keratan sulphate, which along with hyaluronic acid forms proteoglycan aggregates (e.g. aggrecan) o glycoproteins - chondronectin -> responsible for the adhesion of chondrocytes to collagen type II

Answer 500

group of cells which do not separate post division and stay in groups - formed via interstitial growth (proliferation of chondrocytes) – chondrocytes are located in lacunae, if they divide, then both chondrocytes will remain in the same lacunae – this is what we call Isogenous groups

Answer 501

- dense connective tissue around cartilage – ensure growth and nourishment - formed from 2 layers o stratum fibrosum – a lot of fibroblasts -> dense collagen tissue = captures tensile strength o stratum chondrogenicum – inner layer right in undifferentiated mesenchymal cells - does not cover articular cartilage – surface of cartilage is covered by an extracellular matrix - contains collagen type I

Answer 502

interstitial growth – division of chondrocytes o used during development (epiphyseal discs) or in articular cartilage - appositional growth – mesenchymal cells from perichondrium differentiate into chondroblasts o this type of growth is more significant

Answer 503

its surface is not covered by perichondrium - functions as a shock absorber on the bone - collagen fibres are arranged in an arcade style (= are layered) o tangential zone – heavily intertwined collagen fibres are organized parallel to the surface of the cartilage which gives it smoothness and strength o transitional zone o radial zone – collagen fibres are orientated radially and cross the calcified zone to the bone, to which they are firmly connected o zone of mineralized cartilage – firmly sits on the bone and protects it - in the space between the cartilages of bone is bone joint cavity which is filled with viscous fluid so called synovial fluid

Answer 504

- hyaline cartilage o attachment of ribs, nasal cartilage, trachea, bronchi and majority of cartilages in larynx, skeleton before ossification, joints o oval chondrocytes in groups, strongly basophilic matrix o light microscope cannot visualize collagen fibres - elastic cartilage o elastic fibres + collagen II, epiglottis, external auditory canal, auditory (Eustachian) tube o matrix has the same composition as hyaline cartilage but has a network of elastic fibres which extend to the perichondrium and increase elasticity and flexibility during applied pressure and movement - fibrocartilage o collagen I + extracellular matrix, chondrocytes sit individually o intervertebral disks, joints, symphysis o without perichondrium

Answer 505

- strong support of our body, contains high amounts of inorganic components - cells - osteoblasts (synthesize ECM), osteocytes (inactive osteoblasts), osteoclasts (break down ECM)

Answer 506

main component is collagen type I, crystals of hydroxyapatite, glycoproteins (sialoprotein, osteocalcin) and proteoglycans (chondroitin sulphate a keratan sulphate) - important concept - bone lamellae – plate of mineralized collagen fibres organized in the same direction - distinguishes fibrous and lamellar bone as they are made from the same material, their difference lies in the orientation of the fibres

Answer 507

– intertwined collagens fibers in bundles fibers are randomly arranged we can find it in primary bone (at the beginning of development), during the healing of fractures, sites of bone and tendon connections it gradually turns into lamellar bone

Answer 508

– collagen fibres and arranged into lamellae where – secondary bone in-between lamellae are osteocytes macroscopically there are two different forms of lamellar bone x spongiosa – middle of bone, spatial network from thin plates and trabecular, in between trabeculae is bone marrow x compacta – structure from osteons (also known as Haversian systems, concentric lamellae around a central canal) on the periphery are osteoblasts

Answer 509

forms 45% of the mass of bone tissue, longitudinal hexagonal crystal, orientation is determined by collagen fibres - tensile strength (collagen) and flexibility (hydroxyapatite)

Answer 510

spongiosa also known as trabecular bone tissue o found in the cavity of long bones and kits structure resembles a dense network through which blood vessels and nerves pass o anatomical and functional unit is trabeculae which are aligned towards the mechanical load, this allows the trabeculae to withstand pressure – this specific organisation of bone/architecture of bone, is different in everyone and has the ability to change throughout our lives depending on our current mechanical stresses/loads. o spongiosa is significantly responsible for the process of remodelling and healing process of bone tissue - compact bone o this hard tissue is found under the periost and is formed mainly by concentric lamellae and central canal of cylindrical appearance called osteons (or Haversian systems the same thing) o individual centres of osteons contain Haversian channels with blood and lymphatic vessels and nerves. Their function is to ensure proper nutrition, growth and regeneration of bone tissue o Volkmanns channels – form vertical connections between neighbouring Haversian channels, and provide communication between osteons

Answer 511

osteoblasts – form bone matrix, produce collagen I and different proteoglycans and glycoproteins - osteocytes – take up the population majority, do not form the ECM but take part in the metabolism (release minerals from bone) - osteoclast – breakdown bone matrix

Answer 512

produce osteoid, which is unmineralized bone tissue which is progressively mineralised (collagen type I) - originates from mesenchyme, they are progenitor cells of osteocytes o influence of growth factors - BMP2 (bone morphogenetic protein 2) - active osteoblast is a cubical cell rich in RER - throughout its life, it accumulates bone matrix around itself and may remain in it (in this case it will turn into an osteocyte) - on the membrane of osteoblasts is alkali phosphatase, which is important for the mineralization of osteoid - formed from osteoprogenitor cells under the influence of signalling molecules of BMP

Answer 513

closed in mineralised bone matrix, located in lacunae - in contact with other osteocytes through long thin projections, which run through channels of bone matrix - canaliculi - osteocytes communicate through gap junctions

Answer 514

large, multinucleated free cells, which attach to mineralized bone matrix - formed by the fusion of mononuclear precursor cells (monocytes) - belong to a group of macrophages, their main function is to breakdown bone tissue - osteoclast release proteolytic enzymes from cells into matrix and digest the organic components of bone o e.g. collagenase, acidic phosphatase, cathepsin K o some matrix fragments are endocytosed - deepen pits (so called Howship’s lacunae) and after reaching a certain depth they widen them, osteoblasts follow them which refill the lacunae with ECM - have proton pumps, which lower the extracellular pH, which is needed during the destruction of ECM - on their surface facing bone is a groovy plasmalema which looks like a brush border - activity of osteoclasts is regulated by various cytokines and hormones - parathormone (parathyroid gland, increases the level of calcium in blood) and calcitonin (thyroid gland decreases the level of calcium in blood)

Answer 515

Endosteum - layer of mesenchymal cells (precursors of osteoblasts and osteoclasts) and mineralized collagen fibres - covers all inner surfaces of bones Periosteum - cover outer surfaces of bone - two layers o stratum fibrosum – outer dense collagen connective tissue periosteum is attached to the bone through collagen fibres from stratum fibrosum -Sharpey’s fibres o stratum osteogenicum – tightly attached to bone, richly vascularized and innervated, pain sensitive, same cells as in endosteum

Answer 516

- osteoclasts and osteoblasts are grouped together as they work together to breakdown and renew bone o osteoclast breaks down a piece of bone (osteocytes present in this piece die through apoptosis) formation of pits called Howship’s lacunae, osteoclasts sit in these lacunae o osteoblasts in this pit start to synthesize osteoid – unmineralized bone tissue where calcium and phosphor attach and crystallize, which finished the process of bone remodeling o some osteoblasts stay in the newly synthesized osteoid which mineralizes around them and closes them in these osteoblasts become osteocytes

Answer 517

o cytokine M-CSF – encourages the proliferation of precursors of osteoclasts, produced by osteoblasts o precursors of osteoclasts (macrophages) have a receptor RANK RANKL (RANK Ligand) – membrane protein of osteoblasts, binds to RANK and induces the fusion and activation of precursors of osteoclasts (macrophages) OPG (osteoprotegerin) - competitive inhibitor of RANKL, its production is stimulated by oestrogen o Activated osteoclasts act on osteoblasts through negative feedback o hormones (parathormone, calcitonin) functions through RANKL/OPG

Answer 518

Intramembranous ossification and endochondral ossification

Answer 519

- ossification of mainly flat bones – skull, clavicle, lower jaw - it is the ossification of mesenchymal cells straight into bone - starts during embryonic period (around week 8 of pregnancy) on the base of the connective tissue - primary ossification centre o selected centrally located mesenchymal cells cluster and differentiate into osteoblasts o mesenchyme condenses on the external face of the woven bone and from the periosteum - synthesized collagen (type I) surrounds osteoblasts and gradually causes the differentiation of osteoblasts to osteocytes and the calcification of osteoid - first primary spongiosa forms and then through further growth turns into compacta - this is how we describe oppositional growth -> growth to the sides/width

Answer 520

mainly used in long bones - femur, humerus... - it is the ossification of mesenchymal cells into hyaline cartilage and then the replacement of cartilage to bone o cartilage is broken down and replaced by bone, it is not the conversion of cartilage but its destruction and the replacement, part of it remains only in the region between epiphysis and diaphysis in so called cartilage growth plate/epiphyseal plate

Answer 521

endochondral ossification has 6 zones, through which the bone gradually expands o reserve zone – undifferentiated precursors of chondrocytes o zone of proliferation – active chondrocytes divide and form the ECM around themselves, this causes the formation of isogenous groups o zone of hypertrophy – chondrocytes grow o zone of calcified cartilage – extracellular matrix forms pits, which become filled with vessels entering into the cartilage o zone of destruction – chondroclasts and macrophages breakdown cartilage (chondrocytes carry out apoptosis) o zone of ossification – migration osteoprogenitor cells and formation of osteoid

Answer 522

- Enzymopathies are hereditary diseases caused by the malfunction or absence of one or more enzymes - The nature of metabolic diseases- due to mutation of nuclear or mitochondrial DNA, a dysfunctional protein is produced that cannot convert the substrate into a product, leading to multi-organ damage - Nuclear vs Mitochondrial Enzymopathies o Nuclear- may be mutated gene from mother or father, Mendel's laws apply here and the whole body is affected o Mitochondrial- mutation always comes from the mother; Mendel's laws do not apply and the expression of the disorder is variable

Answer 523

Most enzymopathies are autosomal recessive (which means that heterozygotes have no symptoms) - The pathological consequences of enzymopathies are due to: o Substrate accumulation - accumulation of molecules that are not properly degraded and eliminated o Deficiency of the product - absence of the product in the organism causes pathological behaviors of the organism o Alternative degradation of the substrate - often substances that are toxic to the body (cause poisoning) o Combination of the three - Enzymopathies include diseases where the patient is deficient in cofactor or activating / modifying / stabilizing protein - although the enzymes themselves may be perfectly fine, they do not work - Common for locus heterogeneity to be present- mutation of different genes can lead to the same phenotypic manifestation o For example, if one metabolic pathway uses 3 enzymes in series, it does not matter which gene mutates the enzyme, because the entire pathway will be non-functional anyway - Variable expression - different diseases that result from a partial or complete enzyme defect - Does not concern several catalytic ribonucleic acids

Answer 524

hyperphenylalaninemia, tyrosinemia, alkaptonuria, homocystinuria, leucinosis, organic aciduria

Answer 525

galactosemia, fructose intolerance, glycogenosis

Answer 526

methylmalonic aciduria

Answer 527

adenosine deaminase deficiency (SCID), porphyria

Answer 528

congenital adrenal hyperplasia

Answer 529

LCHAD, VLCAD, MCAD deficiency

Answer 530

- MTHR deficiency, biotinidase deficiency

Answer 531

o sphingolipidosis- Tay-Sachs disease, Gaucher disease, Niemann-Pick disease o mucopolysaccharidosis - Hurle Syndrome

Answer 532

inherited metabolic disorder of amino acids A group of enzymopathies caused by mutations in the phenylalanine hydroxylase gene or a genetic defect in some metabolic step of its tetrahydrobiopterin cofactor - Three severity levels - phenylketonuria (PKU) (worst form), variant PKU (intermediate form) and non PKU Hyperphenylalaninemia (least severe form of hyperphenylalaninemia) - There is no treatment, only diet can prevent symptoms (therefore every new-born in the Czech Republic is tested for these diseases)

Answer 533

inherited metabolic disorder of amino acids - Is due to the inability to metabolize phenylalanine to tyrosine o phenylalanine is instead metabolised by a minor metabolic pathway to the toxic phenylpyruvic acid, which irreversibly causes mental retardation and light pigmentation - There are about 400 alleles which by mutation can cause phenylketonuria - Phenylketonuria is part of neonatal screening. - Breast milk also contains phenylalanine - people with phenylketonuria should not eat essentially any protein-rich food

Answer 534

inherited metabolic disorder of amino acids - Lack of skin and hair pigment due to missing / non-functional tyrosinase - A typical albino has red eyes, white hair and white skin - types of albinism o Type I(A) - tyrosinase is missing in the body o Type I(B) - tyrosinase is present but is inactive o Type II (most common) - tyrosinase is present but not as effective - Symptoms are most often sensitivity to sunshine (frequent skin cancers) and sensitivity of eyes (visual disturbances)) - Albinism exists throughout the animal kingdom (and partly also among plants)

Answer 535

inherited metabolic disorder of amino acids due to the lack of the enzyme homogentisate dioxygenase (HGD), homogentisic acid accumulates in the organism, which is then converted to the brown-black pigment alkapton by an alternative route (oxidation) and is stored in the tissues o Ochronosis- brown coloration of tissues (mainly eyes and cartilage) in alkaptonuria - treatment- limited supply of Phe and Tyr

Answer 536

inherited metabolic disorder of amino acids Tyrosine metabolism disorder - fumarylacetoacetate hydrolase (FAH) activity disorder o tyrosine accumulates, converts sideways to toxic succinyl-acetone and damages the liver and kidneys - type I is most widespread (type II and III are rare) - treatment with diet and Nitison (a medicine that slows down the alternative pathway of tyrosine metabolism)

Answer 537

inherited metabolic disorder of amino acids Methionine metabolism disorder (commonly metabolized to homocysteine and then to cysteine) - is due to cystathionine β-synthase (CBS) deficiency, which causes increased urinary homocysteine and methionine levels o The cause of damage is the accumulation of substrate (methionine) in the body - 4 organ systems are affected - eye, skeleton (bones), vascular endothelium (vascular lining) and CNS

Answer 538

inherited metabolic disorder of amino acids a group of disorders of specific enzymes in catabolism of branched chain amino acids (valine, leucine and isoleucine) - the result is the accumulation of toxic by-products (organic acids) and hyperacidification of the organism occurs, which particularly disturbs the brain

Answer 539

inherited metabolic disorder of amino acids - maple syrup disease (MSUD; maple syrup urine disease) - impaired metabolism of branched α-keto acids - disorder of the dehydrogenase in multienzyme complex - keto acids accumulate in the body causing odour of urine and ear wax after maple syrup

Answer 540

inherited metabolic disorder of saccharides is due to malfunction of galactose-1-phosphate uridyl transferase (GALT), leading to the inability to metabolize galactose monosaccharide (a component of lactose) o toxic metabolic by-products are formed that damage the liver, brain, kidneys and eye lenses - failure to follow a strict diet could result in malnutrition, cirrhosis of the liver, cataract and mental retardation

Answer 541

inherited metabolic disorder of lysosomes - damage of HexosaminidaseA (HEX A), leading to inability to degrade sphingolipids GM2-ganglioside - o GM2-ganglioside o GM2-ganglioside then accumulates in cells, mainly in lysosomes - the nervous system is most affected - there are several forms of the disease (depending on the age at which the first symptoms begin to appear), where the most severe (infantile type) leads to death within 5 years of life

Answer 542

inherited metabolic disorder of lysosomes - due to the deficiency or absence of the lysosomal enzyme glucocerebrosidase - substrate (glucosylceramide) accumulates in macrophages - especially affected - spleen, liver, bone marrow, brain, nervous system, lymphatic tissues

Answer 543

inherited metabolic disorder of lysosomes - Glycosaminoglycans (dermatan sulphate and heparan sulphate) accumulate in tissues as a result of α-L-iduronidase I enzyme deficiency, leading to corneal opacity, skeletal changes, hydrocephalus and hepatosplenomegaly

Answer 544

inherited metabolic disorder of purines and pyrimidines a group of diseases caused by mutations in the heme synthesis genes o defects in the early phase of the synthesis cause the accumulation of starting materials - 5-aminolevulinic acid and porphobilinogen accumulation of substrates with toxic effect o defects in the higher stages of synthesis lead to the accumulation of porphyrinogens accumulation of substrates and by-products with toxic effect - porphyria is divided according to o most affected organs producing porphyrins- hepatic, erythropoietic, erythrohepatic o manifestations- skin, liver o course - acute, chronic - Porphyrinogens react with visible light to form radicals that damage cellular organelles, including lysosomes o this releases lysosomal enzymes that cause redness, blistering, scarring, etc.

Answer 545

if caused by mutations in nuclear DNA - normal AR inheritance - if caused by mutations in mtDNA - purely maternal inheritance o if a mother is affected, all her children are affected o If a father is affected, all his children are healthy

Answer 546

- mitochondrial disease is a heterogeneous group of diseases with respiratory chain dysfunction o are metabolic disorders and neurodegenerative or muscle deficiencies due to product deficiency (ATP) - tissues with high ATP consumption (brain, muscles, liver, heart, kidneys, endocrine glands) are most affected - the disorder is multisystemic, exceptionally one organ is affected (LHON syndrome) - very serious illnesses with poor prognosis

Answer 547

- variable expressivity (different phenotypic expression) - in division the distribution into daughter cells is random, therefore the distribution of mutated and normal mtDNA is different o is typical for mitochondrial diseases o in each disease, the disease may have different expressivity – affects different organs, have different severity o Homoplasmia- cells have only mutant mtDNA or only normal mtDNA o heteroplasmia- the cell contains a mixture of normal and mutant mtDNA

Answer 548

- the inheritance of the disease is linked to one particular gene - molecular genetic diagnostics is available for most of them - A causal therapy is usually not available (=therapy which is focused on the cause of the disease) - Onset of symptoms in childhood: ˂ 10 % start after puberty - Low overall incidence: approximately 0.36 %(incidence = number of new cases of disease over time)

Answer 549

1. Autosomal dominant (AD) 2. Autosomal recessive (AR) 3. X – linked dominant (XD) 4. X – linked recessive (XR) 5. mitochondrial - most monogenetic diseases are hereditary metabolic disorders (enzymopathies)

Answer 550

- almost always recessive inheritance - heterozygotes with 50% residual activity of the enzyme are usually without problems - Symptoms are caused by: (a) accumulation of the substrate, (b) lack of product or (c) the formation of toxic intermediates / alternative products

Answer 551

- autosomal dominant disease The most common form is called Adult Lactase Deficiency (Adult Lactose Intolerance) - an enzyme of brush border of enterocyte - It is a form of a common polymorphism – Decreased expression of lactase during adulthood is essentially a normal state - reflects the decline in role of milk in a diet of mammals after a lactation period usual decline in lactase activity with age - Lactase activity depends on a summation of expression of both alleles - AD inheritance - Frequency of the defect: 5 % in northern Europe, 71 % in southern Europe, 90 % in some African and Asian countries - Consequences: watery (osmotic) diarrhea and excessive gas production, Accumulation of non-metabolisable substrate in the lumen of the gastrointestinal tract (bacterial lactase breaks down the disaccharide eg. yoghurt)

Answer 552

- autosomal dominant - Defect in metabolism of LDL particles - mutation of a gene for LDL receptor - Similar is familial defect of apolipoprotein B-100 (FDB) - defective Apo B-100 will not allow the proper binding of LDL to the LDL receptor o difference can be assessed on the basis of DNA analysis o both are inherited dominantly: expressed even when only one allele is damaged (rare to have 2 damaged alleles - Consequences: impaired uptake of LDL particles - increased levels of Cholesterol - Excess Chol is deposited in the walls of blood vessels - the development of atherosclerosis and its complications (MI or stroke) at a young age - * Skin and tendon xanthomas, xanthelasmas of eyelids and arcus lipoides corneae - treatment: diet, pharmacological treatments (statins – competitive inhibitor of HMG-CoA reductase, which catalyses the main reaction in cholesterol synthesis -> leads to an increased number of LDL receptors and increases absorption of LDL by the liver, in the most severe forms (homozygote) LDL apheresis (methods by which excess LDL particles are removed from blood)

Answer 553

- autosomal recessive disorder - Plasma protein inhibitor of proteases (elastase also) - So called Z-mutation - Destruction of vulnerable tissues - eg.. lung tissue - 80-90 % of patients with ZZ-genotype develop pulmonary emphysema in young / middle age - Proteolytic enzymes are released from the macrophages and neutrophils during inflammatory processes - Emphysema is a result of an imbalance of protease /antiprotease activities in the lungs - Potentiates with smoking – smoking causes an even worse course of the disease

Answer 554

- autosomal recessive disorder defect in enzymes of steroid hormones synthesis in the adrenal cortex - the most common is 21-hydroxylase deficiency - adrenal glands don’t produce enough cortisol which leads to low level of cortisol which causes hypophysis to produce ACTH to increase the synthesis of cortisol, but due to the defect of the enzyme the only effect of ACTH is the hyperplasia of adrenal glands - consequences o Insufficient supply of energy (glucose) during stress (diseases, starvation) o Mineral dysbalance: Na+ and water is lost in the urine - dehydration; o hyperkalemia - lethargy, muscle weakness, heart rhythm disturbances o coma and death - excess of ACTH does not increase the synthesis of cortisol – the precursors accumulate and are released into the circulation and further used to create cortical sex hormones (cortical androgens) - in females, it leads to virilization (the appearance of external genitalia begins to be similar to the male sex) so called o. pseudohermaphroditism feminine - female genotype, but male phenotype (masculinization) - Precocious puberty in males (pubertas praecox) - Therapy: supplementation of missing glucocorticoids - compensates the deficit of cortisol and stops the excessive production of ACTH - decreases the formation of excess androgens

Answer 555

-autosomal recessive - Special type of hemoglobin - HbS - Point mutation at the gene for β-globin chain – substitution of Glu for Val at the 6th position o Val is a non polar AA- non polar compounds like to associate. Hb contain a sticky spot – moelcules attach together - * In the deoxy-form HbS forms long chains associated in thick strands - change of the shape: biconcave to sickle cell – impaired elasticity - can not pass through capillaries - obstruction - Shortened lifespan of ery (10-20 days x 120 days) - hemolytic anemia - More resistant to infection with the protozoan Plasmodium - causes malaria (heterozygote advantage in regions with a high incidence of malaria)

Answer 556

- Mutations in the enzymes that control the production of heme (part of cytochromes and Hb) - AD and AR heredity - Symptoms are derived from: o 1)Affected enzyme and severity of the defect o 2) Whether the formation of heme is primarily affected in the liver or developing erythrocytes - mechanism of damage - Intermediates of heme formation contain conjugated double bonds - after exposure to photons of visible light (esp. wavelength = 400 nm) results in the excitation of electrons - o Generated reactive oxygen species - damage to cells - release of proteolytic enzymes from lysosomes - symptoms photosensitivity (skin lesions, redness, blistering, hypertrichosis), abdominal pain, liver and neurological impairment (even psychotic conditions) - diagnosis - determination of porphyrins and precursors in urine, faeces and / or red blood cells, red colored urine - treatment - avoiding of provoking factors, adminitsration of hemin (similar to heme complex, but containing Fe3+, supplemets the lack of heme + represses transcription of the gene for ALA-synthase)

Answer 557

- AR diseases caused by the mutation of gene coding for uroporphyrinogen synthase - Severe photosensitivity - skin lesions, redness, blistering, hypertrichosis), abdominal pain, liver and neurological impairment (even psychotic conditions) - Diagnosis: determination of porphyrins and precursors in urine, faeces and/or red blood cells, red colored urine - Treatment - avoiding of provoking factors, administration of hemin (similar to heme complex, but containing Fe3+,supplements the lack of heme + represses transcription of the gene for ALA-synthase)

Answer 558

- So called. liver porphyria - vomiting attacks with colony abdominal pain, neuropathy and psychiatric conditions - all AD - enzyme activity is typically around 50% of normal values - attacks are related to elevated δ-ALA acid level resulting from derepression of ALA-synthase transcription - AIP - the most common form -porfobilinogene deaminase (hydroxymethylbilan synthase) - frequency of heterozygotes - 5-10 / 100 000 (1/1000 in northern Sweden) - attacks often caused by drugs - ethanol, barbiturates or contraceptives

Answer 559

X-linked recessive disease - spectrum of diseases- only some of them in relation to the X chromosome - defective synthesis or decreased functional activity of some coagulation factors - Haemophilia A VIII (most frequent) - Haemophilia B IX - Haemophilia C (rare): AR diseases, XI - Clinical symptoms depend on the severity of the defect - Severe form of haemophilia – decrease in plasma concentration of clotting factors below 1 % - Moderate form of haemophilia – decline to 1-5% of normal levels - Patients with severe form are in risk of spontaneous bleeding into joints (haemarthrosis), central nervous system, muscle and soft tissues, as well as life-threatening bleeding after an injury or medical procedure. - Patients with moderate haemophilia suffer from similar symptoms but usually not from spontaneous bleeding - No causal treatment – patients have to get regular supplementation of missing factors - Haemophilia A is the most common type of haemophilia

Answer 560

- Screening of 48-72 hours old baby from one drop (from the heel) of his/her blood for genetic diseases - Active and nationwide search for diseases in their early, preclinical stage so that these diseases can be diagnosed and treated before they can manifest themselves and cause irreversible health damage to the newborns - Analyzation of dry blood on a filter paper, while looking for specific markers - enzymes, amino acids, etc.. - Only diseases that are frequent, can be diagnosed and effectively treated to prevent them

Answer 561

o Congenital hypothyroidism (CH) - congenital decreased thyroid function o Congenital adrenal hyperplasia (CAD) o Cystic fibrosis o 8 amino acid metabolism disorders o 6 disorders of fatty acid metabolism o hereditary disorders of vitamin transformation

Answer 562

Phenylketonuria Leucinosis (maple syrup syndrome) - a disorder of BCAA metabolism Citrulinaemia type 1 - argininosuccinate synthetase deficiency Argininaemia- arginase deficiency Homocystinuria from deficiency of cystathionin beta-synthase (CBS) Homocystinuria from deficiency methylenetetrahydrofolate reductase (MTHFR) Glutaric aciduria type I Isovaleric aciduria

Answer 563

Deficit medium chain acyl-CoA chain acyl-CoA dehydrogenase deficiency (MCAD deficiency) Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD deficiency) Very long chain acyl-CoA dehydrogenase deficiency (VLCAD deficiency) Carnitine palmitoyl transferase I deficiency (CPT I deficiency) Carnitine palmitoyl transferase II deficiency (CPT II deficiency) Carnitine-acyl-carnitine translocase deficiency (CACT deficiency)

Answer 564

Biotinidase (BTD) deficiency

Answer 565

Is caused by a disorder of the prenatal development of the thyroid gland (dysgenesis, 80% of cases) or a disorder of some step of thyroid hormone synthesis (dyshormonogenesis, 20% of cases) - manifests as fatigue, sleepiness, overweight, anemia, menstrual cycle disorder...

Answer 566

- loss of one of the five enzymes of steroid hormone biosynthesis (in most cases 21-hydroxylase is missing) - when there is no aldosterone and cortisol, massive salt loss occurs (untreated ends in death) - is associated with elevated levels of 17-hydroxyprogesterone in the blood - if there is no 21-hydroxylase, the common precursors are converted to androgens, which means masculisation in women and premature puberty in men - since steroids are missing in the body, a large amount of ACTH is released into the body (the brain is trying to force the adrenal glands to produce more steroids), leading to excessive bilateral enlargement of the adrenal glands treated with mineralocorticoid and glucocorticoid substitution (= cortisol and aldosterone)

Answer 567

- In CZ the most often mutation in CFTR gene is F508del, which is the gene for a chloride ion channel in the cytoplasmic membrane - During the analysis we search for Trypsinogen (pancreatic proenzyme, a lot of trypsinogen means trouble) - defective export of chlorides and water, leading to increased mucus density and viscosity, clogging the lower respiratory tract and possibly leading to death, either by gradual loss of functional lung tissue or by succumbing to some of the frequent bacterial infections (mean life expectancy is 37 years) - in the Middle Ages heterozygotes had an evolutionary advantage in resistance against certain dehydration diseases (cholera)

Answer 568

-autosomal recessive - deficiency of the enzyme phenylalanine hydroxylase, which converts phenylalanine into tyrosine - phenylalanine accumulates in the blood and its metabolites damage the CNS nerve myelin sheath - a typical finding is elevated levels of phenylalanine and decreased levels of tyrosine - children have muscular hypertonicity and convulsions, rapidly developing severe mental retardation

Answer 569

- The organism is in a state of short-term starvation after fasting overnight (before breakfast) - glycemia- under physiological conditions it is fasted in the range of 3.9-5.6 mmol/l (after meals up to about 10mmol/l) - Low ratio of I/G (low insulin / much glucagon) activates hepatic glycogenolysis and gluconeogenesis (↑ cortisol, growth hormone, glucagon), releasing glucose from the liver o ↑ insulin to glucagon ratio after meal o ↓ insulin to glucagon ratio during fasting

Answer 570

- the main substrate is lactate -> lactate is produced in the muscles, which is transferred to the liver during the Cori cycle, where gluconeogenesis occurs (a smaller part of the lactate is used by the kidneys and the rest is metabolized by the myocardium...) - slight activation of proteolysis in muscles → Ala is converted to pyruvate and gluconeogenesis can occur

Answer 571

gluconeogenesis and TAG mobilization are the primary energy sources of the organism during starvation - of course, proteins can be used, but we do not want that because protein loss = loss of cell function o The basis for survival is, for example, movement, so muscles can not be radically reduced in the long term - minimal use of proteins during prolonged starvation allows the synthesis of ketones, which after some time become the main energy source - lipolysis is very important (glucagon stimulates HSL, insulin inhibits it) - MK is used in liver, heart and muscles

Answer 572

- lasts 2 to 3 days - during this phase, glucagon, catecholamines and cortisol levels increase - this leads to gluconeogenesis for which muscle AMKs are used (ie, proteolysis in the muscles, resulting mainly in Ala and Gln) - glutamine is an energy substrate for enterocytes - ↑ lipolysis in adipocytes = release of MK and glycerol (glycerol on gluconeogenesis) - many tissues are fed directly by MK (eg muscles and heart) - MKs are processed in the liver to supply most of the energy for gluconeogenesis and ketogenesis (ketone bodies suppress proteolysis and oxidation of branched AMK in muscle and reduce Ala release into circulation) - hepatic glycogenolysis is the primary source of blood glucose in an early fasting state

Answer 573

- the main energy substrates are MK and ketone bodies (the effort to conserve proteins, but it also gets to them, is the last backup from which energy can be taken) - pyruvate, lactate, AK, and glycerol are used for gluconeogenesis

Answer 574

- lasts 7 to 8 weeks - at this stage, TAGs are already depleted and protein catabolism is associated with progressive loss of muscle mass and significant suppression of the immune response, increased risk of infection

Answer 575

- Insulin deficiency due to destruction of pancreatic β-cells - hyperglycemia is a hallmark of this disease - glucose is not transmitted to skeletal muscle, because GLUT4 channels that transport glucose into cells are opened by insulin that is lacking in these patients o no β-cells = no insulin = GLUT4 carriers closed = blood glucose = hyperglycaemia o insulin also inhibits gluconeogenesis, so in its absence gluconeogenesis is not inhibited = hyperglycaemia - exceeding the renal threshold for glc leads to glucosuria (= urinary excretion of glucose), which is accompanied by polyuria (increased urination) → dehydration → polypsidia (increased fluid consumption) o when the body works properly we should not get above 10 mM due to glucokinase - Lipolysis (HSL) is not controlled in adipose tissue → increased plasma MK → increased β-oxidation → increased production of ketone bodies in the liver → ketoacidosis - Hyperlipoproteinemia- insulin does not activate lipoprotein lipase (= an enzyme that releases MK from lipoproteins) and the liver, in excess of MK, forms VLDL (very low-density lipoproteins) - Proteocatabolism in muscle

Answer 576

- increased activity of GIT, liver, and pancreas - rapid glucose and AMK resorption through the vena portae (collecting blood from unpaired organs) - increased insulin secretion and glucagon decrease = ↑ I / G ratio (= glycogen synthesis, glycolysis, lipogenesis, proteosynthesis) - Chylomicrons and VLDL - maximum concentration of ~ 2 mM reached 3-5 hours after a meal - what's happening in the liver? o ↑ AK leads to proteosynthesis, branched AK are into muscles (BCAA) o ↑ glycemia leads to glycogen synthesis, glycolysis and conversion of glc to MK and TAG o stimulation of lipogenesis = VLDL formation - adipose tissue o Large amounts of insulin activate LPL (= lipoprotein lipase), resynthesis of TAG in adipocytes and inhibition HSL - muscles o increased glycogen synthesis, conversion of Glc to lactate - proteosynthesis - do not replenish the plasma of Glc-6-P when the liver is re-established

Answer 577

- Obesity is a risk factor for diabetes mellitus II, hypertension and cardiovascular disease - the body remains in a state of fullness o the liver produces TAG, but it is not used during fasting - Long-term fullness = a lot of insulin for a long time → reduction of the number of receptors to insulin (signal strength leads to a decrease of receptors) => insulin resistance - hyperinsulinemia = the cornerstone of metabolic syndrome - obesity, hypertension, ↑ TAG, ↑ LDL and ↓ HDL - as long as β-cells can overcome insulin resistance, glycemia and lipoproteinemia are relatively normal but may progressively progress in T2DM (= diabetes mellitus II)

Answer 578

- 90% of diabetics in the Czech Republic suffer from T2DM - frequent consequence of obesity - insulin resistance → hyperinsulinemia - hyperglycemia and hyperlipoproteinemia o reduced entry and use of Glc in tissues (muscles, adipose tissue) o ↑ synthesis FA, TAG VLDL in liver o ↑ LPL activity – do not produce chylomicrons, unlike diabetes mellitus I) o glucosuria o ketone levels are usually normal because insulin inhibits HSLL