Metabolism Flashcards
1
Q
What is metabolism?
A
Process by which energy is derived from raw materials for support, repair, growth and activity
2
Q
Describe catabolism & anabolism
A
Catabolism - break down of molecules to release energy & reducing power (oxidative)
Anabolism - uses energy, reducing power and raw materials to make molecules for growth and maintenance (reductive)
3
Q
Which minerals are fat soluble?
A
Vitamin D, A, K & E
4
Q
Where is energy stored?
A
Skeletal muscle, adipose tissue and liver
5
Q
Where in the body is energy interconverted?
A
Liver and kidney
6
Q
What is the fasting blood glucose concentration?
A
5mmol/L
7
Q
How much energy is needed for a man per day?
A
120000 kJ/day (2800 kcal)
8
Q
What is basal metabolic rate?
A
Amount of energy expended daily for maintenance of cells, functions of organs and maintaining body temperature
9
Q
What are the factors affecting BMR? (5)
A
Body size Gender Environmental temperature Factors tending to change body temperature (e.g. fever) Endocrine status
10
Q
What is creatine kinase used as a clinical marker for?
A
Myocardial infarction
Creatine kinase is released from cardiac myocytes when damaged
11
Q
What is the name given to a chemical reaction that:
a. releases energy
b. requires energy
A
Releases energy - Exergonic
Requires energy - Endogonic
12
Q
What is creatine phosphate used for? Give formula
A
As a quick source of energy in cells that need to increase metabolic acitivity very quickly (acts as a reserve of high energy). e.g. skeletal muscle
Creatine + ATP + creatine kinase —> creatine phosphate + ADP
13
Q
How is creatinine produced?
A
Breakdown of creatine and creatine phosphate produced by spontaneous reaction at constant rate. Excreted via kidneys
It is a measure of muscle mass.
14
Q
What is the general formula of carbohydrates?
A
(CH2O)n
Contain aldehyde or keto group and multiple OH groups
15
Q
Which stereoisomer of carbohydrates is found in nature?
A
D-isomer
16
Q
Describe the physiochemical properties of CHO
A
Hydrophilic, water soluble, do not pass across cell membranes
17
Q
How are monosaccharides joined together?
A
Through glycosidic bonds - elimination of water
Can either be cis (alpha) / trans (beta) conformation
18
Q
Which conformation of glycosidic bond can be digested?
A
Alpha bond except for lactose (beta bond)
19
Q
Why can cellulose not be digested and what is its use?
A
It contains an beta bond - no enzyme specific to digest this
Used to increase surface area on which digestion can occur
20
Q
What are the bonds present in glycogen?
A
Alpha 1,4 bonds (strand) and alpha 1,6 bonds (branching)
21
Q
Describe metabolism of carbohydrates in the digestive tract
A
Amylase in saliva breaks glycogen to dextrins
Pancreatic amylase breaks polysaccharides to monosaccharides
Lactase, sucrase, pancreatic amylase, isomaltase breaks down disaccharides that become attached to brush border membrane of small intestine epithelial cells
22
Q
How are monosaccharides absorbed?
A
Actively transported into intestinal epithelial cells then down concentration gradient to blood to supply target tissues.
Uptake into cells via facilitated diffusion using transport proteins (GLUT1 - GLUT5) - can be hormonally controlled
23
Q
What is meant by an absolute requirement for glucose and which tissues are dependent on this?
A
Tissues that are unable to gain energy from any other means.
Red blood cells, white blood cells, kidney medulla, lens of the eye, brain, adipose tissue
24
Q
Describe glycolysis pathway to pyruvate
A
Glucose —> Glucose 6 phosphate (Hexokinase - muscle, Glucokinase - liver) —> Fructose 6 phophate —> frutose 1,6-bis-phosphate (phosphofructokinase) —> phosphoenolpyruvate —> pyruvate (pyruvate kinase)
Steps 1 & 3 requires ATP -> ADP therefore committing steps, step 10 generates ATP from ADP (substrate level phosphorylation)
25
Describe glycolysis from pyruvate to TCA cycle
Pyruvate ---> Acetyl CoA - CO2 (pyruvate dehydrogenase) ---> TCA cycle (NADH, FAD2H, GTP, -CO2
26
How is glycerol phosphate produced and why is it important?
Produced from dihydroxyacetone phosphate in the glycolysis pathway via glycerol 3-phosphate dehydrogenase and NADH
Important for trigylceride and phospholipid biosynthesis
27
How is glycolysis regulated?
1. Allosterically - Hexokinase & phosphofructokinase
| 2. Dephosphorylation - pyruvate kinase
28
What occurs in anearobic conditions?
Generation of NAD+ from conversion of pyruvate to lactate via lactate dehydrogenase
29
Where is lactate produced?
RBC and skeletal muscle
| Released into the blood and metabolised by liver (gluconeogenesis) and heart (CO2)
30
How is fructose metabolised?
Fructose ---> fructose-1-phosphate (fructokinase) ---> 2-glyceraldehyde3--phosphate (aldolase) (glycolysis pathway)
31
How is galactose metabolised?
Galactose ---> Galactose-1-phosphate (galactokinase) ---> glucose 1-phosphate converting UDP-glucose to UDP-galactose (galactose-1-phosphate uridyl transferase)
32
What is the alternative pathway if there is a galactokinase deficiency?
Galactose ---> galactitol + NADP+ (aldose reductase)
33
What happens with a depletion of NADPH?
Structure damage due to the reduction in reducing environment allowing disulphide bonds to form changing shape of proteins
34
Describe pentose phosphate pathway
Glucose 6-phosphate can be converted to 5 carbon sugar phosphates (glucose 6-phosphate dehydrogenase) using NADP+ to NADPH
35
What are the functions of the pentose phosphate pathway?
1. Produce NADPH in cytoplasm - maintains free -SH groups on cysteine, biosynthetic reducing power
2. Produce nucleotides
36
What are activating and inhibiting molecules of pyruvate dehydrogenase?
Activating: pyruvate, NAD+, insulin, ADP
Inhibiting: Acetyl-CoA, NADH, ATP
37
What else is the TCA cycle used for?
Interconversion of amino acid building blocks
38
Explain mitochondrial electron transport
Electrons are transferred trhough a seried of carrier molecules to O2 with release of energy. This energy is used to transport H+ across inner mitochondrial membrane to intermembrane space creating proton motive force
39
How is ATP produced within mitochondria?
Proton translocating ATP synthase discharges the hydrogen gradient created by electron transport driving ATP synthesis from ADP + Pi
40
What is oxidative phosphorylation?
Electron transport coupled to ATP synthesis - Electrons transferred from NADH & FAD2H to O2, energy released to generate proton motive force, energy dissipated from proton motive force to drive ATP synthesis
41
What inhibits oxidative phosphorylation?
Cyanide - binds were O2 would bind in electron transport with high affinity
Carbon monoxide
42
What do uncouplers do?
Increase the permeability of mitochondrial inner membrane to protons - dissipates proton gradient, reducing proton motive force
E.g. dinitrophenol, dinitrocresol, fatty acids
43
What is brown adipose tissue and where is it found?
Adipose tissue that contains thermogenin (UCP1) - naturally occurring uncoupling protein
Newborns and hibernating animals
44
Describe what happens in brown adipose tissue
In response to cold noradrenaline activates lipase which releases fatty acids from TAG. Fatty acids activates UCP1. Fatty acid oxidation (Acetyl CoA ---> TCA cycle ---> NADH/FAD2H ---> electron transport). UCP1 transports H+ back into mitochondria and energy is captured as extra heat
45
What is the difference between oxidative phosphorylation and substrate level phosphorylation
Oxidative phosphorylation - requires membrane associated complexes (mitochondria), indirect energy coupling (pmf), requires O2, major production of ATP
Substrate level phosphorylation - requires soluble enzymes (cytoplasmic & mitochondrial matrix), direct energy coupling (phosphoryl-group transfer), does not need O2, minor production of ATP
46
What are the classes of lipids and give examples?
Fatty acid derivatives - fatty acids, triacylglycerols (TAGs)
Hydroxy-methyl-glutaric acid derivatives - ketone bodies, cholesterol
Vitamins - D, A, K, E
47
What is the structure of triacylglycerols?
Three fatty acid side chains connected via an ester bond to glycerol backbone
48
By which processes are TAGs synthesised and destructed?
Esterification
| Lipolysis
49
Describe the metabolism of TAG in the GI tract
Hydrolysis of lipids by pancreatic lipases into fatty acids and glycerol.
Recombined to TAG in small intestine and packaged into chylomicrons (lipoprotein particle).
Released into circulation via lymphatics.
Carried to adipose tissue
Stored as TAG
50
How is excess glucose stored?
Glycogen stored in liver and skeletal muscle
| Converted to glycerol 1-phosphate in adipose tissue. Undergoes esterification to form TAG
51
What is the general formula for fatty acids?
CH3(CH2)nCOOH
| n = 14 - 18
52
What are the chemical properties of fatty acids?
They can be saturated or unsaturated
| Amphipathic (contains hydrophilic and hydrophobic groups
53
Where in the cell does fatty acid catabolism occur?
Mitochondria
54
Explain the process of fatty acid catabolism
Fatty acid is activated by linking to Coenzyme A outside mitochondria (fatty acyl CoA synthase)
Transported across membrane using carnitine shuttle
Cycles through sequence of oxidative reactions (beta-oxidation) where C2 is removed (acetyl-CoA)
55
Describe beta-oxidation
Breakdown of fatty acid to C2 intermediates (acetyl-CoA) with production of FAD2H and NADH
Does not occur in brain, RBCs & WBCs
Stops in the absence of O2
56
Describe glycerol metabolism
Glycerol + ATP ---> glycerol phosphate + ADP (glycerol kinase) --->
i. TAG synthesis
ii. Dihydroxyacetone phosphate (DHAP) + NADH ---> glycolysis
57
What are the functions of acetyl CoA?
Fatty Acid synthesis ---> TAG / phospholipids
CO2
Hydroxymethyl glutaric acid (HMG) ---> Ketone bodies (during starvation) / Cholesterol
58
What are the 3 ketone bodies?
Acetoacetate (liver)
Acetone
Beta-hydroxybuterate (liver)
59
When does the plasma level of ketones increase?
Starvation
| Untreated type 1 diabetes
60
Describe the process of ketone synthesis
Acetyl-CoA ---> Hydroxymethyl glutaryl-CoA (synthase) --->
i. Mevalonate (HMG-CoA Reductase) ---> cholesterol
ii. Acetoacetate (lyase) ---> Acetone / beta-hydroxybuterate
61
How is ketone synthesis regulated?
When insulin/glucagon ratio is high lyase is inhibited and reductase is activated - cholesterol synthesis
When insulin/glucagon ratio is low lyase is activated and reductase is inhibited - ketone body synthesis
62
Describe consequences of high levels of ketone bodies
If above renal threshold then ketonuria
Acetoacetate and beta-hydroxybuterate give ketoacidosis
Acetone can be excreted by lungs - nail varnish on breathe
63
Describe glycogenesis
Glucose + ATP ---> Glucose 6-phosphate + ADP (hexokinase - skeletal muscle/glucokinase - liver) ---> Glucose 1-phosphate (phosphoglucomutase) + UDP + H20) ---> UDP-glucose + 2Pi
Glycogen (n residues) + UDP-glucose ---> Glycogen (n+1 residues) + UDP (glycogen synthase - straight chains/branching enzyme - branching chains)
64
Describe glycogenolysis
Glycogen (n residues) + Pi ---> glucose 1-phosphate + glycogen (n-1 residues) (glycogen phosphorylase/debranching enzyme)
Glucose 1-phosphate ---> glucose 6-phosphate (phosphoglucomutase)
In the liver glucose 6-phosphate is converted to glucose via glucose 6-phosphatase - glucose released into the blood
65
Why causes glycogenolysis occur in the liver and muscles?
Liver - in response to fasting or stress (glycagon/adrenaline)
Skeletal muscle - in response to exercise (insulin)
66
What is von Gierke's disease?
Deficiency of the glucose 6-phosphatse enzyme (in liver)
67
What is gluconeogenesis and where does it occur?
Production of new glucose in liver and kidney cortex
| Reverse direction of glycolysis
68
What are the precursors for gluconeogenesis and the key enzymes required?
Galactose, fructose, glycerol (from TAG), lactate, glucogenic amino acids
Fructose 1,6-bis phosphatase & Phosphoenolpyruvate carboxykinase
69
How is gluconeogenesis regulated?
Regulated by hormones in response to starvation/fasting, prolonged exercise & stress
Glucagon/cortisol stimulates gluconeogenesis
Insulin inhibits gluconeogensis
70
Describe lipogenesis
Occurs in cytoplasm
Acetyl-CoA transported out of mitochondria by carrier molecule citrate
Acetyl-CoA ---> Malonyl-CoA, C2 molecule (Acetyl carboxylase)
Requires NADPH and ATP
Adds C2 (malonyl-CoA) to growing fatty acid chain (fatty acid synthase)
71
What are the main differences between fatty acid oxidation and fatty acid synthesis
Oxidation occurs in mitochondria, glucagon & adrenaline stimulates, insulin inhibits
Synthesis occurs in cytoplasm, glucagon and adrenaline inhibit, insulin stimulates
72
Describe lipolysis
TAGs are broken down into glycerol and fatty acids by hormone-sensitive lipase
73
How is lipolysis regulated?
Glucagon/adrenaline increase hormone-sensitive lipase enzyme
| Insulin decreases activity
74
How is glycerol metabolised?
Transported to the liver via blood.
Glycerol + ATP ---> glycerol phosphate + ADP (glycerol kinase)
Glycerol phosphate --->
i. TAG sunthesis
ii. Dihydroxyacetone phosphate (DHAP) (requires NAD+) ---> glycolysis
75
What are the essential amino acids?
Phenylalanine
Valine
Threonine
Tyrosine
Isoleucine
Methionine
Histidine
Arginine
Lysine
Leucine
76
Describe protein turnover
Muscle protein ---> free amino acids ---> amino group & carbon skeleton --->
i. glucogenic amino acids ---> gluconeogenesis
ii. ketogenic amino acids ---> ketone bodies
77
How is protein catabolism controlled?
Only occurs in extreme stress
Insulin increases synthesis & decreases breakdown
Glucocorticoids (cortisol) decrease synthesis & increases breakdown
78
How is the amino group removed and where does this occur?
Occurs in the liver
| Either through transamination (transfer of amino group) or demaination
79
What are the reaction involved with transamination?
Amino acid + alpha-keoglutarate ---> glutamate + keto acid
| Amino acid + oxaloacetate ---> aspartate + keto acid
80
What are the two key enzymes in deamination?
```
Alanine aminotransferase (ALT) - alanine ---> glutamate
Aspartate aminotransferase (AST) - Glutamate ---> aspartate
Their plasma level is measured - liver function test
High levels = liver damage
```
81
Describe deamination
Disposal of amine group to form ammonia which is converted to ammonium ion
Either removed in urea or added to an amino acid, glutamine
82
What occurs in the urea cycle
Ammonia is added within the mitochondrial matrix
Glutamate ---> Aspartate ---> urea cycle
Occurs within the liver
83
Why is ammonia toxic?
Reduces TCA cycle as is reacts with the alpha-ketoglutarate to form glutamate - energy supply disrupted
pH effects - makes more alkaline
Affects neurotransmitter synthesis
84
How are lipids transported in the blood?
Lipid soluble therefore require carriers
i. lipoprotein particules (small assemblies of lipid molecules surrounded by apolipoproteins) - Each lipoprotein has its own set of specific apolipoproteins
ii. transport proteins - albumin
85
What is the role of apolipoproteins?
Activation of enzymes
| Recognition of cell surface receptors
86
What are the different classes of lipoprotein particles?
Chylomicrons - Formed in small intestine, TAGs from diet to adipose tissue, released via lymphatic system into blood
Very low density lipoproteins (VLDL) - Formed in liver, TAGs from liver to adipose tissue
Low density lipoproteins (LDL) - Formed in liver, cholesterol rich, carry from liver to tissues
High density Lipoproteins (HDL) - formed in tissues, cholesterol from tissues to liver
87
What is the importance of the HDL/LDL ratio
It is an expression of how much cholesterol is being stored in tissues and how much is being removed back to the liver
88
How are TAGs transfered from chylomicrons and VLDL?
Endothelial cells of capillaries have lipase on outside which bind chylomicrons and VLDL. These cleave TAG into glycerol (remain in circulation to go to liver) and fatty acids (enters tissues for metabolism)
89
How is cholesterol transferred from LDL?
Cells have LDL receptors
Receptor/LDL complex enters through endocytosis
Cholesterol ester released by lysosomes and cleaved into cholesterol and fatty acid
90
How do HDL load?
HDL synthesied as shells in liver
Sequester cholesterol from capillaries
Mature into HDL particles
Carry cholesterol back to liver and other cells
91
What are reactive oxygen species (ROS)?
(O2)- unpaired electron - produced during electron transport chain
92
How are superoxide radicals removed?
Superoxide radicals ---> hydrogen peroxide (superoxide dismutase, SOD) ---> H20 + O2 (catalase)
93
What are hydroxyl radicals and how are they produced?
*OH produced from H2O2 or (O2)- by ionising radiation (UV, x-rays, gamma rays)
94
What is nitric oxide and peroxynitrite?
*NO
| Arginine ---> *NO (inducible nitric oxide synthase (iNOS) + O2 ---> peroxynitrite, ONOO-
95
What is oxidative burst?
Rapid release of superoxide and hydrogen peroxide from cells usually leukocytes by NADPH oxidase - kills pathogens
96
What are the cellular defences for reactive oxygen species?
SOD - superoxide dismutase
Catalase
NADPH - maintains reducing environment (prevents disulphide bonds forming), formed mainly by pentose phosphate pathway by glucose 6-phosphate dehydrogenase
Glutathione (GSH) - reduces disulphide bonds of proteins by being an electron donor (in the process producing tlutathione disulphide)
Other antioxidants - Vit C, E, A, polyphenols (red wine), beta-carotene (carrots), selenium, zinc
97
What are Heinz bodies?
Denatured heamoglobin within RBCs caused from a NADPH (causing dyfunction of glutathione) or glucose 6-phosphate dehydrgenase deficiency.
Electron from heamoglobin is transfered to oxygen molecule creating ROS leading to damage and premature lysis.
98
What is pharmacology, pharmacodynamics and pharmacokinetics?
Pharmacolgy - Study of how chemical agents affect the function of living systems
Pharmacodynamics - What the drug does to the body
Pharmacokinetics - What the body does to the drug
99
What are the building block of pharmacokinetics?
```
Absorption
Distribution
Metabolism
Elimination
(ADME)
```
100
What are the phases of drug metabolism?
Phase 1 - Adds or exposes reactive group (oxidation, reduction, hydrolysis)
Phase 2 - Altered drug molecule is combined with a water soluble group (conjugation)
101
What is the enzyme responsible for phase 1 metabolism of drugs?
Cytochrome P450 enzyme system (CYP)
| Cofactor - NADPH (from pentose phosphate pathway)
102
Where does phase 2 of drug metabolism occur?
Liver
103
What are the phase 2 drug metabolism reactions?
Glucuronidation, sulphate conjugation and glutathione conjugation
104
What are the factors effecting drug metabolsim?
Genetic factors - polymorphisms (individual variation), gene deletions (enzyme deficiency)
Environmental factors - enzyme inhibition (grapefruit juice etc), enzyme induction (metabolism of one agent induces enzymes in the liver - increased metabolism of other drugs)
105
What occurs during alcohol metabolism?
Alcohol + NAD+ ---> Acetaldehyde + NADH (toxic metabolite) (Alcohol dehydrogenase & CYP2E1) ---> Acetic acid (aldehyde dehydrogenase)
106
Describe the difference between the efferent and afferent pathway
Afferent - body to brain
| Efferent - brain to body
107
What controls the biological clock?
Suprachiasmatic nucleus in hypothalamus
108
What is an endocrine hormone?
Chemical signal produced in endocrine gland/tissue that travel in the blood stream to cause effect on other tissues - only interact where there are receptors
109
What is the control of the endocrine system?
Hypothalamus - anterior pituitary gland - endocrine glands
110
What is the hypothalamic-pituitary-adrenal axis?
Hypothalamus releases corticotrophin releasing hormone (CRH) with stimulates anterior pituitary gland to release adrenocorticotrophic hormone which stimulates the adrenal cortx to release cortisol
Regulated by negative feedback
111
How are hormones transported?
Most are lipid soluble so travel bound to a protein. There is a dynamic equilibrium between bound and free forms.
112
What are the roles of carrier proteins of hormones?
Increase solubility
Increase half-life
Readily accessible reserve
113
What are the classes of human hormones?
Polypeptide hormones - e.g. insulin, growth hormone, tyrotrophin-releasing hormone
Glycoprotein hormones - all have two polypeptide chains e.g. tyroid stimulating hormone, follicle stimulating hormone, luteinising hormone, human chorionic gonadotrophin
Amino acid derivative hormones - tyrosine e.g. T4 (tetra-iodothyronine) and T3 (tri-iodothyronine), adrenaline, histamine
Steroid hormones - all derived from cholesterol e.g. calciferold (vit D), corticosteroids (adrenal cortex), progestins, androgens, oestrogens (sex hormones)
114
How do hormones elicit a response?
If they are unable to cross the cell membrane (water soluble) then they bind to a cell surface receptor activating a second messenger which exerts metabolic effects within cell
If they are lipid soluble they pass across the membrane and bind to a receptor in the cytoplasm and effect transcription of a protein
115
Where does the control of appetite originate?
Satiety centre (appetite centre) in the arcuate nucleus in hypothalamus
116
Describe the neuronal composition of the arcuate nucleus
Primary neurones - sense glucose, fatty acids in blood and respond to hormones
Secondary neurones - synthesise input from primary neurons, co-ordinate a response
117
Describe the different primary neurones of the arcuate nucleus
Excitatory - Neuropeptide Y (NPY), agouti-related peptide (AgRP) ---> stimulate appetite
Inhibitory - Pro-opiomelanocortin (POMC) which can be cleaved into i. beta-endorphin ---> reward system and ii. alpha-melanocyte stimulating hormone (alpha-MSH) ---> suppresses appetite
118
Describe the feedback from the gut to the hypothalamus
Ghrelin - peptide hormone release from wall of stomach when empty
Stimulates excitatory neurones in arcuate nucleus, stimulates appetite
Filing of stomach inhibits ghrelin release
PYY - peptide hormone released from wall of small intestine, suppresses appetite
119
Describe the feedback from the body to the hypothalamus within regards to appetite
Leptin - peptide hormone released from adipocytes
Stimulates inhibitory neurones in arcuate nucleus, supresses appetitie
Leptin also induces expression of uncoupling proteins in mitochondria - energy dissipated as heat
Insulin - suppresses appetite, same mechanism as leptin
Amylin - peptide hormone, secreted from beta-cells in pancrease, supresses appetite
120
What is foetal programming?
The fetus adapts to conditions in utero, such as supply of nutrients - biochemical adaptation become programmed in predisposing to adult disease conditions
Epigenetics - inherited phenotype resulting from changes in a chromosome without changes in DNA sequence
DNA methylation - changes in histone structure - suppression of gene transcription
121
Describe the exocrine function of the pancreas
Produces digestive enzymes secreted directly into duodenum via oancreatic duct - forms bulk of gland
122
Describe the endocrine function of the pancreas
Hormone production from islets of langerhans
Secrets: Insulin, glucagon, somatostatin, pancreatic polypeptide, ghrelin (If gays suck penis, good)
beta-cells - insulin
alpha-cells - glucagon
delta-cells - somatostatin
123
Describe insulin structure
Two un-branched peptide chain joined together by 2 di-sulphide bonds between cysteine residues
124
Describe insulin synthesis
1. Insulin mRNA translated as preproinsulin
2. Removal of signal peptide during insertion to ER gives proinsulin
3. Within ER exposed to endopeptidases which excise C peptide giving insulin
4. Insulin and free C peptide are packaged into vesicles in golgi which accumulate in cytoplasm
5. Exocytosis
125
Describe insulin secretion from Islets of Langerhans
1. Glucose uptake into beta-cells in islets of langerhans via facilitated diffusion with GLUT2
2. Glycolysis
3. Increase ATP concentration blocks ATP-sensitive potassium channel
4. Depolarisation as K+ cannot move out of cell
5. Voltage gated calcium channel opens
6. Ca2+ triggers exocytosis of insulin
126
What does insulin do?
1. Increases glucose uptake by tissues & glycogen synthesis (insertion of GLUT 4 channel)
2. Increases uptake of amino acids for protein synthesis in muscles
3. Inhibits breakdown of amino acids in liver
4. Increases storage of TAG into adipose tissue
5. Inhibits breakdown of fatty acids
127
Describe insulin receptor and mechanism
Insulin binds to insulin receptor (2 subunits, alpha and beta chains, alpha extracellular, beta transmembrane)
Mechanism:
1. alpha chains move together and fold around insulin
2. beta-chains move together making an active tyrosine kinase
3. Initiates phosphorylation cascade which results in increased GLUT 4 expression
4. Resulting in cells taking up more glucose
128
What is the structure of glucagon?
1 polypeptide chain, no disulphide bridges
129
What are the effects of glucagon?
Glycogenlysis (glycogen breakdown)
Gluconeogenesis (Breakdown of amino acids to make glucose)
Lipolysis (Increase fatty acid breakdown)
130
Which hormones are produced in the pituitary gland?
```
TSH - thyroid stimulating hormone
ACTH - adrenocorticotropic hormone
GH - growth hormone
LH - luteinising hormone
FSH - follicle stimulating hormone
Prolactin
```
131
What hormones do the adrenals secrete and the location of their secretion?
Cortex:
Mineralocorticoids (aldosterone) - zona glomerulosa
Glucocorticoids (cortisol, corticosterone) - zona fasciculata
Androgens (sex hormones)- zona reticularis
Medulla:
Adrenaline
132
How are steroid hormones synthesised?
Synthesised from cholesterol via progesterone
133
Describe hypothalmic-pituitary-adrenal axis for cortisol
1. Corticotrophin releasing hormone is released by the hypothalamus in response to stress
2. Causes ACTH secretion from corticotrophs in anterior pituitary
3. Binds to receptors on zona fasiculata and reticularis in adrenals
4. Binding leads to activation of cholesterol esterase converting cholesterol esters to free cholesterol to synthesise cortisol
5. Corisol is transported to target tissues via corticosteroid-binding globulin
134
How does cortisol elicit an effect?
1. Crosses plasma membrane and binds to cytoplasmic receptors
2. Hormone/receptor complex then enters nucleus to interact with specific regions of DNA
135
Describe adrenaline synthesis
Tyrosine ---> dopamine ---> noradrenaline ---> adrenaline
| Then bound in vesicles until required
136
What are the effects of adrenaline?
Increases cardiac output, increased blood supply to muscles
Increased mental alertness
Increased glycogenolysis in liver and muscles
Increases lipolysis in adipose tissues
137
Explain the connection between ACTH and increased pigmentation
The precursor of ACTH is POMC (pro-opiomelanocortin). POMC also is the precursor for alpha-MSH (melanocyte stimulating hormone) and endorphins.
The alpha-MSH region lies within the ACTH sequence, therefore giving ACTH some MSH-like activity when present in excess.
138
What are the effects of cortisol?
Effects in starved and stressed states
| Increases proteolysis, lipolysis and gluconeogenesis
139
What are the two hormones produced by the thyroid gland?
Tetra-iodothyronine (T4) - longer half life
Tri-iodothyronine (T3) - more potent
Target organs can cleave T4 to make T3
140
Describe the control of thyroid function
Hypothalamus releases thyrotrophin releasing hormone (TRH)
Stimulates pituitary to release thyroid stimulating hormone (TSH)
Stimulates release of T3 and T4 from thyroid
Controlled by negative feedback
141
What are the acute and chronic effects of TSH on thyroid gland
Acute - stimulates synthesis, storage and secretion of T3 and T4
Chronic - stimulates growth and division of follicle cells (enlarged gland causes goitre)
142
Describe thyroid hormone synthesis and secretion
ATE ICE
1. Active transport of iodide into thyroid follicular cell
2. Thyroglobulin synthesised in ribosomes and packaged into secretory vesicles
3. Exocyctosis of thyroglobulin into follicular lumen
4. Iodination of tyrosine residues in thyroglobulin to form active thyroglobulin (perioxidase required to form active iodine)
5. Coupling of DIT (di-iodinated tyrosine) and MIT (mono-iodinated tyrosine) on thyroglobulin
6. Endocytosis of thyroglobulin into follicular cell via colloid vesicles, lysosomes digest vesicle and proteolysis of DIT and MIT leaving T3 and T4 which diffuses into blood
143
How are T3 and T4 transported in the blood?
On thyronine binding globulin (TBG) (as it is lipid soluble)
144
What are the general effects of thyroid hormones?
Increase basal metabolic rate
Stimulate most metabolic pathways
Promotes normal growth and development of tissues
Increases responsiveness of tissues to sympathetic nervous system (noradrenaline)
145
How does the skeleton interact with calcium?
It acts as the major reservoir - stored as hydroxyapatite crystals (Ca10(PO4)6(OH)2) in collagen fibrils
Helps buffer serum levels - releasing calcium phosphate into intersticium
146
Describe bone deposition and reabsorption
Deposition: Osteoblasts produce collagen matrix which is mineralised by hydroxyapatite
Reaborption: Osteoclasts produce acid micro-environment in which hydroxyapatite dissolves liberating Ca2+ and Pi
147
Described how calcium balance is maintained
Interstinal - uptake in small intestine (energy dependent)
Bone - deposition and reabsorption
Kidney - Filtered calcium is reabsorbed (99%)
148
Describe the hormones involved in calcium regulation
Parathyroid hormone (PTH) & Vitamin D - increase serum Ca2+ levels
PTH produced by chief cells in parathyroid gland, regulated by negative feedback - released as pre-hormone which undergoes proteolytic cleavage
Calcitronin - no evidence for humans
149
What is the action of PTH
Bone: Stimulates osteolysis
1. Induces osteoblastic cells to synthesis and secrete cytokines
2. Cytokines stimulate differentiation and activity in osteoclasts and protect them from apoptosis
3. PTH decreases osteoblasts activity exposing bony surface to osteoclasts
4. Reabsorption of mineralised bone and release of Pi and Ca2+ into extracellular fluid
Kidney: Increases Ca2+ reabsorption & inhibits Pi reabsorption
Gut: Stimulates conversion of Vitamin D to its active form which increases uptake of Ca2+ from gut
150
Describe role of Vitamin D in calcium levels
2 forms of vitamin D - D3 (cholecalciferol - skin/diary) and D2 (ergocalciferol - yeast/fungi added to margarines)
Hydroxylation in the liver and kidney produce calcitriol - final hydroxylation in kidney regulated by PTH
Calcitriol increases Ca2+ and PO4 absorption in intestine, increases Ca2+ absorption and Pi excretion in kidney and mobilises calcium stores in bone
151
Describe the role of calcitonin
Secreted by parafollicular cells - possible role during pregnancy to preserve maternal skeleton
152
What is the role of glutathione?
Tripeptide with antioxidant properties preventing damage from reactive oxygen species
It reduces disulphide bonds formed within cytoplasmic proteins to cysteines by serving as an electron donor, in the process becoming glutathione disulphide (can be converted back by glutathione reductase and NADPH)
153
Describe the process by which glucose is stored as glycogen
Glucose 6-phosphate ---> glucose 1-phosphate (phosphoglucomutase)
Glucose 1-phosphate + UTP + H2O --> UDP-glucose
Glycogen + UDP-glucose ---> glycogen (n+1 residues) + UDP (glycogen synthase/branching enzyme)
154
Describe the process of glycogenolysis
Glycogen + Pi ---> glycogen (n-1 residues) + glucose 1-phosphate
Glucose 1-phosphate ---> glucose 6-phosphate (phosphoglucomutase)
Muscle: glucose 6-phosphate ---> glycolysis
Liver: glucose 6-phosphate ---> glucose (glucose 6-phosphatase)
155
What is Von Gierke's disease?
Deficiency in glucose 6-phosphatase
| (Gluconeogensis) glucose 6-phosphate ---> glucose
