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Biochemistry > Carbohydrate Metabolism I > Flashcards

Carbohydrate Metabolism I Flashcards

1
Q

Favorable & Unfavorable Processes

A
  1. Favorable processes (deltaG is negative2) .
  2. Unfavorable processes (DeltaG is Positive)
  3. Coupling of a favorable processes (negDeltaG) with an unfavorable processes (posDeltaG) to yield an overall negative DeltaG
  4. Endergonic reactions (energy requiring) can be coupled to the exergonic (energy yielding) hydrolysis of ATP.
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2
Q

ATP Hydrolysis

A
  1. The change in free energy asssociated with the hydrolysis of ATP is due to the:
    a) repulsion of adjacent negatively charged oxygen atoms and
    b) the resonance stabilization associated with the products i.e. ADP
  2. ATP + H2O —-> ADP + Pi + ENERGY
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3
Q

ATP Generation

A
  1. ADP + Pi –> ATP + H2O
  2. Requires input of 7.3 kcal per mole of ATP
  3. ATP can be generated in cytosol (glycolysis)
  4. ATP can be generated in mitochondria (aerobic respiration) - vast majority of ATP production here.
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4
Q

ATP Consumption

A

ATP is constantly being consumed:

  1. ATP hydrolysis ATP + H2O –> ADP + Pi + ENERGY
  2. Coupling to endergonic reactions
  3. Active Transport (lower to higher gradient)
  4. Muscular contractions
  5. Maintenance of cell volume
  6. Powering of cilia
  7. Nerve impulses
  8. Phosphorylation (enzymatically donating and covalently attaching a phosphate group to a substrate)
  • Kinases add phophate group
  • Transferase remove phosphate group (and transfer it to the target protein)
  1. ATP has other roles in the body, including extracellular signaling
  2. ATP is constantly replenished by the oxidation of foods
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5
Q

ATP Physiological Significance

A
  1. Not all biologically significant “high energy compounds” (which btw, ATP is not really) contain a phosphate group, e.g. Acetyl-CoA
  2. A person engaging in moderate physical activity produces about 60 Kg of ATP per day, while the total human body stores approximately 50 g; even that is later used up in everyday activity.
    • 2100 Kcal/7 Kcal (to make ATP) = 300 moles of ATP
    • 300 moles (w/mw) = x/500 –> 150,000 g = 150 Kg
    • In reality, only 60 Kg ATP (NOT efficient)
  3. Equilibrium between ATP, ADP, and AMP is maintained by different mechanisms, which are all very critical.
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6
Q

Cellular Reception

A

Metabolic regulation can be:

  1. Intracellular
    1. Product inhibition
    2. Allosteric inhibition
    3. Allosteric activation
    4. Etc.
  2. Intercellular
    1. Surface to surface cell contact
    2. Hormones, growth factors, cytokines, neurochemicals, etc.
    3. Synaptic signlaing between cells transmitting messages
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7
Q

Mechanisms for transmission of regulatory signals between cells

A
  1. Synaptic signaling via Neurotransmitters through nerve cell
  2. Endocrine signaling via hormone through capillaries
  3. Direct contact via signaling cells through Gap Junctions.
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8
Q

Cells must respond to signals from

A
  1. Endocrine (distant locations); glands, hormones via capillaries
  2. Paracrine (nearby locations); “paracrine factors”
  3. Autocrine (same cells)
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9
Q

Second Messenger System

A
  1. Operate as an amplifying cascade that transmits the binding effect of hormones, growth factors, cytokines, neurochemicals, etc., to a specific cellular response.
  2. The cell releases second messenger intracellularly in response to exposure to extracellular signals - the first messenger.
  3. There are a number of different membrane receptors including G Protein-Coupled Receptors (GPCR’s).
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10
Q

G Protein-coupled receptor

A
  1. The extracellular domain contains the binding site for a ligand (a hormone or neurotransmitter).
  2. Has seven transembrane helices within the lipid bilayer.
  3. Intracellular domain (tertiary structure) that interacts with G-proteins.
  4. The act of extracellular signal binding transmits the message into the cell via inducing conformation changes in the receptor.
  5. These ligands bind with weak forces since at some point they need to get readily detached.
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11
Q

G Protein in action

A
  1. Unocccupied receptor does not interact with Gs (stimulation) protein, which is a heteroTrimer with GDP bound.
  2. Occupied receptor changes shape and interacts with Gs protein. Gs protein releases GDP and binds GTP.
  3. α Subunit of Gs protein (GTP bound) dissociates and activates adenylyl cyclase, which is responsible for ATP → cAMP + PPi (two phosphates).
  4. When hormone is no longer present, the receptor reverts to resting state. GTP on the α subunit is hydrolyzed to GDP, and adenylyl cyclase is deactivated.
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12
Q

Various G Alpha subunits

A
  1. Gs - stimulates adenylyl cyclase
  2. Gq - stimulates inositol triphosphate and diacylglycerol
  3. Gi - inhibits adenylyl cyclase
  4. Gt - associated with transducin

*No need to know too much in details*

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13
Q

Actions of cAMP

A
  1. cAMP-dependent protein kinase A has 2 Regulatory (repressor) subunits and 2 Catalytic (kinase) subunits i.e. heterotetramer.
  2. ATP —adenylyl cyclase—> cAMP
  3. 4 cAMP units bind to the Regulatory subunits (2 in each subunit) and Catalytic subunits are dissociated and become active catalytic unit of protein kinase
  4. Certain protein substrate then gets phosphrylated via ATP hydrolysis carried out by Active catalytic unit of protein kinase, thusly resulting in intracellular effects.
  5. Protein phosphatase will revert the phosphorylation process and return the protein substrate to original state.
  • “Phosphorylatable” amino acids include Serine, Threonine, and Tyrosine in proteins.
  • Note that ATP is not only used for energy purposes but also for cellular processes i.e.phosphorylation.
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14
Q

Protein Kinase A (PKA)

A
  1. PKA is highly selective
  2. There are also cAMP-independent protein kinases
  3. Catalytic subunits phosphorylate serine (S), Threonine (T), and Tyrosine (Y) sidechains.
  4. Cholera toxin activates adenylyl cyclase in intestinal mucosa, resulting in the loss of salts from the intestinal epithelium followed by osmotically generated diarrhea.
  5. Pertusis toxin inhibits the inhibition of adenylyl cyclase.
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15
Q

Cyclic Nucleotide Phosphodiesterase

A
  1. Cyclic AMP is hydrolyzed to 5’-AMP by cyclic nuclotide phosphodiesterase (PDE); phosphodiester bond = bonds between sugars and phosphate groups
  2. There are 11 different families of cyclic nucleotide PDE’s: 1, 3, 4, 5, etc.
  3. There is pharmacological potential in inhibition of different PDE’s, which means increased level of cAMP:
    • Methylxanthine derivatives (theophylline and caffeine) not responsible for specific names
    • Sildenafil; can lead to melanoma however
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16
Q

Facilitated Glucose Transporter (GLUT)

A
  1. GLUTs allow glucose and other sugars to enter the cell under certain conditions
  2. There are about a dozen different GLUT (glucose transporter isoforms) including:
    1. GLUT-1, 3, 4, etc involved in basal glucose uptake from blood and other extracellular fluids. Found in most tissues.
    2. GLUT-2 is found in liver and kidney cells AND basolaterl membrane of small intestine. It has HIGH Vmax (capacity) and HIGH Km (low affinity); this allows them to be only “really” active when the blood glucose level is high (low affinity) and once needed, get the job done efficiently (high capacity). Both liver and kidney regulate carbohydrate.
      • Liver is METABOLIC (e.g. gluconeogenesis, glycogenlysis, & glycogenesis)
      • Kidney recycles or excrete excess glucose
    3. GLUT-5: Transport of fructose
    4. GLUT-4: Insulin sensitive GLUT found in adipose tissue and skeletal muscle tissue. Insulin (hormone) recruits inactive GLUTs in the Golgi and translocates them to the plasma membrane.
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17
Q

Facilitated transport of GLUT

A

Facilitated transport

  1. Glucose binds GLUT
  2. Direction of GLUT is reversed
  3. GLUT returns to original state
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18
Q

Sodium Glucose Transport Protein (SGLT)

A

Glucose is transported from LOW concentration (intestinal lumen) to HIGH concentration (epithelial cell) AGAINST the gradient by process of symport or co-transport

  1. Active transport of Na+ FROM cell into blood creating electrochemical gradient; Na+/K+-ATPase aka sodium-potassium pump; ATPase present since the transport needs energy to power up the pump.
  2. Na+ enters cell through Sodium Glucose Transport Protein (SGLT) & Glucose is co-transported with Na+; SYMPORT where without glucose available, Na+ does not enter by itself i.e. entry of Na+ is depndent on presence of glucose
  3. Glucose is transported out of cell, following concentration gradient by GLUT (facilitated passive glucose transport).
  4. SGLT operates in cells of the intestine, renal tubules, and choroid plexus (brain structure containing cerebrospinal fluid). *no specific name*
  5. Although SGLT and GLUT don’t use up ATP themselves (both are passive transports), they indirectly requires ATP due to the activity of sodium-potassium pump to create the Na+ gradient in the first place.
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19
Q

Oral rehydration Therapy

A
  1. Oral rehydration therapy is predicated on the symport of Na+-Glucose
  2. Adding glucose into the water help quick hydration along with a pinch of salt.
    3.
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20
Q

Blood glucose concetration

A
  • Blood glucose concentration is about 5 mmol/L (about 90 milligrams per 10 liters)
  • 180 (MW of glucose) x 0.005 molar x 6 liters of blood = approx. 6 grams of glucose in the blood.
  • Very low sugar level in the body meaning it is very efficient in its metabolism/homeostasis.
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21
Q

Carbohydrates

A
  1. Name “carbohydrate” is derived from the fact that simple sugars can be represented by the formula (CH2O)n e.g. C6H12O6; “Carbon-Water”
  2. # C = #O
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22
Q

Carbohydrate Function

A
  1. Sources of calories (carbohydrates contain about 4 Kcal per gram)
  2. Storage of energy (glycogen)
  3. Bound to proteins and lipids (glycoproteins and glycolipids)
  4. Structural components e.g. Cellulose
  5. “Sugar coating” of cells
  6. Constituents of nucleotides; sugar phosphate backbones of DNA i.e. deoxyribose
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23
Q

Representative human monosaccharides

A
  • 3 Carbons: trioses e.g. Glyceraldehyde
  • 5 Carbons: pentoses e.g. Ribose
  • 6 Carbons: hexoses e.g. Glucose
  • 9 Carbons: nonoses e.g. Neuraminic acid
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24
Q

Alpha Glucose

A
  • Aldoses: aldehyde group in the Anomeric Carbon
  • Ketoses: keto group in the Anomeric Carbon
  • They have the SAME formula but just different structure e.g. aldose vs ketose; ribose vs ribulose; glucose vs fructose, etc.
  • Bottom line they are ISOMERS to each other
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25
Q

Enantiomers in carbohydrates

A
  • Enantiomers are non-superimposable mirror images of each other
  • With only few exceptions, the D-glucose is the only naturally occurring sugar which the body can metabolize (hence the name, “Dextrose”)
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26
Q

Epimers

A
  1. Epimers are isomers that differ in configuration about one asymmetric carbon
  2. Anomers are epimers that differ in configuration about the Anomeric carbon
  3. Epimers are NOT enantiomers (a complete mirror image)
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27
Q

Cyclization

A
  1. Cyclization creates an anomeric carbon, which generates the alpha and the beta configurations of glucose.
  2. These two configurations are known as anomers (specific type of epimers), while Carbon-1 of glucose also known as the Anomeric Carbon.
  3. The alpha and beta anomers in solution spontaneously interconvert and are in equilibrium with one another. This is known as MUTAROTATION.
  4. At equilibrium, 36% of the molecules are alpha D-glucose, 63% are in beta D-glucose, while less than 1% is the open chain form of D-glucose
  5. There are enzymes that can potentiall identify one or the other anomer.
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28
Q

Reducing Sugar

A
  1. If hydroxyl group on the anomeric carbon of a cyclized sugar is not linked to another compound by a glycosidic bond (nor anomeric carbon is a ribulose/fructose), the ring can open into D-glucose (without alpha or beta designation at this point)
  2. This non-linked sugar is known as a reducing sugar i.e. a reducing agent.
  3. Glucose is a reducing sugar
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29
Q

Reducing Sugar Assays

A
  1. Oxidation of the glucose (a reducing agent) reduces the cupric ions (Cu2+) to cuprous ions (Cu1+), yielding a color change. This color change is proportional to the concentration of glucose (measurable). Same principle goes for all the test shown below.
  2. Tests for reducing sugars include:
    1. Benedict’s reagent
    2. Fehling’s solution
    3. Tollen’s reagent
    4. Clinitest tablets ≈ Benedict’s reagent
  3. The presence of reducing sugar in the urine might be indicative of metabolic disorders of fructose or galactose metabolism, as well as diabetes.
  4. Glucose at a concentration of 5mM (mmol) is the major reducing chemical in blood.
  5. Common enzymatic assay for blood glucose uses glucose oxidase and peroxidase. The H2O2 produced will oxidize a (colorless) chromogen to a (color-bearing) chromophore
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30
Q

Glycosidic bonds naming

A

Glycosidic bonds are named according to the:

  1. Number identifying the specific connecting carbons
  2. Specific configuration, either alpha or beta
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31
Q

Representative Hexose Monosaccharides

A
  1. D-fructose; constituent of sucrose
  2. D-galactose; constituent of lactose
  3. D-glucose; source of energy
  4. D-mannose - constituent of glycoproteins
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32
Q

Physiologically important Disaccharides

A

Two monosaccharides joined by a glycosidic linkage in a condensation reaction form a disaccharide; loss of H2O

  1. Sucrose (glucose—-fructose in alpha-1,2-beta)
    1. NOT a reducing sugar
    2. Present in sugar cane and other fruits e.g. sugar beats
    3. Hydrolyzed (breaking glycosidic linkage) by sucrase
  2. Lactose (galactose—-glucose in beta-1,4 linkage)
    1. Reducing sugar
    2. The sugar found in milk
    3. Hydrolyzed by lactase
  3. Maltose (glucose—-glucose in alpha-1,4 linkage)
    1. Reducing disaccharide
    2. Product of a hydrolysis of starch (large polymer of glucose; Nutritional vs. Cellulose (structural))
    3. Hydrolyzed by maltase
    4. Body can metabolize (but not make) starch
  4. Isomaltose (glucose—-glucose in alpha-1,6 linkage)
    1. Reducing disaccharide
    2. Product of starch and glycogen partial hydrolysis
    3. Hydrolyzed by isomaltase
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33
Q

Polysaccharides

A
  1. Polysaccharides are polymers of monosaccharides
  2. Cellulose (inedible), glycogen (made by body), and starch (don’t make but edible) are homopolymers of glucose.
  3. Starch is found in granules inside of seeds and tubers
  4. Starch is a mixture of 2 polymers: Amylose and Amylopectin
    1. Amylose is a straight (spiral) chain polysaccharide composed of D-glucose monomers
    2. Amylopectin is a branched chain polysaccharide composed of D-glucose monomers joined by both alpha-1,4 glycosidic bonds and also alpha-1,6 glycosidic bonds (branching)
    3. Starch contains about 25% amylose and 75% amylopectin
  5. Glycogen (“animal starch”) serves as a reserve carbohydrate in animals
  6. Glycogen is similar to amylopectin but is more highly branched
  7. Cellulose is the most abundant of all carbohydrates on this planet, serving as a structural component in plants
  8. Cellulose is not digested by humans as humans lack the enzyme that can celave the beta-1,4 glycosidic linkages; it is COMPLETELY different fom alpha-1,4 or beta-1,6 as each bond has its own uniqueness and their own enzymes.
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34
Q

Aglycones

A
  1. Carbohydrates can be attached by glycosidic bonds to noncarbohydrates
  2. These noncarbohydrates are known as Aglycones
  3. Aglycones can include the following:
    1. Purine and pyrimidine bases
    2. Steroids
    3. Lipids
    4. Proteins
    5. Etc.
  4. N-glycosidic bond to asparagine
  5. O-glycosidic bond to serine (not every single AA’s get glycosylated but selected ones)
    6.
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35
Q

Glycosidases

A
  1. Glycosidases hydrolyze glycosidic bonds
  2. Glycosidases can exhibit specificity for:
    1. Structural context
    2. Configuration of the glycosidic residue
    3. Number of monomers in the chain
    4. Specific type of bond
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36
Q

Salivary glands

A
  1. The salivary glands secrete about 1 liter of liquid daily into the oral cavity
  2. This fluid contains alpha-amylase, an endoglucosidase that hydrolyzes dietary starch and glycogen within internal alpha-1,4 bonds at random intervals thusly exposing a lot more surface area of large starch. This also maximizes the effectiveness of exoglucosidases that hydrolyzes only the first and last bond of the carbohydrate chains.
  3. The products of this digestion include starch dextrins, isomaltose, maltose, and maltotriose (trisaccharide of glucose); only Starch is broken down at this point while lactose, sucrose, and cellulose remain in tact.
  4. Amylose does NOT go as far as producing monomers from glycosidases but at most to disaccharides
  5. The bigger the polysaccharides are, the lesser sweet it is (e.g. starch)
  6. Isomaltose, maltose, and maltotriose are small enough to give off sweetness however.
  7. Other oral digeswtive functions of saliva include:
    1. Hydration of food; in order for the enzyme to do their jobs of breaking food down. Thus, eating any food takes a lot of water into it for proper digestion e.g. saliva, bile, stomach acid, etc. resulting in net loss of water; reason why eating raw foods is good for water content preservation.
    2. Reduction of size of food (increasing the surface-to-volume ratio), thusly enhancing its enzymatic digestability; e.g. endoglucosidases and exoglucsidases cooperation.
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37
Q

Digestion

A
  1. The salivary alpha-amylose is inactivated in the stomach by the HCl secreted by the peptic cells, which also kills bacteria, denature proteins, and activate pepsinogen.
  2. The stomach contents enter the duodenum, into which the pancreatic bicarbonate enters
  3. The acidity is neutralized, and the carbohydrates are further digested by pancreatic alpha-amylase
    1. Salivary and pancreatic alpha-amylases are isoenzymes; both are enzymes.
  4. The final digestion of carbohydrates occurs primarily at the mucosal lining of the upper jejunum (middle) by disaccharidases of the intestinal brush-border membrane
  5. The disaccharidases include the following:
    1. Lactase (beta galactosidase)
    2. Isomaltase
    3. Sucrase
    4. Trehalase (trehalose assoc. w/ fungi)
    5. Maltase
  6. These disaccharidases are associated with the luminal side of the intestinal brush-border
  7. Most of the dietary sugars are absorbed in the duodenum (beginning) and the upper jejunum which are consequently transported to liver.
38
Q

Sugar Absorption

A
  1. Different sugars have different machanisms of absorption utilizing differet transporters
  2. Galactose and glucose are transported into the mucosal cells by SGLT-1 (sodium-dependent glucose cotransporter)
  3. Fructose is transported by GLUT-5, which does not require sodium
  4. Glucose, galactose, and fructose are all transported into the portal circulation by GLUT-2.
39
Q

Defects in disaccharidases

A
  1. Defects in disaccharidases can result in the passage of the undigested disaccharide into the large intestine.
  2. This can lead to:
    1. Osmotic diarrhea; presence of osmotically active material draws water from the mucosa into the large intestine
    2. Fermentation of the disaccharide by colonic bacteria, generating osmotically active metabolites e.g. two-&three-carbon compounds (also osmotically active), carbon dioxide, and H2 gas.
  3. Can be caused by:
    1. Protein malnutrition (Kwashiorkor)
    2. Colitis
    3. Sprue (Tropical, host of many infections, and/or Coeliac sprue, non-tropical, “gluten problems,” small intestine autoimmune disorder)
    4. Excess alcohol consumption
    5. Genetic deficiencies of disaccharidases
    6. Drugs that injure the mucosa of the small intestine.
    7. Severe diarrhea where brush border enzymes are rapidly lost, causing a temporary, acquired enzyme deficiency.
40
Q

Adult Hypolactasia (Lactose Intolerance)

A
  1. About 75% of human adults expereienced a decrease of lactase activity as children (6-7 yr olds)
  2. Up to 90% of adults of African or Asian descent are lactase-deficient
  3. This deficiency in lactase activity is brought about by genetically based reduction in the quantity of lactase via variation in chromosome 2.
  4. Treated by consumption of yogurts and cheeses with limited lactose, and green vegetables such as broccoli; use lactase-treated products; take lactase in pill form prior to eating.
  5. Adult hypolactasia can be tested by giving an oral dose of lactose and determining the levels of:
    1. Blood glucose; if lactose intolerant, the blood glucose level will not change after consumption of milk, whereas it will increase in ‘normal’ individual.
    2. Hydrogen content of one’s breath
41
Q

Sucrase-isomaltase deficiency

A
  1. Sucrase-isomaltase deficiency (sucrose intolerance) is found at a prevalence of about 1 in 5,000 individuals of European descent, and about 1 in 20 individuals of the native populations of Greenland, Alaska, and Canada
  2. This disorder is transmitted genetically
  3. There is a very wide range of phenotypic heterogeneity
  4. The gastrointestinal symptoms associated with deficient sucrase activity can be treated with oral enzyme replacement therapy
42
Q

Identification of disaccharidase deficiency

A
  1. Performing oral tolerance test with the individual disaccharides
  2. Measurement of hydrogen gas in the breath allows for determing the amount of ingested carbohydrate not absorbed by the body and instead metabolized by the intestinal flora.
43
Q

Clinical Correlations

A
  1. Recent analysis shows that individuals belonging to groups that historically have eaten more starch tend to have a higher copy number of amylase genes relative to those individuals belonging to groups that historically have eaten a diet lower in starch.
  2. Lactose persistence (lactose tolerance) is a trait found in some humans but in NO other mammal
  3. This is a genetic trait having been selected for after the domestication of animals that were used for the provision of milk
  4. There is a greater frequency of lactose persistence (lactose tolerance) among individuals of Northern European descent. African Americans, Hispanic Americans, Native Americans, and Asian Americans have a lower frequency of lactase persistence.
  5. Lactose is sometimes used as an excipient in medications
    • a natural or synthetic substance formulated alongside the active ingredient of a medication, included for the purpose of bulking-up formulations that contain potent active ingredients (thus often referred to as “bulking agents,” “fillers,” or “diluents”), or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating drug absorption or solubility.
  6. A relative sweetness scale (in descending order):
    1. Fructose
    2. High fructose corn syrup
    3. Sucrose
    4. Glucose
    5. Galactose
    6. Maltose
    7. Lactose

Artificial sweetners (#x sweeter than sucrose)

  1. Saccharin (300x)
  2. Cyclamate (30x)
  3. Aspartame (180x) - Nutrasweet; insulin issues
  4. Sucralose (600x)
  5. Cellulose (wood pulp) in different forms is sometimes added as a food additive
  6. Another salivary endoglycosidase is lysozyme. Lysozyme hydrolyzes glycosidic bonds in bacterial cell walls; protection against bacteria.
44
Q

3 Major sources for blood glucose

A
  1. Alimentary (dietary) glucose
  2. Glucose released from storage (glycogen is storage form)
  3. Glucose made from proteins
45
Q

Glucose Oxidation (Summary)

A
  • Glucose + 6O2 → 6CO2 + 6H2O + Energy (Exergonic)
  • Glucose Oxidation consists of 3 processes
  1. Glycolysis occurs in the cytosol *no need to memorize equations*
    1. Aerobic glycolysis: Glucose + 2ADP + 2Pi + 2NAD+ → 2Pyruvate + 2ATP + 2NADH + 2H+ + H2O
    2. Anaerobic glycolysis: Glucose + 2ADP + 2Pi → 2Lactate + 2ATP + 2H2O
  2. TCA cycle (aka Citric Acid Cycle or Krebs Cycle) occurs in the mitochondrial matrix
  3. Electron transport chain occurs in the inner mitochondrial membrane. It is involved with
    1. Electron Transport
    2. Oxidative Phosphorylation
46
Q

Anaerobic glycolysis used by

A
  1. Tissues with few or no mitochondria
  2. Erythrocytes (no mitochondria; require very little ATP; passive ‘transporter’)
  3. Leukocytes
  4. Lens
  5. Cornea
  6. Medula of the kidney
  7. Testes
  8. Ischemic tissues (tissues which cannot utilize their blood supplies)
  9. Muscles during intense exercise
47
Q

Turkey analogies for aerobic vs less aerobic muscles

A
  1. Dark meat - legs, more blood, more oxygen, more aerobic, involves constant movement.
  2. White meat - breast, less blood, less oxygen, less aerobic, involves more abrupt movment.
  3. If a muscle is involved in constant movement, it is more likely to be an aerobic one
  4. If a muscle is involved in more abrupt, not-sustained, quick movements, it is more likely to be more anaerobic; short term energy
  5. Both Aerobic and Anaerobic glycolysis are essential evolutionarily.
48
Q

Aerobic vs. Less Aerobic Muscle

A

Most skeletal muscles in humans consist of both Type I and Type II fibers, NOT completely separated from each other; various combinations of both.

  1. Type I Fibers
    1. Aerobic
    2. Rich in mitochondria
    3. Rich in myoglobin
    4. Dominant in muscles associated with endurance
    5. Relatively resistant to fatigue
    6. Slow twitch
  2. Type II Fibers
    1. More anaerobic
    2. Fewer mitochondria
    3. Less myoglobin
    4. Dominant in muscles associated with rapid movement
    5. Easily fatigued
    6. Fast twitch
49
Q

2 Phases of Glycolysis

A
  1. 5 initial steps whose net effect is such that they are endergonic. They convert glucose into two separate triose (three carbon) phosphates
  2. 5 additional steps whose net effect is such that they are exergonic where ADP + Pi + energy → ATP + H2O happens
  3. They convert triose phosphates to pyruvate
50
Q

3 Irreversible glycolytic regulatory enzymes

A

All of them are characterized by being highly exergonic and play important regulatory roles hence they are considered irreversible although the reaction itself is reversible.

  1. Hexokinase
  2. Phosphofructokinase
  3. Pyruvate kinase

E.g. glucose in general is reversible via gluconeogenesis, which makes sure that energy level is at least critical amount in the body so that brain doesn’t starve from glucose

51
Q

Phosphorylation of glucose

A
  1. Glucose is brought into the cell via SGLT-1 in the case of e.g. small intestine.
  2. Hexokinase or GLucokinasephosphorylates Glucose molecule to give Glucose 6-phosphate
  3. When phosphorylated, it becomes more polar and harder to pass through the membrane; thus it is now trapped inside the cell and goes through the rest of glycolysis.
  4. The phosphorylation of glucose prevents leakage of glucose 6-phosphate from the cell as it is not recognized by the GLUT
52
Q

After glucose phosphorylation (fyi)

A
53
Q

Hexokinase vs. Glucokinase activity on glucose phosphorylation

A
  1. Hexokinase is easily saturated as product inhibition by Glucose 6-phosphate maintains the activity below Vmax; both Km and Vmax are very low (high affinity, low capacity)
  2. Glucokinase, on the other hand, functions to remove glucose from the blood. The liver will respond by channeling glucose into storage pathways, while the beta cells of the pancreas will respond by secreting insulin, which promotes making glycogen.
  3. Glucokinase has both High Km (low affinity) and High Vmax (high capacity; ‘unlimited’). Thus glucokinase is not really active or useful when one is fasting but rather after a big meal. It is found mostly in liver cells and more glucose in the blood, the more it removes and stores as much as it can. These glucose are then stored as Glycogen aka “animal starch”; Liver is the primary location of glycogen storage.
  4. 5-6 mmol/L blood glucose level = fasting blood glucose level. However, Hexokinase is already near full capacity at even lower blood glucose level thus making sure essential organs e.g. brain don’t starve at critical conditions. However, it is inhibited (via product inhibition) very rapidly.
54
Q

Hexokinase vs Glucokinase comparison

A

Glucokinase is NOT found in kidney; only in liver and pancreatic beta-cells

55
Q

Explanation of differences between Hexokinase and Glucokinase

A
  1. When post-prandial (after meal) levels of glucose are high, liver glucokinase allows the liver to take up circulating glucose and store it as glycogen.
  2. When blood glucose levels drop, the liver can use other sources of metabolic fuel i.e. glycogen.
  3. The absence of product inhibition of glucokinase serves to ensure that liver uptake and storage of blood glucose (glycogen) can continue.
  4. The low Km of Hexokinase allows tissue (esp. brain) to efficiently phosphorylate glucose even when glucose is in low supply, giving glucokinase the chance to do its work.
56
Q

Glucokinase regulatory protein (GKRP)

A
  1. Glucokinase (GK) is NOT directly inhibited by its product, G6P. Rather, when Fructose 6-phosphate level becomes high, it induces GK to hide inside the nucleus where GKRP is located, thus causing negative inhibition. This then prevents the glucose frome being unnecessarily trapped in a cell, esp. when blood glucose level is critically low.
  2. High glucose level, on the other hand, will induce the activation of glucokinase but when it becomes low (and thus “too much” F6P in the cell), glucokinase is ‘inhibited’ so that more glucose is available to be transported out and get used by tissues that desperately needs the glucose.
  3. Glucokinase then is a ‘inhibitory’ enzyme of the glycolysis whereas Insulin is the ‘inducer’ of the glycolysis.
  4. Mice deficient in glucokinase regulatory protein (GKRP) do not respond rapidly to injected glucose. This metabolic impairment is thought to be due to the absence of a nuclear reserve of glucokinase (always active and storing every bit of glucose available).
  5. Glucokinase is NOT glucokinase regulatory protein
57
Q

Energy Investment phase continued (from glucose phosphorylation)

A
  1. Phosphofructokinase-1 is a committed enzyme, where once glycolysis gets to this point, the process can’t go back; “committed” step.
  2. ATP inhibit the process; if you have enough ATP, you don’t need more energy
  3. Citrate inhibit the process; citrate is a way to signal the cell that there is sufficient energy in the system; alluding to citrate cycle.
  4. AMP instigates the process; high AMP signals low ATP thus need more ATP.
  5. Fructose 2,6-bisphosphate instigates the process (further analyzed).
  6. PFK-1 can be regulated allosterically by elevated levels of the following energy-associated signals:
    1. Activated by: AMP
    2. Inhibited by: ATP & Citrate
  7. Inhibition of PFK-1 leads to the accumulation of G6P which can be routed towards
    1. Gluconeogenesis in liver or kidney
    2. Glycogen synthesis
    3. Hexose monophosphate shunt

*WHENEVER YOU SEE PHOSPHORYLATION, IT IS CONSIDERED ENERGY INVESTMENT PHASE*

58
Q

Fructose 2,6-bisphosphate as a second messenger

A

Fructose 2,6-bisphosphate can be seen as a second messenger, as its concentration changes in response to hormonal stimulation i.e. Insulin (promotes) or Glucagon (inhibits).

  1. High blood glucose level promotes insulin generation
  2. High insulin/glucagon ratio causes decreased cAMP and reduced levels of active protein kinase A.
  3. Decreased protein kinase A activity favors dephosphorylation of PFK-2(phosphofructokinase-2)/FBP-2(fructose bisphosphatase-2) complex.
  4. Dephosphorylated PFK-2 is active, whereas FBP-2 in inactive; this favors formation of fructose 2,6-bisphosphate.
  5. Elevated concentration of fructose 2,6-bisphosphate activates PFK-1, which leads to an increased rate of glycolysis.

Glucagon level is increased, on the other hand, when there is ample amount of ATP/when you have VERY LOW blood sugar (as most glucose has been already converted into glycogen perhaps).

59
Q

Regulatory Enzymes of Glycolysis

A
  1. Regulatory enzymes of glycolysis, i.e. Hexokinase/Glucokinase, Phosphofructokinase (PFK-2), and Pyruvate Kinase, in general, can be activated by:
    1. Insulin
    2. AMP
    3. Substrate e.g. glucose (for hexokinase), F6P (for PFK-2), and phosphoenolpyruvate (for pyruvate kinase); product, however, will engage in negative feedback either directly or indirectly (glucokinase)
  2. Regulatory enzymes of glycolysis, in general, can be inhibited by:
    1. Glucagon (hormone just like insulin)
    2. ATP
    3. NADH
    4. cAMP (product of glucagon action; insulin vice versa)
    5. Acetyl CoA
    6. Citrate
    7. Product inhibition (negative feedback)
  3. Elevated insulin/glucagon ratio promotes glycolysis
  4. Elevated glucagon/insulin promotes gluconeogenesis
  5. Insulin is released in response to high blood sugar.
  6. Glucagon is released in response to low blood sugar.
60
Q

Insulin vs. Glucagon

A
  1. Insulin and glucagon can induce/repress the transcription of glycolytic enzyme genes. It is slower than allosteric mechanisms, but more sustained mechanism.
  2. Ingestion of a regular basis of carbohydrates or administration of insulin can elevate the levels of these glycolytic enzyme transcripts.
  3. Sustained blood glucose level at high level means it now becomes a transcription effect, which work on during irreversible steps i.e. regulatory steps.
61
Q

Energy Generating phase

A
  1. Phosphoenolpyruvate (PEP) + ADP —–Pyruvate kinase—-> Pyruvate + ATP
  2. Allosterically activated by the presence of Fructose 1,6-bisphosphate in feed-forward manner.
  3. Increased PFK-2 activity results in elevated levels of Fructose 1,6-bisphosphate, which activates pyruvate kinase.
  4. The name of the enzyme may be misleading; PEP is really getting dephosphorylated.
  5. Note that 2,3-BPG is associated with anaerobic activity, which is what RBC goes through without its own mitochondria.
  6. About 15-25% of glucose converted to lactate in erythrocytes is shuttled through BPG shunt, while very minute amounts are shuttled through BPG shunt in other cell types.
  7. Hypoxia induces synthesis of 2,3-BPG
62
Q

Pyruvate Kinase Alterations

A

Know that there are a lot of alleles and mutations associated with Pyruvate Kinase, where it does not work as efficiently as it should.

63
Q

Glucagon activity on Pyruvate kinase

A
  1. Glucagon phosphorylates pyruvate kinase, thusly inactivating it.
  2. This inhibits glycolysis and promotes gluconeogenesis in the liver and kidney.
64
Q

Genetic Diseases associated with Glycolysis

A

Glycolysis has some redundant processes that can cover its back if it were to fail; it’s still very much essential but its failure doesn’t necessarily mean mortality.

  1. Hereditary deficiency of GLUT-1 (insulin independent transporter) can lead to seizures in infancy and delayed development
  2. Deficiency of a specific isoform of aldolase can lead to hemolytic anemia.
  3. Deficiency of triose phosphate isomerase can lead to hemolytic anemia and neurological symptoms.
  4. Phosphofructokinase (PFK-2) deficiency is a glycogen storage disease.
  5. *Pyruvate kinase deficiency affects about 1 per 10,000 individuals.
    1. It can result in hemolytic anemia
    2. The severity of the disease is a function of both enzymatic activity and activation of compensatory mechanisms: pyruvate kinase deficiency menas that RBC’s don’t have necessary ATP available to power up the pumps that maintain its shape. Increase in 2,3-BPG level helps alleviate the condition (of anemia) as it makes RBC to more readily give up its oxygen, thereby making RBC’s more effective –> compensatory mechanism.
    3. Pyruvate deficiency in mice appears to be protective against malaria.
65
Q

Inhibition of Glycolysis

A
  1. Sodium fluoride is generally added to blood samples prior to reading blood glucose levels.
  2. Fluoride ions inhibit enolase, which yield PEP in glycolysis, and thus inhibit glycolysis.
  3. As such, drinking fluoridated water provides fluoride at a level that inhibits oral bacteria enolase activity without harming humans. Disruption of the bacteria’s glycolytic pathway - and, thus, its normal metabolic functioning - prevents dental caries from forming.
  4. The mechanisms for arsenic toxicity are the following:
    1. Disruption of sulfhydryl-containing enzymes
    2. Substitution of phosphorus anion in phosphate, preventing net ATP and NADH synthesis while allowing glycolysis to proceed. Glycolysis keeps on going but get nothing out of it.
66
Q

Anaerobic Glycolysis

A
  1. The following tissues derive their energy from anaerobic glycolysis:
    1. Erythrocytes; have no mitochondria
    2. Skeletal muscles in a state of great exertion
    3. The lens and cornea of the eye, testes, leukocytes, and kidney medulla.
  2. Reduced oxygenation of tissues can increase anaerobic glycolysis, resulting in the accumulation of lactic acid in the tissues and spillover into the blood.
  3. Lactate can be used by the liver to generate glucose (gluconeogenesis); lactate is NOT a junk; still used to generate even more energy via gluconeogenesis.
  4. These conditions lead to the accumulation of NADH, as there is no opportunity to oxidize the NADH to NAD+ in the electron transport chain.
  5. Lactate can be used by the heart or kidney to regenerate pyruvate, which is further oxidized aerobically in the mitochondria.
67
Q

Interconversion of pyruvate and lactate

A
  1. The pyruvate is reduced to lactate by lactate dehydrogenase.
  2. This reversible reaction serves to oxidize NADH to NAD+, providing more NAD+ for continued glycolysis (during the energy generation phase)
  3. Glycolysis subsequently generates NADH from NAD+.
  4. Lactate is made only so that NAD+ can be made, where NAD+ is required for glycolysis to make for NADH and keep glycolysis moving in Anaerobic cycle.
  5. NADH is HIGH energy; NAD+ is low energy.
  6. In aerobic pathway, NADH is oxidized to NAD+ (giving off energy) in the mitochondria to make ATP.
  7. In anaerobic pathway, instead, NAD+ is regenerated by the formation of lactate via anaerobic respiration when person cannot go through aerobic respiration e.g. hypoxia, heart attact, etc. Thus, the formation of lactate is the end product (not junk) of anaerobic glycolysis in eukaryotic cells.
68
Q

Is lactate responsible for most of the muscle soreness felt on days following physical exertion?

A

NO, lactate is not responsible for muscle strain; it is more likely tears in muscle.

Immediately after extertion, yes may be but in long term, its due to the tears.

69
Q

Formation of lactate

A

Conditions that raise the [NADH]/[NAD+] promote the formation of lactate:

  1. CO poisoning (reduced release of O2 by hemoglobin)
  2. Sickling crisis (sickle cell anemia; clogged up blood vessels)
  3. Ischemic tissue (sickle cell, stroke, etc.)
  4. Myocardial infarction aka heart attack
  5. Mitochondrial disease
  6. Alcohol Intoxication
    1. The oxidation of alcohol results in significiant amounts of NADH in the liver.
    2. Alcohol is a good competitive inhibitor
    3. Alcohol dehydrogenase reaction –> extreme hangover; Acetyl dehydrogenase
    4. Dehydrogenases in general take H+ away, which is then used to make NADH in blood.
    5. Increase in the [NADH]/[NAD+] promotes the formation of lactate
    6. ethanol –Alcohol dehydrogenase–> aldehyde –Aldehyde Dehydrogenase–>acetic acid
    7. Both of the dehydrogenases promote the production of NADH thusly promoting the formation of lactate.
70
Q

TCA Cycle

A

The TCA cycle represents the metabolic destination for the oxidation of carbohydrates, proteins, and lipids

  1. The TCA cycle participates in other processes such as transamination, deamination, lipogenesis, and gluconeogenesis.
  2. The TCA cycle produces the reduced co-enzymes (i.e. NADH where H=reduction) that provide substrates for the respiratory chain (ETC), which subsequently oxidizes these substrates (product = NAD+ oxidized)
  3. Few genetic defects associated with TCA cycle have identified in humans, as the severity of these defects might present an overwhelming metabolic challenge.
  4. The TCA cycle is associated, directly or indirectly, with the metabolism of fatty acids, amino acids, heme, GABA, pyrimidines, etc.
  5. The TCA cycle is amphibolic (both anabolic and catabolic)
    1. Insulin → anabolic; glucagon → catabolic; they are antagonistic to each other in terms of glycogen production but complements each other; both hormones/processes essential.
  6. Almost all of the TCA enzymes are located in the mitochondrial matrix.
  7. The TCA cycle is down-regulated by a high ATP/ADP ratio or an elevated NADH/NAD+ or FADH2/FAD ratio
  8. Most of the steps in the cycle are indeed reversible. However, the cycle as a whole is not reversible in a sense that starting molecule of acetyl CoA cannot be regenerated.
  9. The TCA Cycle is a cycle, without a real beginning or an end.
  10. The TCA cycle generates 2 molecules of CO2 (acetyl-CoA is a 2 Carbon molecule)
  11. The TCA Cycle generates:
    1. 3 molecules of NADH
    2. 1 molecule of FADH2
    3. 1 molecule of GTP
  12. Ah! Citrate Is A-Key Substantive Substrate For Mitochondrial Oxidation.
71
Q

Acetyl CoA

A
  1. Acetyl CoA can be formed (in addition to the decarboxylation of pyruvate) from fatty acids and amino acids. It is a precursor molecule for the synthesis of ketone bodies, fatty acids, and cholesterol.
  2. Carried out by pyruvate dehydrogenase complex.
  3. The pyruvate dehydrogenase complex is a huge multi-enzyme complex. This complex contains over 90 enzyme-associated monomers/dimers.
  4. Process produces Acetyl CoA, NADH, and CO2.
  5. Acetyl CoA (feedback) and NADH inhibits the production of Acetyl CoA.
  6. Pyruvate (3 Carbon) to Acetyl CoA (2 Carbon)
72
Q

Pyruvate Dehydrogenase Complex

A
  1. Activity of pyruvate dehydrogenase complex requires specific nutrients:
    1. Thiamine (Vitamin B’s)
    2. Panthothenic acid
    3. Niacin
    4. Riboflavin
    5. Lipoic acid (synthesized in small amounts in humans)
  2. Arsenic, on top of making glycolysis useless, also stops the pyruvate dehydrogenase from doing its job by interferring with thiamines.
73
Q

Pyruvate dehydrogenase complex (PDC) inhibition and activation

A
  1. PDC is allosterically inhibited by elevated levels of high energy signals, including NADH, ATP, and acetyl CoA
  2. Decrease in PDC activity –> less acetyl CoA prodcution & NADH
  3. PDC is activated by calcium, at least in theory.
74
Q

Energy yield of TCA cycle

A

Iin the end, total of 24 ATPs because the entire glucose oxidation process is a “duplicate” where in glycolysis, glucose was cut inoto two 3 Carbon molecules.

75
Q

Oxidative phosphorylation

A
  1. Inner membrane is arranged in cristae (folds) which increase the surface area. Enzymes associated with oxidative phosphorylation and electron transport are located in this inner membrane.
  2. Inner membrane is highly impermeable (focus here)
  3. Outer membrane is highly permeable
  4. Mitochondrial matrix contains: TCA cycle enzymes, fatty acid oxidation enzymes, mtDNA&mtRNA, and mitochondrial ribosomes.
76
Q

Oxidative Phosphorylation cont.

A
  1. The transport of the electrons is coupled to the pumping of protons (H+’s) from the mitochondrial matrix to the intermembrane space at certain places along the ETC.
  2. The electrons can be transferred as lone electron, hydrogen atoms, or hydride ions.
  3. This results in an electrochemical gradient.
  4. The energy given off by NADH hydrolysis powers the pumps that take in H+ from the mitochondrial matrix out to the intermembrane space, which creates the electrogradient. H+ here is from the matrix itself NOT from NADH.
  5. The inner membrane is impermeable so H+ gradient outside (in the intermembrane space) can’t go back but only through one protein domain called Complex 5, which with the passage of H+, powers the production of ATP.
  6. Very highly regulated enzymatic reaction
  7. FADH2(2-1.5 P/O) is used in place of NADH (3-2.5 P/O) for lesser energy also.
  8. The electrochemical differential is resolved by the H+’s entering into the mitochondrial matrix
  9. The point of entry is at Complex V, which contains the enzyme complex ATP Synthase
  10. The ratio of H+ pumped to electrons transferred is between 1 and 2, depending on the specific respiratory enzyme complex.
  11. The ultimate electron accpetor is oxygen
  12. 4H+ + O2 + 4 Cyt.C-Fe++ → 2H2O + 4 Cyt.C-Fe+++
  13. Catalyzed by the Cytochrome C in Complex IV; involves ferrous getting oxidized to ferric.
  14. One molecule of H2O is produced for each molecule of both FADH2 and NADH. THe synthesis of water is catalyzed by cytochrome oxidase, which is located on complex IV.
77
Q

High energy molecules

A
  1. NADH yields about 3 ATP
  2. FADH2 yields about 2 ATP
  3. GTP yields about 1 ATP
  4. NADH is made from Vitamin Niacin (nicotinic acid; B3)
  5. FADH2 is made from Vitamin Riboflavin (B2)
  6. NADH wants to lose H+ and somethiing else is always ready to get reduced by energy released by NADH
  7. Oxygen on the other hand, always want to gain H+ and constantly gets reduced.
78
Q

Redox potentials

A

The free energy changes associated with these different redox potentials are utilized to pump H+’s from the matrix into the intermembrane space.

  1. Strong reducing agent such as NADH readily gets oxidized. Large negative E0
  2. Strong oxidizing agent such as 1/2 O2 readily gets reduced. Large postive E0
  3. E0 is the potential for redox reaction, where negative E0 wants to give away electrona dn positive E0 wants to gain electron.
79
Q

Electron Transport Chain

A
  1. The ETC is composed of 3-5 protein complexes, which are integral inner mitochondrial membrane protins and two mobile carriers, coenzyme Q (uniquinone) and cytochrome C.
  2. Almost all constituents of the ETC are proteins. There are about 100 different proteins.
  3. Coenzyme Q (ubiquinone) is NOT a protein; it is a derivative of quinone; vitamin-like substance; electron-carrier from complex I to III.
  4. Cytochrome C is also an electron-carrier from complex III to IV; involved in the initiation of apoptosis.
  5. Some of these proteins may:
    1. Contain iron-sulfur
    2. Contain Copper
    3. Be flavoproteins
    4. Be cytochromes (in contrast to hemoglobin, the heme iron of these cytochromes can switch back between the ferrous and the ferric states)
    5. Possess enzymatic ability.
  6. The oxidative phosphorylation of the ETC complements the substrate level phosphorylation found in both glycolysis and the TCA cycle; TCA cycle and glycolysis are not oxidative and only has substrate level phosphorylation.
  7. Coenzyme Q (Ubiquinone) possesses significant anti-oxidative capabilities. It also is being investigated for pharmacological properties.
80
Q

Energy derived from aerobic respiration

A
  1. The P:O ratio refers to the number of moles of ATP synthesized relative to the number of moles of O2 consumed.
  2. The P:O for NADH is 3 to 2.5
  3. The P:O for FADH2 is 2 to 1.5
  4. Glycolysis yields both ATP and NADH
  5. Pyruvate dehydrogenase yields only NADH
  6. TCA Cycle yields GTP, NADH, and FADH2
  7. Physiological variables could change the numbers. These variables include the energy expenditure associated with different shuttle systems.
  8. The free energy of hydrolysis of an ATP phosphoanhydride bond is 7.3 Kcal/mole. Approximately 37 molecules of ATP being formed from ADP yields the following: 37 x 7.3 = 270.1 Kcal/mole
  9. The oxidation of glucose in a bomb calorimeter yields 686 Kcal/mole.
  10. Ergo, the efficiency of ATp synthesis is 270.1/686 = 0.394 = 39.4% efficiency.
81
Q

Site-specific inhibitors of ETC

A
  1. Site-specific inhibitors prevent the passage of electrons in the ETC
  2. Rotenone is a broad spectrum insecticide and piscicide (fish)
  3. Amytal is a barbiturate (hypnotic)
  4. Antimycin A is a piscicide
  5. Sodium azide is used as a chemical preservative in laboratories and hospitals; it is also found in automobile airbags.
  6. Sodium azide and cyanide kills bacteria because the oxidative phosphorylation takes place in their cell membrane where ours happen in mitochondria; disrupt it and kills the bacteria.
  7. Oligomycin (antibiotic) binds to a specific domain of ATP synthase and blocks the H+ channel (no ATP made)
  8. Oligomycin stops the transport of electrons; inhibitor of ATP synthase
82
Q

Uncoupling proteins

A
  1. Uncoupling agent let H+ slip back into the mitochondrial matrix without capturing any energy as ATP, once it already exited to intermembrane space. The energy associated with the H+’s entry into the mitochondrial matrix is utilized not for the production of ATP, but for the production of heat.
  2. Bilirubin, thyroxine, and certain ionophores have been shown to possess uncoupling capacity.
  3. Uncoupling occurs naturally in brown adipose tissue (more vascularized and metabolizing)
  4. Brown adipose tissue is rich in mitochondria, which contains an uncoupling protein called thermogenin. This protein increases the permeability of the inner membrane to H+ ions, thusly uncoupling electron transport from oxidative phosphorylation.
  5. Brown adipose tissue is found in newborn humans, as well as in hibernating animals.
  6. Babies need a lot of brown adipose tissue because they are not good at thermoregulation, has minimal motion so muscle doesn’t generate much heat; large surface to volume ratio since organs inside hasn’t developed a lot yet, big heads, no hair, etc.
83
Q

Mitochondria

A
  1. Mitochondrial disorders are generally associated with tissues that require critical levels of operant energy, such as the muscular or the nervous system.
  2. Mitochondrial genome consists of 16.5 thousand base pairs vs. human genome of 3 billion; way too small for sustaining any life by itself.
  3. Mitochondrial genome is circular
  4. Genome encodes for 37 genes: 13 polypeptides associated with oxidative phosphorylation, 22 tRNA’s, and 2 rRNA’s
  5. Mitochondrial genetic code is not identical to that of other organisms
  6. About 90% of the proteins associated with oxidative phosphorylation are encoded in the cell nucleus and imported into the mitochondria; mitochondrial genome got (at least some of them) integrated into human genome.
  7. Number and shape of mitochondria is variable e.g. number increases during oogenesis, decreasing the possible paternal mitochondrial contribution.
  8. Rate of mutation in mitochondrial genome is approximately 10 times greater than nuclear genome.
    1. increased level of free radicals (with a lot of interaction with oxygen)
    2. more “primitive” DNA repair mechanisms.
  9. Extremely complex inheritance patterns
    1. Maternal
    2. Autosomal dominant/recessive
    3. Sex-linked dominant/recessive
  10. The release of mitochondrial Cytochrome C in response to cell death stimulus leads to the formation of a large protein complex called apoptosome. The apoptosome is involved in the initiation of the caspase cascade or apoptosis.
  11. Cytochrome has similarity to hemoglobin in a sense that it has a heme group. The heme group of cytochrome c accepts electrons and transfers electrons to the complex IV.
  12. Cytochrome also has relation with lysosome which is also involved in the apoptosis but ultimately, mitochondria is the regulator of programmed cell death.
84
Q

Blood glucose level

A
  1. Blood glucose level normally ranges from 4-8 mM (translating into approx. 70-150 mg/dl…3.5-7.5 grams in 5 liters)
  2. Fasting or vigorous exercise can reduce amount of bloood glucose
85
Q

Gluconeogenesis

A
  1. Gluconeogenesis is the synthesis of “new” glucose.
  2. Gluconeogenesis and glycogenolysis are essential for the maintenance of blood sugar during fasting and also during vigorous exercise.
  3. Glucose is essential for:
    1. Brain
    2. Erythrocytes
    3. Adipose tissue (as a source of glycerol, glyceride)
    4. Skeletal muscle operating anaerobically
    5. Mammary gland (precursor of lactose)
    6. etc.
86
Q

Cori Cycle

A
  1. Cori Cycle refers to the metabolic pathway in which lactate produced by anaerobic glycolysis in the muscles moves to the liver and is converted to glucose, which then returns to the muscles and is metabolized back to lactate.
87
Q

Glucose-Alanine Cycle

A
  1. Glucose-Alanine Cycle is the series of reactions in which amino groups from the muscle are transported to the liver. It is quite similar to the Cori cycle. When muscles produce lactate during times of decreased oxygen, they also produce alanine. This alanine is shuttled to the liver where it is used to make glucose. The glucose-alanine cycle is less productive than the Cori cycle.
88
Q

Interconversion of pyruvate and lactate

A
  1. Glycolysis generates NADH from NAD+
  2. NADH is oxidized to NAD+ in the mitochondria.
  3. In the absence of oxygen, the NAD+ is regenerated by the formation of lactate. This reaction is catalyzed by lactate dehydrogenase.
89
Q

Sources of carbon for gluconeogenesis

A
  1. Glycerol (from Triglycerides) released from adipose lipolysis
  2. Muscle lactate
    1. Muscle does not engage in gluconeogenesis as it is missing the essential enzyme glucose 6-phosphatase; instead, livers (and kidneys) do the work; muscles are “selfish”
    2. The muscle lactate is transported to the liver, in which gluconeogenesis can occur.
  3. Amino acids derived from muscle proteolysis (glucogenic amino acids) i.e. Alanine in Glucose-Alanine cycle
90
Q

Gluconeogenesis occurs primarily in the liver (and to a limited extent in the kidney, etc.)

A
  1. Gluconeogenesis enzymes are located primarily in cytosol (of liver cells).
  2. Glucose 6-phosphatase (yielding Glucose) is bound to smooth endoplasmic reticulum; since sER is involved in releasing things, glucose is released from the cells and sent into the blood stream by sER.
  3. Pyruvate carboxylase is located in mitochondrial matrix.
  4. Pyruvate carboxylase (PC) is an enzyme of the ligase class that catalyzes the irreversible carboxylation of pyruvate to form oxaloacetate (OAA).
91
Q
A

Biochemistry (9 decks)

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