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36 Cards in this Set
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Rate-determining enzyme of GLYCOLYSIS
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Phosphofructokinase-1 (PFK-1), which converts glucose-6-phosphate to fructose 1,6-bisphosphate
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Regulation of PFK-1
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Activators: Fructose 2,6-bisphosphatase and AMP
Inhibitors: ATP and citrate Note: PFK-2 kinase converts fructose-6-phosphate to fructose-2,6-BP and is stimulated by insulin. PFK-2 phosphatase (reverse reaction) is stimulated by glucagon. |
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Rate-limiting step of Gluconeogenesis?
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Fructose-1,6-bisphosphatase, which converts fructose-1,6-bisphosphate to fructose-6-phosphate. This is the reverse of the regulated step in glycolysis by PFK-1.
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Enzymes in gluconeogenesis
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1) Pyruvate carboxylase: in the mitochondria, converts pyruvate to oxaloacetate, which enters the malate aspartate shuttle and is moved from the mitochondrion to the cytosol as malate and then coverted back to oxaloacetate in the cytosol.
2) PEP Carboxykinase, which converts oxaloacetate to phosphoenolpyruvate. 3) Fructose-1,6-bisphosphatase, which converts fructose 1,6-bisphosphate to fructose 6-phosphate (regulated step). 4) Glucose-6-phosphatase, which converts glucose-6-phosphate to glucose. This step occurs in the ER. Note: 2 enzymes (pyruvate carboxylase and PEP carboxykinase) are required to reverse the action of pyruvate kinase in glycolysis (PEP -> pyruvate) |
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Regulation of fructose-1,6-bisphosphatase
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Inhibited by AMP and fructose 2,6-bisphosphate
Stimulated by citrate Energy stores are low so need gluconeogenesis! |
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Regulation of hexokinase
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Inhibited by glucose-6-phosphate (end-product feedback inhibition).
NOT induced by insulin. |
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Hexokinase
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Ubiquitous. High affinity (low Km), low capacity (low Vmax).
NOT induced by insulin. Catalyzes glucose to glucose-6-phosphate in all tissues. |
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Glucokinase
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In liver and pancreatic beta cells. Low affinity (high Km) for glucose, high capacity (high Vmax). Induced by insulin.
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Regulation of Glucokinase
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Induced by insulin. No direct feedback inhibition, so promotes rapid clearance of blood glucose by the liver in the fed state.
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Rate-determining enzyme in the TCA cycle?
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Isocitrate dehydrogenase, which catalyzes formation of alpha-ketoglutarate from isocitrate, releasing CO2 and NADH.
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Regulation of isocitrate dehydrogenase
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Inhibited by ATP and NADH (byproducts of reaction).
Activated by ADP. |
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TCA cycle enzymes
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1. Pyruvate dehydrogenase (pyruvate -> acetyl CoA)
2. Citrate synthase (acetyl CoA -> citrate) 3. Isocitrate dehydrogenase (isocitrate -> alpha-ketoglutarate + NADH produced) 4. alpha-KG dehydrogenase (alpha-KG -> succinyl CoA +NADH produced) succinyl CoA -> succinate (produces GTP) succinate-> fumarate (produces FADH2) fumarate -> malate (produces NADH) |
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Products of TCA cycle
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3 NADH, 2 CO2, 1 FADH2, 1 GTP per acetyl-CoA
12 ATP per acetyl-CoA 24 ATP per glucose (2 acetyl-CoA) |
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Net Glycolysis
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Glucose + 2Pi + 2ADP + 2NAD+ --> 2pyruvate + 2ATP + 2NADH + 2H20 + 2H+
2pyruvate -> 2acetylCoA |
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Total net ATP by aerobic metabolism (complete oxidation of glucose to carbon dioxide and water).
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36 to 38 ATP.
Depends on whether glycerol phosphate shutle or malate-aspartate shuttle (get more) is used to convert NADH to ATP. |
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# of ATP produced via ATP synthase from NADH? from FADH2? GTP?
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NADH : 3ATP
FADH2: 2ATP GTP:1ATP |
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Cofactors of pyruvate dehdyrogenase (same for alpha-ketoglutarate dehydrogenase in TCA cycle)
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1. vitB1 (pyrophosphate, thiamine, TPP)
2. vitB2 (FAD, riboflavin) 3. vitB3 (NAD, niacin) 4. Lipoic acid (which can be inhibited by arsenic) 5. vitB5 (CoA, pantothenate) |
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Pyruvate dehydrogenase deficiency
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Causes backup of substrate (pyruvate and alanine), resulting in lactic acidosis. Can be congenital (usually fatal at early age) or acquired (as in alcoholics, due to B1 deficiency).
Findings: neurologic deficits, like in Wernicke-Korsakoff's Treatment: increased intake of ketogenic nutrients (high fat, high lysine and leucine- the only purely ketogenic amino acids). |
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Pyruvate kinase deficiency
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Autosomal recessive. Most common enzyme deficiency in the glycolytic pathway. Get hemolytic anemia due to damaged RBCs being destroyed by the spleen (acanthocytes, spur cells).
Increased 2,3-BPG (from buildup of 1,3-BPG) causes decreased oxygen affinity and somewhat offsets the anemia. Increased unconjugated bilirubin (indirect) from hemolytic anemia- released by RBCs. Conjugation takes place in the liver... |
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Regulation of Pyruvate kinase.
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Inhibited by ATP and alanine. Also inhibited by active protein kinase A (stim by glucagon).
Activated by fructose 1,6-bisphosphate, product of the PFK-1 reaction. Reaction: phosphoenolpyruvate + 2ADP -> pyruvate + 2ATP |
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Regulation of Pyruvate dehydrogenase
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Stimulated by insulin and ADP.
Inhibited by ATP, NADH, and acetyl-CoA. NADH and acetyl-CoA are reaction end-products and are products of beta-oxidation of fatty acids. So, inhibit glycolysis when fasting. Acetyl CoA stimulates pyruvate carboxylase to favor oxaloacetate production and gluconeogenesis. Reaction: pyruvate+NAD +CoA --> acetyl-CoA + CO2 + NADH |
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What is the pentose phosphate pathway?
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Purpose is to provide a source of NADPH from an abundantly available glucose-6-phosphate. NADPH is required for reductive reactions, eg. glutathione reduction inside RBCs. Also, this pathway yields ribose for nucleotide synthesis and glycolytic intermediates. 2 distinct phases (oxidative and nonoxidative), both of which occur in the cytoplasm. No ATP is used or produced.
Sites: lactating mammary glands, liver, adrenal cortex (sites of fatty acid or steroid synthesis), RBCs. Reactions: 1. Oxidative, catalyzed by Glucose,6-P-dehydrogenase (G6PD) - rate-limiting, irreversible Glucose-6-P --> Ribulose-5-P + CO2 + 2NADPH 2. Nonoxidative, reversible, catalyzed by transketolases Ribulose-5-P --- (requires B1) --> Ribose-5-P + G3P + F6P [F6P-> glycolysis] |
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Describe respiratory burst (oxidative burst)
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Involves the activation of membrane-bound NADPH oxidase (eg. in neutrophils, macrophages). Plays an important role in the immune response - > results in the rapid release of reactive oxygen intermediates (ROIs).
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Enzymes in respiratory burst (6).
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1. NADPH oxidase- uses NADPH to make oxygen free radical (deficiency causes chronic granulomatous disease- at risk for infection by catalase+ organisms)
2. Superoxide dismutase (make H2O2) 3. Myeloperoxidase (make HOCl free radicals, fight bacteria) Steps 1,2,3 occur in the phagolysosome. 4. Catalase/glutathione peroxidase (H2O2 from Step 2 taken into neutrophil -> produce H2O) 5. Glutathione reductase (reduce glutathione, producing NADP+) 6. G6PD (regenerate NADPH from HMP shunt) Steps 4,5,6 occur within the neutrophil/WBC. |
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Chronic granulomatous disease
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NADPH oxidase deficiency. Patient's white blood cells can utilize H2O2 generated by invading organisms and convert it to ROIs. Patients are at increased risk of infection by catalase-positive organisms, like S.Aureus and Aspergillus, because they neutralize their own H2O2 leaving WBCs without ROIs for fighting off the infection.
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G6PD Deficiency
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X-linked recessive. Most common human enzyme deficiency. More prevalent among blacks, confers malarial resistance.
NADPH is necessary to keep glutathione reduced and active, which detoxifies free radicals and peroxides. Decreased NADPH in RBCs leads to hemolytic anemia due to poor RBC defense against oxidizing agents (fava beans, sulfonamides, primaquine, antituberculosis drugs). Infection can also precipitate hemolysis (free radicals generated via inflammatory response can diffuse into RBCs and cause oxidative damage). See Heinz bodies (oxidized hemoglobin precipitated within RBCs) and Bite cells (resulting from phagocytic removal of Heinz bodies by macrophages). |
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Rate-limiting step of glycogen synthesis?
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Glycogen synthase
Catalyzes conversion of UDP-glucose and glycogenin to glycogenin-(alpha-1,4)-glucose. Forms an alpha-1,4 glycosidic bond between a glucose unit from UDP-glucose at the nonreducing end of an existing glycogen fragment or glycoprotein like glycogenin. UDP-glucose is the activated form of glucose needed for glycogen synthesis. [Glucose 1-phosphate + UTP --> UDP-glucose] |
Catalyzes
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Rate-limiting step of glycogenolysis?
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Glycogen phosphorylase
Cleaves alpha-1,4 bonds with inorganic phosphate to produce glucose 1-phosphate. Sequentially removes glucose units from the ends of all chains but stops 4 glucose units from each branch point. Debranching enzyme (alpha-1,6-glucosidase) removes remaining units. |
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Rate-limiting step of HMP shunt?
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Glucose-6-phosphate dehydrogenase (G6PD)
[Glucose-6-P --> Ribulose-5-P + CO2 + 2NADPH] |
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Rate-limiting step of de novo pyrimidine synthesis?
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Carbamoyl phosphate synthetase II (cytosolic enzyme)
[CO2 + glutamine + 2ATP --> Carbamoyl phosphate + 2ADP + Pi + glutamate] Stimulated by ATP. Inhibited by UTP (an end-product of synthesis). |
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Rate-limiting step of de novo purine synthesis?
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Glutamine-PRPP amidotransferase (PRPP synthetase). The purine ring is assembled on ribose 5-phosphate supplied by PRPP.
[Ribose-5-phosphate + ATP --> PRPP + AMP] |
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Rate-limiting step of urea cycle?
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Carbamoyl phosphate synthetase I (mitochondrial enzyme).
[CO2 + NH4+ +2ATP---> Carbamoyl phosphate + 2ADP +Pi] Stimulated by N-Acetyl glutamate. |
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Rate-limiting step of fatty acid synthesis?
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Acetyl-CoA carboxylase
[Acetyl-CoA + CO2 ---needs biotin ---> Malonyl-CoA] Stimulated by insulin, citrate. Inhibited by glucagon, epinephrine, ADP, and palmitate (end product). |
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Rate-limiting step of fatty acid oxidation?
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Carnitine acyltransferase I
First of 2 enzymes in carnitine shuttle. Carnitine carries acyl group across membrane into mitochondria, where beta-oxidation of acetyl-CoA occurs. [Malonyl CoA --- carnitine shuttle into mitochondrion ---> Acyl CoA]. |
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Rate-limiting step of ketogenesis?
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HMG-CoA synthase
[acetoacetyl CoA ---> HMG-CoA] HMG-CoA is then converted to acetoacetate by HMG CoA lyase. |
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Rate-limiting step of cholesterol synthesis?
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HMG-CoA reductase
[HMG-CoA ---> mevalonate] Inhibited by statins, cholesterol, and glucagon. Stimulated by insulin. |
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