TCA Cycle and Oxidative Phosphorylation Flashcards Preview

Fundamentals of Molecular Medicine > TCA Cycle and Oxidative Phosphorylation > Flashcards

Flashcards in TCA Cycle and Oxidative Phosphorylation Deck (119):
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What are the important elements of this case?

What is the diagnosis?

 

 

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Mitochondrial Encephalopathy 

Mutation in Mitochondrial Transfer RNA

Mitochondria has its own ribosomes and its own tRNA and 13 genes of its own. 

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What is the role of the TCA Cycle?

 

 

 

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Mitochondria

Innermembrane Features

Outtermembrane Features

What type of Reaction Occurs in the Mitochondria?

 

 

Pyruvate carboxylase is within the Mitochondria. 

Invagination increases surface area

Innermembrane transversing needs specific transporters. 

Oxidative phosphorylation needs oxygen to make ATP. 

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Overview of TCA.

Reaction Type?

Products?

Electron Carriers? How Many?

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What is the significance of the TCA Cycle?

Fatty Acids produce?

Amino Acid Degredation leads to?

Biosynthesis and TCA?

 

 

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6

SIMPLE THERMODYNAMICS

What determines if a reaction is favorable?

 

Gibbs Free Energy Definitions and Conditions

 

Standard Gibbs Free Energy

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THERMODYNAMICS CONT.

 

Gibbs Free Energy Eqn for a Reaction.

Condition for the Reaction to Proceed.

Approaching Coupled Reactions. 

We are never under standard conditions so this reaction needs to include the [RT ln (C)(D)/(A)(B)]

Coupled reactions Standard Free Energy Changes can be added together. 

Being favored thermodynamically doesn’t mean it will occur spontaneously. 

Thermodynamically just means in the right conditions it will be favored. 

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THERMODYNAMICS

 

Determine the thermodynamics of the First Step of Glycolysis

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9

THERMODYNAMICS

 

How can reactions with positive Gibbs Free Energy still proceed?

Use Malate conversion to Oxaloacetate as an Example.

 

 

If the second expression, which is correcting non-standard conditions, is more negative than 29.7 kJ/mole than the reaction would be overall negative gibbs free energy and the reaction would continue. That means the conc. of the reactants should be small and the products should be larger. But in this case OAA conc. is small not large so we don’t have an over all negative. 

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10

 

 

 

2 Methods for Pyruvate to enter Mitochondria

 

 

ANtiport is also driven by the proton gradient. Citrate has 3 neg. charges and pyruvate only has one so there is a difference in negative charges. 

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Pyruvate Dehydrogenase

Once pyruvate is converted to Acetyl CoA you’ve lost the ability to go to gluconeogenesis. 

Pyruvate Fates — Alanine, Lactate, Acetyl CoA, and one more…? Go back to glucose via gluconeogenesis.

E3 Subunit will be used by all enzymes that catalyze oxidative decarboxylation reactions.

E3 has an electron acceptor bound to it (FAD).  

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E1 Subunit

 

 

Catalytic Subunit

Pyruvate Decarboxylase

Binds Thiamin Pyrophosphate

 

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E2 Subunit

 

 

Catalytic Subunit

Transacetylase

Utilizes Lipoic Acid

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E3 Subunit

 

 

Catalytic Subunit

Dihydrolipoyl Dehydrogenase

Shared with other enzymes

also has bound FAD

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Cofactors required by PDH (Pyruvate Dehydrogenase)

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Thiamin Pyrophosphate

 

 

 

Derived from Thiamin, Vitamin B1

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What is FAD?

 

 

Ribotal is the reduced form of Ribose

Vitamin B2 is riboflavin which is essential for making FAD

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How does FAD accept Electrons?

 

 

FAD can exist in a radical form. 

Better Oxidizing Agent than NAD but not as good as a reducing agent. 

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19

 

 

 

Coenzyme A

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20

 

 

 

Lipoic Acid

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21

 

 

 

Importance of Pyruvate Dehydrogenase

Thiamine is in the husk of rice, but not the polished or white rice.

Now days the only patients with BeriBeri are chronic alcoholic because alcohol interferes with absorption. 

Any enzymes that use pyruvate as a substrate and becomes defective ends up with a build up of pyruvate which will end up in lactate which causes lactic acidosis. 

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Thiamin Deficiency 

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Pyruvate Dehydrogenase Complex Deficiency 

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Mutations in the E3 Subunit of Pyruvate Dehydrogenase

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25

 

 

 

What is Beriberi 

 

 

Dry Beriberi — Nervous System effects include Loss of feeling/Speech/Nystagmus. 

People don’t usually get both. 

Dry BeriBeri develops and can get worse which leads with Wernicke Encephalopathy then -Korsakoff Syndrome. 

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Dry Beriberi 

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Wet Beriberi

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Wernicke Koraskoff Syndrome?

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Wernicke Encephalopathy

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Korsakoff Syndrome

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31

 

 

 

How do the TCA cycle enzymes work?

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32

 

 

 

Aconitase and Citrate

 

 

Citrate is a symmetrical Molecule. But Aconite treats it as a asymmetrical molecule. so it always uses the same bond and adds OH to the same side every time.

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Isocitrate Dehydrogenase

 

 

 

This reaction doesn’t require any other co-factor than NAD which is very different from the other decarboxylation reactions of TCA. 

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Alpha-KG Dehydrogenase 

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35

 

 

 

Succinyl CoA Synthetase

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Once we've formed Succinate, what is our overall reaction

 

 

 

Half way point. 

The rest of the cycle captures the remaining 4 electrons (of the 8 total)

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37

 

 

 

TCA supplies intermediates for 

 

 

 

Heme Synthesis and Amino Acid Synthesis 

38

A patient has a genetic defect that causes intestinal epithelia cells to produce dissacharidases of much lower activity than normal compared with a normal person, after eating a bowl of milk and oatmeal sweetened with table sugar, this patient will have higher levels of which of the following:

 

Maltose sucrose and lactose in stool

Starch in the stool

Galactose and Fructose in the Blood

Glycogen in the muscle

Insulin in the blood

 

 

Maltose sucrose and lactose in stool

 

Disaccharides can’t be absorbed only monosaccharides. 

39

 

A young infant who was nourished by a synthetic formula had a sugar in the blood and urnine tis compound gave a positive sugar reducing test but was negative when measured with glucoses oxidase treat meant of the blood and urin with acid (which cleaves glycosidic bonds did not increase the amount of reducing sugar measured. which one of the following?

 

 

Fructose

40

 

 

Type 1 diabetic self injected insulin poor to their evening meal but was then distracted and forgot to eat a few hours later the individual fainted. Paramedics did a STAT blood glucose level and found it to be low. (Question) 

 

 

 

 

Adipose tissue

41

To fully oxidize the carbons in acetyl coA to carbon dioxide and water, how many electron need to be captured from acetyl coA?

2

4

6

8

10

Explain this question.

 

 

 

8

42

 

 

 

Succinyl CoA is a high energy bond because...

 

 

 

Thio-ester

43

 

 

 

Can an enzyme change the favorability of a reaction?

 

 

 

Enzymes don’t change the favorability of a reaction, it only reduces the amount of energy needed to reduce the transition state. 

44

 

 

 

Positive Delta G

 

 

 

Positive Delta G is unfavorable and reverse reaction is favorable. 

45

 

 

 

Why is 1.0 Molar Unreasonable for biological reactions?

 

 

 

Water can never be 1 Molar it’s 55 Molar. 

46

Which Vitamin is NOT required for TCA cycle Reactions?

Niacin

Riboflavin

Pantothenic Acid 

Lipoid Acid

Thiamin 

Vitamin C 

 

Vitamin C — Needed for Collagen Biosynthesis and Hydroxylation Reactions

 

Pantothenic Acid — needed for CoA

47

 

 

 

1 kcal is how many kJ?

 

 

 

4.18 kJ

48

 

 

 

Succinate Dehydrogenase

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Fumarase

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Malate Dehydrogenase

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Free Energy Changes for the TCA Cycle

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Energy Generation in the TCA Cycle

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53

Whats the yield of ATP when one molecule of fructose is completely oxidized to carbon dioxide and water?

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32

34

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32

54

 

 

 

Energy Yield from the Total Oxidation of Glucose

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Regulation of the TCA Cycle

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PDH Kinase Control/Regulation

The same inhibitors of PDH are activators of PDH Kinase which inhibit PDH even further. 

Large amounts of Pyruvate will inactivate PDH Kinase which will allow the PDH to be more active and act on pyruvate. 

Insulin activates the Phosphatase so we can make our fatty acids. 

Ca will activate the phosphatase when muscles contract ca is released

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57

Which other enzymatic activity is inhibited by direct phosphorylation?

Glucokinase

Hexokinase

Liver PFk-1

Liver PFK-2 Phosphatase

Liver Pyruvate Kinase

 

Glucokinase

Hexokinase

Liver PFk-1

Liver PFK-2 Phosphatase

Liver Pyruvate Kinase

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More on PDH Kinase

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Regulation of the TCA Cycle

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Regulation of the Cycle Pt. II

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Disruption of the TCA Cycle

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Why can't acetyl CoA Produce Net Glucose?

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Role of Oxaloacetate

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Loss of TCA Cycle Intermediates

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Anapluerotic Reactions

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Anapluerotic Reactions Continued

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Summary of TCA Cycle Regulation 

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Summary of TCA Cycle Regulation Continued

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69

Which TCA Cycle intermediate would be the first intermediate to accumulate in the presence of ARsinite?

citrate

Isocitrate

Alphaketoglutarate

Succinyl coA

Succinate

Fumarate

Malate

 

 

 

Alpha ketoglutarate

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Arsenite inhibits enzymes that 

 

 

 

Arsenite inhibits enzymes that require lipoid- acid 

71

Which enzyme would be inhibited in the presence of ARSENATE?(Inhibits free phosphate) 

citrate

Isocitrate

Alphaketoglutarate

Succinyl coA

Succinate

Fumarate

Malate

 

 

 

Succinate

72

 

 

A full term male infant the only child of unrelated parents was born after normal eat two months of age he was brought to the hospital and got lactic academia which responded to pharmacological levels of biotin:

 

 

Pyruvate Carboxylase (All carboxylases require biotin which is vitamin B7)

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Role of Oxidative Phosphorylation 

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How Energy is Captured

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75

A scientist has developed a drug which when added to eukaryotic cells leads to elevated lactate levels. Analysis of mitochondrial contents also demonstrated elevated alpha ketoglutarate levels in drug treated cells. this drug may be interfering with a reaction that requires which vitamin?

Biotin

Vitamin K

Pantothenate

Ascorbate 

Pyridoxine

 

 

 

Pantothenate

76

The conversion of fructose to pyruvate under aerobic conditions, results in the generation of which of the following?

2 ATP 4 NADH

2 ATP 2 NADH

4 ATP 4 NADH

4ATP 2NADH

3ATP 3 NADH

 

 

 

2 ATP 2 NADH

77

WHAT TYPE OF GRADIENT WILL BE CREATED BY PROTONS ?

ELECTRICAL GRADIENT

PH GRADIENT

BOTH ARE CORRECT

NEITHER ARE CORRECT

WHAT TYPE OF GRADIENT WILL BE CREATED BY PROTONS ?

ELECTRICAL GRADIENT

PH GRADIENT

BOTH ARE CORRECT

NEITHER ARE CORRECT

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How is Energy Yield Caclulated for a Proton Gradient?

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What determines the sign of E'0

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An Example in Standard Change in Electrical Energy

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Related Delta E to Delta G

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Explain the improtant features of this table

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Higher == Better Oxidizing Agents

Lower = Better Reducing Agents

Better reducing agents give out less ATP

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83

An organism has a 4-component electron transfer chain, with the following redox potential in volts

A = 0.45

B = -.13

C = +0.77 

D = -.32

What is their order in terms of reducing agents:

 

D to B to A to C

A to b to c to d 

D to c to b to A

C to a to b to d

An organism has a 4-component electron transfer chain, with the following redox potential in volts

A = 0.45

B = -.13

C = +0.77 

D = -.32

What is their order in terms of reducing agents:

 

D to B to A to C

A to b to c to d 

D to c to b to A

C to a to b to d

84

 

 

 

Overview of the Electron Transport Chain

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85

Which one of the following enzymes will synthesize a high energy bond only in the presence of oxygen?

Phosphoglycerate kinase

Pyruvate Kinase

Succinate Thiokinase

All require oxygen to synthesize ATP 

None require oxygen to synthesize ATP

Which one of the following enzymes will synthesize a high energy bond only in the presence of oxygen?

Phosphoglycerate kinase

Pyruvate Kinase

Succinate Thiokinase

All require oxygen to synthesize ATP 

None require oxygen to synthesize ATP

86

 

 

 

Complex I

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87

What other enzymes requires FAD?

g3P dehydrogenase

Isocitrate dehydragenase

pyruvate dehydrogenase

succinate thiokinase

malate— dehydrogenase

What other enzymes requires FAD?

g3P dehydrogenase

Isocitrate dehydragenase

pyruvate dehydrogenase

succinate thiokinase

malate— dehydrogenase

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Structure of FMN and FAD

 

 

 

CoQ is stable as a radical or with 2 e- 

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Complex IV

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Complex II 

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Summary of the Electron Transport Chain

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The Proton Motive Force

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Calculation of the PMF

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Why does a lack of oxygen inhibit the TCA cycle?

Citrate synthase is inhibited

Fumaraseis inhibited

aconitase is inhibited

Succinyl coA thiiokinase is inhibited

Isocitrate dehydrogenase is inhibited 

Why does a lack of oxygen inhibit the TCA cycle?

Citrate synthase is inhibited

Fumaraseis inhibited

aconitase is inhibited

Succinyl coA thiiokinase is inhibited

Isocitrate dehydrogenase is inhibited 

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The ATP Synthase

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How does the Synthase Work?

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Principles of the Chemiosmotic Hypothesis 

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98

If you add a small amount of dilute hydrochloric acid to a suspension of mitochondria which of the following will occur?

Atp will be hydrolyzed

ATP will be synthesized 

phosphate will leave the mitochondria

nothing

If you add a small amount of dilute hydrochloric acid to a suspension of mitochondria which of the following will occur?

Atp will be hydrolyzed

ATP will be synthesized — artificial proton gradient lead to the synthesis of the ATP

phosphate will leave the mitochondria

nothing

99

 

 

 

What is the P:O Ratio and What is uncoupling?

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What happens to Cytosolic NADH?

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101

 

 

 

Malate Aspartate Shuttle

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Coupling of Oxidative Phosphorylation

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How can one Inhibit Ox. Phos.

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104

Why does blocking ATP synthase block oxidation?

Reduced protons gradient

Enhanced proton gradient

Lack of ADP

Inhibition by High ATP

 

 

 

Enhanced proton gradient

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Inhibitors of Oxidative Phosphorylation

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Classes of ETC Inhibitors

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Oxygen Consumption Graph

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ADP Entry into the Mitochondria

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Regulation of Oxidative Phosphorylation

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Energy Yield From Glucose

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Energy Yield from Glucose cont. 

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112

 

 

 

Ox. Phos. Diseases

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TCA Cycle and Cancer

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What is Alpha Keto Glutarate Needed for?

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Inhibition of N-Methyl Lysine Hydroxylase

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Inhibition of Methylcytosine Dioxygenase

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117

 

 

 

Hypoxida Inducibe Factor

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118

 

 

 

TCA Cycle Enzymes and Tumors

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MELAS— tRNA leu is mutated in the mitochondria

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