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Biochemistry > Block 2 TCA Cycle > Flashcards

Block 2 TCA Cycle Flashcards

1
Q

What is the net reaction of acetyl CoA synthase?

A

Acetate + CoASH + ATP –> AcCoA + AMP + PPi

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2
Q

Where are the two types of AcCoA synthase found?

A

ACS1 - liver, cytosolic

ACS2 - heart & muscle, in mitochondrial matrix

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3
Q

How is the high-energy phosphate bond of GTP formed?

A

Substrate level phosphorylation catalyzed by succinate thiokinase

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4
Q

How many ATPs are produced per NADH and FADH2 in ETC? What’s the net yield per acetyl group oxidized?

A

2.5 ATP/NADH, 1.5/FADH2

Net yield: about 10 ATP/acetyl group (3 NADH, 1 FADH2, 1 GTP)

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5
Q

For the complete oxidation of glucose, where do the produced ATPs come from, and what is the overall yield?

A

Per pyruvate (2/glucose), 1 NADH from PDH (2.5), 3 NADH in TCA (7.5), 1 FADH in TCA (1.5), 1 GTP in TCA (1.0), glycolysis (2), 2 NADH from glycolysis (3 or 5). Total = 30-32.

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6
Q

What is citrate synthase (CS)?

A

1st enzyme TCA, AcCoA + OAA -> citrate (C). Irreversible, -7.7 kcal.

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7
Q

What inhibits citrate synthase? What reverses its effects?

A

Citrate; ATP citrate lyase (cytosol)

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8
Q

What is aconitase (A)?

A

2nd enzyme TCA, citrate (C3 OH) -> isocitrate (I) (C2 OH) with cis-aconitate intermediate; contains iron-sulfer cluster (Fe-cysteine, not heme); +1.5 kcal

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9
Q

What is isocitrate DH (ID)?

A

3rd TCA; decarboxylates isocitrate to alpha-ketoglutarate; irreversible, -5.3 kcal; also yields NADH

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10
Q

What is alpha-ketoglutarate DH (KD)?

A

4th TCA; ox decarboxylation of a-KG to succinyl CoA; -8 kcal

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11
Q

What are the required coenzymes for alpha-KG?

A

Thiamine pyrophosphate (TPP), lipoic acid (carb + protein), AcCoA, FAD, NAD+

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12
Q

How is the energy released from a-KG DH reaction conserved?

A

Stored in reduced NADH & thioester bond of succinyl CoA

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13
Q

What are the three enzymes that are part of the a-KG complex?

A

1) a-KG DH
2) Transsuccinylase
3) Lipoamide DH

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14
Q

What does a-KG DH do as part of the a-KG complex?

A

Carries weakly bound TPP and decarboxylates it

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15
Q

What does transsuccinylase do as part of the a-KG complex?

A

Transfers remaining 4 carbons of a-KG from TPP to AcCoA = succinyl CoA (reducing lipoic acid)

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16
Q

What does lipoamide DH do as part of the a-KG complex?

A

Transfers electrons from reduced lipoic acid to FAD then NAD+. Resulting NADH contains most of the free energy.

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17
Q

What is succinate thiokinase/succinyl CoA synthase (ST)?

A

5th TCA; converts sucCoA to succinate to trap high energy of sucCoA thioester bond in GTP

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18
Q

What is nucleoside diphosphate kinase?

A

Converts GTP + ADP to GDP + ATP

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19
Q

What is substrate level phosphorylation?

A

Formation of high energy phosphate bond where none existed previously, without use of molecular O2; -0.7 kcal

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20
Q

What is succinate DH (SD)?

A

6 TCA; oxidizes succinate to fumarate; contains Fe-S cluster; uses covalently attached (via His) FAD to accept 2 e-; imbedded in IMM; 0 kcal

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21
Q

What is fumarase (F)?

A

7 TCA; adds H2O to fumarate, to oxidize to malate; 0 kcal

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22
Q

What is fumarase deficiency/fumaric aciduria/Polygamist Down’s?

A

Children of cousin parents, neonatal polyhydramnios, encephalopathy, mental retardation, unusual facial features, brain malformations, seizures

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23
Q

What is malate DH (MD)?

A

8 TCA; oxidizes C-2 OH of malate to form OAA using NAD+ as e- acceptor; +7.1 kcal

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24
Q

What is the net energetics of the TCA cycle?

A

-13.1 kcal

25
Q

What is the significance of the energy released from cleavage of AcCoA?

A

Makes entry into TCA cycle more thermodynamically favorable

26
Q

What is the significance of the energy released from cleavage of succinyl CoA?

A

Provides energy for generation of GTP

27
Q

From where does the energy of formation of AcCoA from pyruvate come?

A

Oxidative decarboxylation of pyruvate by PDH

28
Q

In what other pathway can citrate be used?

A

Fatty acid synthesis

29
Q

In what other pathway can a-KG be used?

A

Amino acid synthesis, and neurotransmitter synthesis (glutamate, GABA)

30
Q

In what other pathway can succinyl CoA be used?

A

Heme synthesis (condensed with glycine to form delta-aminolevulinic acid, a heme precursor)

31
Q

In what other pathway can malate be used?

A

Gluconeogenesis

32
Q

In what other pathway can OAA be used?

A

Amino acid synthesis

33
Q

How is gluconeogenesis supplied during a fast?

A

In liver, gluconeogenic precursos converted to malate, leaves mitos via specific transporter to enter cytosolic gluconeogenic pathway

34
Q

What happens to citrate in the liver after a meal?

A

Converted to AcCoA and OAA by citrate lyase. AcCoA is precursor for FAs.

35
Q

What is an anaplerotic reaction?

A

Reactions that supply 4-carbon intermediates to TCA cycle so it can keep running

36
Q

What are the 4-C intermediates of the TCA cycle?

A

Succinate, fumarate, malate, OAA

37
Q

What is the anaplerotic reaction supplying OAA?

A

Conversion of pyruvate and CO2 to OAA by pyruvate carboxylase (with biotin to form covalent intermediate with CO2)

38
Q

What happens if OAA levels in the TCA cycle drop?

A

Rate of citrate synthesis decreases, increase in AcCoA, stimulates pyruvate carboxylase

39
Q

What is pyruvate carboxylase?

A

Converts pyruvate + CO2 –> OAA; also converts alanine and lactate to glucose

40
Q

How is OAA converted to phosphoenolpyruvate?

A

By phosphoenolpyruvate carboxykinase in the cytosol

41
Q

What are the reagents in the anaplerotic reaction supplying succinyl CoA?

A

Isoleucine, valine, methionine

42
Q

What is the anaplerotic pathway that supplies a-KG?

A

His, Pro, Gln, Arg -> glutamate a-KG by transaminases & glutamate DH

43
Q

What is aspartate aminotransferase?

A

Converts Asp + a-KG OAA + Glu

44
Q

What are the reagents the anaplerotic reaction supplying fumarate?

A

Tyrosine, phenylalanine

45
Q

What drives the TCA cycle? What are the feedback mechanisms regulating it?

A

Rate of ATP use; phosphorylation state of ATP and reduction state of NAD+ or NADH/NAD+ ratio

46
Q

What is the rate-limiting step of the TCA cycle?

A

a-KG DH because it has a low catalytic capacity under physiological conditions

47
Q

What are the subunits of the pyruvate DH complex?

A

Catalytic: pyruvate dehydrogenase with TPP, dihydrolipoyl transacetylase with lipoamide, dihydrolipoyl DH/reductase with FAD.
Regulatory: PDH kinase, PDH phosphatase

48
Q

What is PDH kinase?

A

Regulatory subunit of PDHC, P serine residue on PDH to inactivate it, is inhibited by ADP

49
Q

What is PDH phosphatase?

A

Removes P to activate PDH

50
Q

What are the activators and inhibitors of PDH?

A

Act: pyruvate, NAD+, insulin, ADP, Ca2+ (also ADH, a-adrenergic agonists)
Inh: AcCoA, NADH, ATP

51
Q

What symptoms are displayed by children with PDHC deficiency?

A

Elevated serum lactate, pyruvate, alanine = chronic lactic acidosis; sever neurological defects, usually death

52
Q

What are potential treatments for PDHC deficiency?

A

Ketogenic diet, minimizing carbohydrates; dichloroacetate to increase PDHC activity by inhibiting PDHC kinase; carnitine loading; thiamin

53
Q

How might thiamin and carnitine loading help PDHC patients?

A

Thiamin for thiamin-deficient patients or patients with PDHC E1 subunit with abnormally high Km/low affinity for TPP; carnitine helps long-chain FA into mito, increasing ketone body formation by liver

54
Q

What is the most prevalent defect in PDHC deficiency? How is the PDHC diagnosis made?

A

E1 component; diagnose by measuring PDHC in cultured skin fibroblasts

55
Q

Why are PDHC E3 defects unique?

A

E3 gene shared by other a-keto acid DH like a-KG DH and branched chain AA like valine, leucine, isoleucine

56
Q

What is beriberi? What causes its symptoms?

A

Thiamin deficiency -> neuro and cardio disorders. Severely malnourished alcoholics are also deficient. Symptoms: thiamin required for PDH, a-KG DH, and transketolase to transfer activated aldehyde units

57
Q

In a person with beriberi, what happens after ingestion of glucose?

A

Blood pyruvate is especially high, but PDH and a-KG DH activity levels abnormally low = low glucose to nervous system

58
Q

Why are mercury and arsenite dangerous?

A

Both have high affinity for neighboring sulfhydryl groups and inhibits dihydrolipoyl DH part of PDH = CNS pathology

59
Q

How are beriberi and arsenic poisoning treated?

A

Sulfhydryl reagents with adjacent sulfhydryl groups to compete with dihydrolipoyl groups to bind metal ion; e.g. 2,3-dimercaptopropanol

Biochemistry (17 decks)

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