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Biochem > PDH & CAC > Flashcards

PDH & CAC Flashcards

1
Q

Pyruvate dehydrogenase complex

A

Composed of 3 enzyme subunits in mitochondria thatcatalyzes the oxidative decarboxylation of pyruvate into Acetyl-CoA, CO2, NADH

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2
Q

Oxidation of FA, glucose, aa, acetate, and ketone bodies all generate ___, which is the substrate for the CAC

A

Acetyl-CoA

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3
Q

Acetyl CoA produced in the PDH complex or from the oxidation of FA or aa enters the ____ . What happens?

A

CAC

Oxidize the acetyl-CoA

Form more NADH & FADH2

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4
Q

What happens in the ETC?

A
  • NADH and FADH2 get oxidized and the electrons are donated to the ETC, where the final electron acceptor is O2 –> H2O
  • Meanwhile, the proton motive force forms a proton gradient
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5
Q

Oxidative phosphorylation

A

Dissipation of the proton gradient formed by the ETC to direct the stored potential energy into ATP synthesis

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6
Q

In the mitochondria,

Cytosolic content passes readily across the ___ because it has porins.

Content of the ___ is essentially contiguous with the cytosol.

The ___ is impermeable to the charged molecules; requires transporters to enter the ___.

A

Cytosolic content passes readily across the outer mitochondrial membrane

Content of the intermembrane space is contiguous with the cytosol

The inner mitochondrial membrane is impermeable to charged molecules; requires transporters

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7
Q

Pyruvate from glycolysis is transported into the mitochondrial matrix by

A

Active symporter with H+

(H+ going down its gradient, Pyruvate going against it)

Disrupting this dissipates the H+ gradient -> less ATP can be made

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8
Q

PDH complex requires what 5 vitamins?

A

Vitamin B1: Thiamine –> TPP (active form)

B2: Riboflavin

B3: Niacin

B5: Pantothenic acid

Lipoate/Lipoic acid

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9
Q

Vitamin B1 (thiamine)

A

Bioactivated to form TPP

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10
Q

Riboflavin (vitamin B2)

A

Used to synthesize FAD

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11
Q

Niacin (vitamin B3)

A

used to synthesize NAD

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12
Q

Pantothenic acid (vitamin B5)

A

precursor of CoA-SH

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13
Q

Lipoic acid (Lipoate)

A

Conjugated to the PDH complex via an amide bond

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14
Q

What is the net reaction of the PDH complex? Is it thermodynamically favorable?

A

Oxidative decarboxylation of pyruvate into Acetyl CoA and CO2 w/reduction of NAD+ to NADH

Yes, it is thermodynamically favorable.

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15
Q

As the reactions proceed, the substrate is linked to the PDH complex and channeled ___

A

inwards toward the center, moving from E1 > E2 > E3

(efficient substrate always stays bound to the complex)

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16
Q

First reaction of PDH complex - E1 is the pyruvate dehydrogenase subunit

A
  • Pyruvate is oxidatively decarboxylated, releasing CO2
  • The resulting 2C hydroxyl-ethyl group is transferred to TPP (attached to E1) –> Hydroxyethyl-TPP
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17
Q

The second reaction of the PDH complex - Dihydrolipoyl transacetylase (E2)

A
  • E1 oxidizes the hydroxyethyl group into an acetyl group
    • ​The e- donated reduces a disulfide bond of lipoate
  • E2 transfers the acetyl group from TTP to lipoyllysine (lipoate attached to a Lys on transacetylase) via thioester linkage –> reduced Acyl-lipoyllysine
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18
Q

The third reaction of PDH complex - Dihydrolipoyl dehydrogenase (E3)

A
  • 3rd rxn: Acetyl group is transferred from lipoyllysineto another thioester linkage in CoA​ –> Acetyl CoA
  • 4th rxn: E3 reoxidizes the lipollysine and transfers the e- to FAD –> FADH2
  • 5th rxn: FADH2 transfers its electrons to NAD+ –> NADH
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19
Q

The long ____ group swings from the active site of E1 to E2 to E3, tethering the intermediates to the enzyme complex allowing substrate channeling

A

lipollysine

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20
Q

PDH complex is regulated by

A
  • Mainly phosphorylation
    • PDH kinase inactivates
    • Phosphatase activates
  • ​Allosteric regulation
    • Direct inhibits
      • Acetyl-CoA & NADH
      • ATP & long-chain fatty acids (LCFA)
    • Directly activates - CoA, AMP, NAD+
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21
Q

Regulation of PDH kinase (inactivates the PDH complex)

A
  • Activated by: acetyl-CoA & NADH (products)
  • Inactivated by:
    • Pyruvate (substrate)
    • ADP (indicates need ot make more ATP)
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22
Q

Ca++ has what impact on phosphatase?

A

Activates phosphatase

–> activates PDH

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23
Q

Beriberi

A

thiamine deficiency (seen in alcoholics)

  • Disrupts the PDH complex and CAC enzyme, a-KGDH
    • neurological & cardiovascular disorders
    • lactic acidosis
24
Q

Why does beriberi cause neurological disorders

A

Nerves prefer to metabolize glucose.

  • Disrupting PDH & a-KGDH means they can only metabolize glucose through glycolysis –> way less E
  • Less acetyl-CoA for FA synthesis
  • Always have a lot of glucose, so the body makes little ketone bodies (alternate source for muscle & nerves)
25
Q

Treatment for beri beri

A

Increasing ketogenic amino acids & fat to bypass the PDH complex & generate acetyl-CoA

26
Q

Arsenite or Mercury poisoning

A

Binds tightly to SH groups to disrupt lipollysine in PDH & a-KGDH

Cardiac & neurological problems, similar to beriberi

27
Q

Leigh’s Disease

A

Subacute necrotizing encephalomyelopathy caused by defective PDH complex genes (usu E1)

Similar symptoms to beriberi, but rapid progressive degeneration of the CNS and presents w/ hyptonia seizures; ophthalmaloplegia (eyes don’t track together); ataxia; extreme episodes of lactic acidemia; symmetricla patches of dying brain cells

28
Q

CAC / TCA cycle / Krebs Cycle

A

Further oxidation of carbs (from glycolysis), fats (FA B-oxidation, and many aa to generate ATP.

  1. Transfers e- from acetyl-CoA to NAD+ to FAD while the acetyl is oxidized to CO2
    1. 3 redox rxns make NADH
    2. 1 redox rxn makes FADH2
  2. NADH & FADH2 runs through the ETC and oxidative phosphorylation pathway -> ATP
  3. A GTP is produced by substrate level phosphorylation
29
Q

2/3 of our ATP is generated by the production of __ from the CAC

A

NADH, FADH2, and GTP

30
Q

First CAC reaction

A

Citrate synthase: Condenses 2-carbon acetyl-CoA with a 4-carbon oxaloacetate to form the 6-carbon citrate.

Irreversible

Feedback inhibition from citrate (which also inhibits glycolytic PFK-1)

31
Q

which of the 8 reactions of CAC are redox reactions? What do they make?

A

Rxns 3, 4, 6, 8

Reduces 4 electron carriers to produce 3NADH and 1FADH2

32
Q

In the CAC, reaction ___ is a substrate-level phosphorylation reaction, producing a molecule of __.

A

Rxn 5 is a substrate phosphorylation rxn making GTP

33
Q

The second CAC reaction

A

Citrate –aconitase–> isocitrate

Isomerization rxn

34
Q

The third reaction of CAC

A

Isocitrate + NAD+

–<strong>Isocitrate dehydrogenase</strong>-->

a-ketoglutarate + NADH2 + CO2

Irreversible

35
Q

What is the 4th reaction of CAC?

A

a-ketoglutarate + NAD+

–aKGDH complex–>

succinyl-CoA + NADH + CO2

Generates the second NADH and the second CO2​

36
Q

5th reaction of CAC

A

Succinyl-CoA –succinyl-CoA synthetase–> Succinate + GTP

Enzyme is named after the reverse rxn; also goes by succinylthiokinase.

This is the substrate phosphorylation rxn!

37
Q

6th rxn of CAC

A

Succinate + FAD –succinate dehydrogenase-> Fumarate + FADH2

thsi enzyme is associated with the mitochondrial membrane, unlike the rest of the CAC enzymes in the matrix; more efficient.

38
Q

Final 2 reactions of CAC

A

Fumarate + H2O –fumarase–> malate

Malate + NAD+ –malate dehydrogenase–> oxaloacetate + NADH

39
Q

Equation of CAC

A

Acetyl-CoA + 3NAD + FAD + GDP+Pi + 2H2O

–>

2CO2 + 3NADH + FADH2 + GTP + 2H+ + CoASH

40
Q

Each NADH molecule supplies enough electron reducing power to set up a proton motive force used to synthesize ___ ATP molecules

Each FADH2 molecule can generate __ ATP

A

NADH - 2.5ATP

FADH2 - 1.5ATP

41
Q

The total ATP form 1 round of CAC is

A

10 ATP

3NADH -> 7.5 ATP

FADH2 -> 1.5

GTP -> 1

42
Q

The CAC is allosterically regulated within the mitochondria by..

A

ADP & Ca2+stimulates rxns 3 & 4

**NADH** inhibits rxns 3, 4, and 8

Citrate feedbacks & inhibits citrate synthase.

43
Q

CAC intermediates are precursors for other biosynthetic pathways.

Citrate

a-ketoglutarate

Oxaloacetate

Succinyl CoA

A

Citrate - FA & sterols

a-Ketoglutarate -> Glutamate -> aa, purines

Oxaloacetate -> Aspartate -> aa, purines, pyrmidines

Succinyl CoA -> porphyrins, heme

44
Q

Anaplerotic reactions - what are they and what’s an example?

A

Reactions that replenish the CAC intermediates

Ex) Pyruvate carboxylase (mitochondrial form)

45
Q

Pyruvate carboxylase reaction mitochondrial vs cytosolic

A

Both turn pyruvate to oxaloacetate (anaplerotic)

Mitochondrial form does it for the CAC

Cytosolic form does it for gluconeogenesis

46
Q

5 major anaplerotic reactions

A
  • Pyruvate –Pyruvate carboxylase–> oxaloacetate
  • Aspartate –> oxaloacetate
  • aa –> Glutamate -> a-ketoglutarate
  • Val, Ile, or FA –> succinyl-CoA
  • aa –> Fumarate
47
Q

Glycolysis produces NADH in the cytosol - how does its electrons get into the mitochondria to use ETC? how does this affect ATP production?

A

Glycerol phosphate shuttle - 1.5 ATP per NADH

Malate-aspartate shuttle - 2.5 ATP per NADH

48
Q

Glycerol phosphate shuttle

A
  1. DHAP + NADH –<strong><em>Cytosolic G3P dehydrogenase </em></strong>–> G3P + NAD+ + H-
  2. G3P + FAD –<em><strong>IMM-bound G3P dehydrogenase</strong></em> –> DHAP + FADH2
    1. The e- from G3P oxidation are used to reduce FAD in the matrix

The reducing equivalents that were in NADH in the cytosol are now in FADH2 in the mitochondrial matrix.

49
Q

Reactions of the malate-aspartate shuttle

(liver & heart)

A
  1. malate + NAD+ –<em><strong>malate dehydrogenase</strong></em>–> oxaloacetate + NADH
  2. Transamination rxn: a-amino group from Glu is transferred to Oxaloacetate and replaced wiht a keto group.
    1. –> aketoglutarate
    2. –> Aspartate
    3. Requires PLP as a cofactor
    4. Enzyme is Aspartate transaminase
50
Q

AST reaction

A

convert Aspartate to Oxaloacetate

convert a-ketoglutarate to Glutamate

used in liver fxn tests

51
Q

Malate-Aspartate shuttle

Getting the electrons of NADH from the cytosol into the mitochondria

A
52
Q

Why does NADH form 2.5 ATP and not 3?

A

Glutamate protonated in the cytosol to glutamic acid.

Once in the matrix, glutamic acid turns back into glutamate, causing a loss of proton motive force across the IMM

53
Q

Which steps of CAC include carbon dioxide as a product?

A

Rxns 3 & 4

54
Q

What CAC enzyme is subject to product inhibition?

A

citrate synthase is inhibited by citrate

55
Q

What is the energy yield from glucose in the presence of oxygen but absence of PDH?

A

2 ATP from each mole of glucose in glycolysis

+

ATP from running the 2NADHs in the cytosol thru ETC and OxPhos (1.5 or 2.5 depending on the shuttle).

-> 5ATP (2 + 3) if glycerol phosophate shuttle

-> 7ATP (2 + 5) if malate aspartate shuttle

56
Q

In brain and neural tissue, more PDH complexes are

A

unphosphorylated (active)

57
Q

Energy charge (adenylate charge)

A

Biochem (28 decks)

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