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BIOC 311 > CAC > Flashcards

CAC Flashcards

1
Q

When and by who was discovered the CAC?

A

1937

  1. Albert Szent-Györgyi → respiration
  2. Hans Krebs → CAC
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2
Q

What does it mean for the CAC to be amphibolic?

A

It is a site of anabolism and catabolism

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3
Q

What part of the CAC corresponds to anabolism and catabolism?

A

Anabolism → CAC intermediates are the starting point of anabolic pathways (ex: gluconeogenesis, fatty acid synthesis, amino acid synthesis)
*Mostly in cancer cells, highly proliferating cells, adipose cells making fat from citrate

Catabolism → CAC intermediates are the end point of catabolic pathways
- Aerobic catabolism of carbs, lipids and aa merge into the CAC (ex: oxaloacetate ↔ AA)
*Catabolic = casse

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4
Q

What is a Cataplerotic reaction vs an anaplerotic reaction from the stand point of the CAC?

A

Cataplerotic (cata = emtpying) → depletes the CAC intermediates → decreases cycle chain
*Ex: fatty acid synthesis uses citrate

Anaplerotic (ana = filing up) → replenish the depleted CAC intemediates
*Ex: Pyruvate carboxylase makes oxaloacetate

*CAC intermdediates are simple compounds so Cataplerotic reactions are part of anabolism of the cells and Anaplerotic reactions are part of catabolism of the cell

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5
Q

What is the Pyruvate Carboxylase reaction?

A

CO2 + Pyruvate → Oxaloacetate
*Replenishes the last step to allow the cycle to run again (anaplerotic)

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6
Q

What are the main function of the CAC?

A
  1. Producing reducing equivalents
  2. Produce intermediates for biosynthesis
  3. Produce ATP
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7
Q

Does the CAC harvest energy?
Is the CAC aerobic or anaerobic?

A

Yes, through electric gradients

Neither!! → Just an enzymatic pathway
*Could say anaerobic

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8
Q

What is the overall reaction of the CAC?

A

3 NAD+ + FAD + GDP + Pi + acetyl-CoA → 3 NADH + FADH2 + GTP + CoA + 2CO2

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9
Q

Which steps confer directionality to the CAC?
*Also the 3 regulated steps

A

Step 1 - Citrate synthase
Step 3 - Isocitrate dehydrogenase
Step 4 - a-Ketoglutarate dehydrogenase
*∆G < 0

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10
Q

What happens in Step 1 of the CAC?
What is the ∆G?

A

Oxaloacetate + Acetyl-CoA → Citrate
*Citrate Synthase
∆G˚ = -31.5kJ/mol

Citryl-CoA contains a thioester high-energy bond → hydrolysis of this bond is ∆G˚=-31.5 kJ/mol
Makes the reaction irreversible

Low pool of Oxaloacetate which would reduce the ∆G in vivo, but used readily because of the breakage of the thioesther bond

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11
Q

What is the only reaction where a C-C bond is formed?

A

Step 1: Oxaloacetate (4C) + Acetyl-CoA (2C) → Citrate

  1. Enol of Acetyl-CoA attacks carbonyl C in oxaloacetate
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12
Q

What reaction occurs at step 2 of the CAC?

A

Aconitase
Citrate ↔ Isocitrate (∆G˚ ~ 0kJ/mol)

Isomerization of citrate to isocitrate with cis-aconitate as an intermediate
1) Dehydration of Citrate
2) Re-hydration of cis-aconitate

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13
Q

What reaction occurs at step 3 of the CAC?

A

Isocitrate dehydrogenase
Isocitrate + NAD+ →a-ketoglutarate + CO2 + NADH + H+ (∆G˚ = -21kJ.mol)

*This step is highly inhibited by NADH

1) Dehydrogenase activity generates NADH
2) Decarboxylase activity generates CO2
3) CO2 comes from oxaloacetate, not from acetyl-CoA (exergonic, irreversible)

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14
Q

What happens in step 4 of the CAC?

A

Ketoglutarate dehydrogenase
a-ketoglutarate + CoA + NAD+ → succinyl-CoA + CO2 _ NADH + H+ (∆G˚ = -33 kJ/mol)

  • Oxidation decarboxylation generates NADH and CO2
  • Decarboxylation provides the energy to generate high energy intermediate: Succinylcholine-CoA

*Just like PDH, a-KGDH has E1/E2/E3 (very similar)

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15
Q

What happens in step 5 of the CAC?

A

Succinyl-CoA Synthase
Succinyl-CoA + GDP + Pi ↔ succinate + GTP (∆G˚ ~ 0kJ/mol)

  • Use of the high energy succinyl-CoA to generate ATP (exergonic + endergonic cancel out)
  • Energy of succinyl-CoA is conserved through succinyl-phosphate, 3-phospho-His residue, then GTP (in some cells, make ATP directly)
    → At this point, 1 equivalent acetyl-CoA (2C) has been completely oxidized to 2x CO2
    → 2x NADH and 1 GTP have been generated
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16
Q

What happens in step 6 of the CAC?

A

Succinate Dehydrogenase
Succinate + E-FAD ↔ fumarate E-FADH2 (∆G ~ 0kJ/mol)

  • SDH His residue is covalently bound to FAD (FAD can’t diffuse as free metabolite)
  • Dehydrogenation oc succinate produed SDH-FADH2
  • SDH = Complex II of ETC → SDH-FADH2 restores FAD by feeding e- in ETC
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17
Q

What happens in step 7 of the CAC ?
(Fumarase)

A

Fumarate + H2O ↔ malate (∆G ~ 0kJ/mol)

Fumarase catalyzes the hydration of the double bond of fumarate to generate malate

18
Q

What happens in step 8 of the CAC?

A

Malate + NAD+ ↔ oxaloacetate + NADH + H+ (∆G˚ = +29.7kJ/mol; ∆G ~ 0kJ/mol)

Although the reaction is endergonic (∆G˚ = +29.7kJ/mol), the tue ∆G ~ 0kJ/mol because in vivo, at equilibrium [Malate]&raquo_space;» [Oxaloacetate]
The next reaction (Citrate Synthase reaction) is highly exergonic (∆G˚ = -31.5kJ/mol), which allows formation of Citrate to be exergonic even at low [oxaloacetate]
*Coupling of Step 1 and 8 helps CAC go forward (Oxaloacetate produced in step 8 is immediatly sucked to step 1)

19
Q

How many ATPs are made in aerobic glycolysis vs anaerobic glycolysis?

A

Anaerobic glycolysis = 2 ATP
Aerobic glycolysis = 2 ATP + 5 ATP (from 2 NADH in ETC) = 7 ATP

20
Q

What is the net energy production / cycle of the CAC?

A

3 NADH (2.5ATP/NADH) → 7.5 ATP
1 FADH2 (1.5ATP/FADH2) → 1.5 ATP
1 GTP → 1 ATP
Total/cycle = 10 ATP
Total/glucose = 2 cycles = 20 ATPs in the CAC

21
Q

What is the net energy production of PDH (PDC)?

A

1 NADH (x2.5ATP/NADH) = 5 ATP/Glucose

22
Q

What are the different mechanisms of regulation of the CAC?
(not specific steps)

A
  • Substrate availability
  • Product inhibition → product binding to the active site
  • Competitive feedback inhibition → In the active site
  • Allosteric activation → in a distant site
  • Allosteric inhibition → in a distant site
23
Q

What is the central metabolite responsible for regulation of the CAC?

A

NADH

Reoxidation of NADH to NAD tightly coupled to oxygen consumption and ATP synthesis
→ CAC is regulated by feedback mechanisms that coordinate its production of NADH with energy expenditure

24
Q

How does Succinyl-CoA regulate the Citrate synthase step?

A

Citrate synthase has Acetyl-CoA as a substrate, which is very similar to Succinyl-CoA (CoA is what takes the most place) → competitive feedback inhibition as SCoA can bind to active site

25
Q

How is the Citrate Synthase step regulated by substrate availability?

A

Acetyl-CoA and oxaloacetate
- In vivo, [Acetyl-CoA] and [oxaloacetate] do NOT saturate
The reaction rate varies on both concentrations (availability)
*[Acetyl-CoA] is controlled by PDC

26
Q

How is the Citrate Synthase step regulated by product inhibition?

A

Citrate = product of the reaction → competitive inhibitor of oxaloacetate binding site to citrate synthase

*If citrate builds up, it will bind to the active site and block oxaloacetate’s binding

27
Q

How is the Citrate Synthase step regulated by
1. Competitive feedback?
2. Allosteric inhibition?
3. Allosteric activation?

A
  1. Competitive feedback: Succinyl-CoA competes with Acetyl-CoA site
  2. Allsoteric inhibition: NADH (not a product)
  3. Allosteric activation: ADP
    *Allosteric binds to distant site on Citrate Synthase
28
Q

What regulates Isocitrate Dehydrogenase?

A

Allosteric activation → ADP and Ca2+
*Associated with exercise

Product inhibition → NADH which displaces NAD+ (at its active)
*Because Isocitrate Dehydrogenase (step 3) produced NADH

29
Q

What happens when isocitrate dehydrogenase is turned OFF?

A

Isocitrate accumulates and is then reconverted back to citrate as step 2 is a reversible reaction → citrate goes to the cytoplasm

Citrate in the cytoplasm:
- Activates Acetyl-CoA carboxylase → activates fatty acid synthesis
- Inhibits PFK → inhibits glycolysis
(example of the CAC being Amphibolic)

30
Q

What is a surplus of citrate an indicator of?

A

It is an indicator of a high energy charge

31
Q

How is regulation of a-ketoglutarate dehydrogenase done in the CAC?

A

Product inhibition → NADH, Succinyl-CoA

Allosteric activation → Ca2+

32
Q

What metabolite regulates Pyruvate carboxylase reaction?

A

Alosteric activator → Acetyl-CoA

Pyrvate + CO2 → Oxaloacetate
*When Acetyl-CoA accumulates, it needs an oxaloacetate to enter the CAC

*Pyruvate is the most important branch point in the metabolism of a cell that live on carbohydrates!!!

33
Q

Wha are examples of cataplerotic reactions in the CAC?

A

Cataplerotic reactions are used for anabolism (Empty the CAC)
- Glucose biosynthesis → from oxaloacetate

  • Fatty acid biosynthesis → Starts with Acetyl-CoA (can’t be transported out of the mitochondria so needs to go to Citrate to be transported out → enzyme breaks citrate to release Acetyl-CoA)
  • Amino acid biosynthesis → Transamination of Oxaloaxetate → Aspartate // a-Ketoglutarate → Glutamate (both reversible)
34
Q

What is the major source of free energy in aerobic organisms?

A

The CAC

35
Q

Why are anaplerotic reactions critical?

A

The CAC can’t be interrupted so intermediates drawn off must be replenished

36
Q

What are 3 important anaplerotic reactions in the CAC?

A

Anaplerosis → replenishes the CAC

  1. Pyruvate carboxylase: Pyruvate (3C) + CO2 → Oxaloacetate (4C)
  2. Pyruvate dehydrogenase: Pyruvate (3C) → Acetyl-CoA (2C) + CO2
  3. Transaminase: Pyruvate → Alanine coupled with Glutamate → a-ketoglutarate The N from glutamate is transfered to make alanine
37
Q

What is the reaction equation of Pyruvate Carboxylase?

A

Pyruvate + HCO3- + ATP ↔ Oxaloacetate + ADP + Pi + 2H+
*Requires ATP
In vivo, concentration of oxaloacetate is so low, it really only goes forward

38
Q

What are different ways Oxaloacetate can be replenished in the CAC?

A
  1. Pyruvate carboxylase: Pyruvate + CO2
  2. Transamination: Aspartate ↔ Oxaloacetate
  3. PEP carboxylase in plants and bacteria: Phosphoenol-pyruvate ↔ Oxaloacetate
39
Q

How can Malate be replenished in the CAC?

A

Malic enzyme: Pyruvate (3C) + HCO3- + NADPH + H+ ↔ L-Malate + NADP+ + H2O

The forward replenishes the CAC (Anaplerosis)
The reverse produces NADPH for fatty acid synthesis (Cataplerosis)

*Malate eventually goes to oxaloacetate in the CAC so replenishes Malate will replenish Oxaloacetate (an all other intermediates)

40
Q

What are the main transmination pairs in the CAC?
What is a transaminase reaction?

A

Glutamate ↔ a-Ketoglutarate
Aspartate ↔ Oxaloacetate
(Pyruvate ↔ Alanine)

Transaminase = transfer of an amine group
*In the CAC is allows C backbones to be burned as energy when there is AA build-up

41
Q

What is the importance of Glutamate dehydrogenase?
How is it regulated?

A

GDH can act as a transaminase
Glutamate + NAD+ + H2O → a-Ketoglutarate + NH4+ + NADH + H+

*Can go both ways, but the reverse is highly unfavourable because it releases Ammonia which binds very weakly to GDH so low chances of it binding as a substrate for the reverse reaction (would need extra high concentration)

ATP = allosterical inhibitor of GDH (high energy levels)
ADP = allosterical activator of GDH

BIOC 311 (11 decks)

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