Regulation of citric acid cycle Flashcards
1
Q
Which enzymes are the citric acid rate-controlling enzymes
A
- Citrate synthase
- isocitrate dehydrogenase
- 2-oxoglutarate dehydrogenase
2
Q
What are the three main ways enzymes in the citric cycle are regulated
A
- Substrate availability
- product inhibition
- competitive feedback inhibition by intermediates further along the cycle
3
Q
How do the substrates regulate citric acid cycle
A
- Acetyl-CoA and oxaloacetate are not present in mitochondria in concentrations that would staurate citrate synthase
- Therefore metabolic flux varies with substrate concentration and availability
4
Q
How is the production of acetyl-CoA regulated
A
- Activity of pyruvate dehydrogenase
5
Q
How is oxaloacetate concentration regulated
A
- In equilibrium with malate
- its concentration fluctuates with NADH/NAD+ concentration ratio
- k= [oxaloacetate][NADH]/[malate][NAD+]
- As respiration rate increases [NADH] decreases
- This means [oxaloacetate] increases which stimulates the citrate synthase reaction
6
Q
What is the role of NAD+
A
- [citrate] falls as wokr increases, indicating the rate of citrate removal increases more than its formation
- The rate of citrate removal is controlled by NAD+-dependent-isocitrate dehydrogenase
- Citrate synthase also inhibited by NADH
- NAD+-dependent-isocitrate dehydrogenase is more sensitive to [NADH] changes than citrate synthase
7
Q
What happens when [citrate] falls upon transition from low to high work and respiration rates
A
- citrate is a competitive inhibitor of oxaloacetate for citrate synthase
- the fall of [citrate] caused by increased isocitrate dehydrogenase activity increases the rate of citrate formation
- 2-oxoglutarate dehydrogenase is also strongly inhibited by its products, NADH and succinyl-CoA. Its activity increases when [NADH] decreases
- Succinate thiokinase also competes with acetyl-CoA in the citrate synthase reaction
- These interlocking system keeps the citric acid cycle coordinately regulated
8
Q
What are allosteric regulators of citric acid cycle enzymes
A
- ADP
- ATP
- Ca2+
9
Q
How does [ADP] and [ATP] affect citric cycle
A
- Increased workload is accompanied by increased [ADP], resulting from increased rate of ATP hydrolysis
- ADP acts as an allosteric activator of isocitrate dehydrogenase by decreasing its Km for isocitrate
- ATP which builds up when muscle is at rest inhibits the enzyme
10
Q
How does Ca2+ affect citric acid cycle
A
- Ca2+ activates pyruvate dehydrogenase phosphatase which activates pyruvate dehydrogenase complex to produce acetyl-CoA
- It also activates both isocitrate dehydrogenase and oxoglutarate dehydrogenase
- The same signal stimulates muscle contraction and the production of ATP to fuel it