Regulation of citric acid cycle
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citric acid cycle regulation phosphofructokinase pyruvate dehydrogenase citrate synthase isocitrate dehydrogenase authoritative
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Regulation of the citric acid cycle (TCA/Krebs cycle)
The cycle is regulated to match ATP production with cellular energy demand. Its overall rate depends mainly on:
- Energy charge: ATP/ADP ratio
- Redox state: NADH/NAD⁺ ratio
- Ca²⁺ concentration: especially in contracting skeletal and cardiac muscle
- Availability of substrates: acetyl-CoA, oxaloacetate, NAD⁺, and ADP
A high ATP or NADH level signals that energy is plentiful and slows the cycle. Increased ADP, NAD⁺, and Ca²⁺ signal energy need and increase flux.
Major control points
| Enzyme / step | Activators | Inhibitors | Key point |
|---|---|---|---|
| Pyruvate dehydrogenase (PDH) | ADP, pyruvate, Ca²⁺ | ATP, NADH, acetyl-CoA | Controls entry of carbohydrate-derived acetyl-CoA into the cycle |
| Citrate synthase | Oxaloacetate availability | ATP, NADH, citrate, succinyl-CoA, long-chain fatty acyl-CoA | Catalyzes acetyl-CoA + oxaloacetate → citrate |
| Isocitrate dehydrogenase | ADP, Ca²⁺ | ATP, NADH | Main rate-limiting control site in many descriptions |
| α-Ketoglutarate dehydrogenase | Ca²⁺ | NADH, succinyl-CoA, ATP | Product inhibition and energy-state regulation |
1. Respiratory control: the most important overall mechanism
The TCA cycle produces NADH and FADH₂, which must be reoxidized by the electron transport chain.
- When ATP is being used, ADP rises.
- Oxidative phosphorylation speeds up, converting NADH back to NAD⁺.
- More NAD⁺ permits dehydrogenase reactions in the TCA cycle to proceed.
- Therefore, high ADP and NAD⁺ increase TCA-cycle activity.
Conversely, when ATP demand is low, ADP is low and NADH accumulates. This suppresses the cycle. Harper's describes this as regulation primarily through availability of oxidized cofactors, particularly NAD⁺, linked to ADP availability and ATP use. Harper's Illustrated Biochemistry, 32nd ed., p. 172.
2. Regulation of pyruvate dehydrogenase
PDH links glycolysis to the TCA cycle:
Pyruvate → acetyl-CoA
It is regulated by reversible phosphorylation:
-
PDH kinase phosphorylates and inactivates PDH.
- Activated by ATP, NADH, and acetyl-CoA.
- Inhibited by ADP and pyruvate.
-
PDH phosphatase dephosphorylates and activates PDH.
- Stimulated by Ca²⁺ in muscle.
- Stimulated by insulin in certain tissues, especially adipose tissue.
Thus, when fatty-acid oxidation supplies abundant NADH and acetyl-CoA, PDH is inhibited, sparing pyruvate for other pathways.
3. Role of calcium
During muscle contraction, cytosolic and mitochondrial Ca²⁺ increase. Ca²⁺ activates:
- PDH phosphatase, indirectly activating PDH
- Isocitrate dehydrogenase
- α-Ketoglutarate dehydrogenase
This increases acetyl-CoA oxidation precisely when ATP demand rises.
4. Anaplerotic regulation
The cycle requires sufficient oxaloacetate (OAA) to combine with acetyl-CoA. If OAA is depleted for gluconeogenesis or biosynthesis, the cycle slows even if acetyl-CoA is abundant.
Important replenishing reaction:
[
\text{Pyruvate} + \text{CO}_2 + ATP \rightarrow \text{Oxaloacetate}
]
This is catalyzed by pyruvate carboxylase, which is activated by acetyl-CoA. Therefore, excess acetyl-CoA promotes OAA formation, supporting continued TCA-cycle function. Harper's Illustrated Biochemistry, 32nd ed., p. 171.
High-yield summary
TCA cycle is stimulated by:
- ADP
- NAD⁺
- Ca²⁺
- Adequate oxaloacetate and acetyl-CoA
TCA cycle is inhibited by:
- ATP
- NADH
- Citrate
- Succinyl-CoA
- High acetyl-CoA, mainly through inhibition of PDH
Mnemonic:
“High ATP/NADH stops; ADP/Ca²⁺ accelerates.”
“High ATP/NADH stops; ADP/Ca²⁺ accelerates.”
The principal regulated irreversible reactions are catalyzed by PDH, citrate synthase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase. This is consistent with the NCBI overview of the Krebs cycle.
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