Expansion
Irreversibly converts pyruvate to acetyl-CoA, requiring five cofactors
Expansion
Pyruvate dehydrogenase converts pyruvate to acetyl-CoA, irreversibly linking glycolysis to the Krebs cycle. It is a multienzyme complex in the mitochondrial matrix.
Five cofactors (Tender Loving Care For Nancy)
- T - Thiamine pyrophosphate (B1)
- L - Lipoic acid
- C - Coenzyme A (from pantothenate, B5)
- F - FAD (from riboflavin, B2)
- N - NAD (from niacin, B3)
Because the step is irreversible, acetyl-CoA cannot be converted back to pyruvate, and therefore fatty acids cannot be used to make glucose. This single fact underlies the whole logic of fasting metabolism.
Regulation: inhibited by its products acetyl-CoA and NADH, and by phosphorylation; activated by insulin, calcium and exercise.
Failure of the complex causes lactic acidosis, since pyruvate is diverted to lactate:
- Thiamine deficiency, the commonest cause
- Arsenic and mercury, which bind lipoic acid
- Congenital pyruvate dehydrogenase deficiency, presenting with lactic acidosis and neurological impairment, sometimes treated with a ketogenic diet that bypasses the block