Pyruvate Dehydrogenase Complex
The pyruvate dehydrogenase complex links glycolysis to the citric acid cycle under aerobic conditions.
PYRUVATE DEHYDROGENASE COMPLEX (PDC)
- Pyruvate + CoA + NAD+ --> Acetyl CoA + CO2 + NADH
- Located in mitochondrial matrix
- Irreversible reaction
E1, pyruvate dehydrogenase/pyruvate decarboxylase
- Catalyzes pyruvate to acetyl (releases CO2)
- Cofactor: thiamine pyrophosphate (Vitamin B1)
E2, dihydrolipoyl transacetylase
- Attaches CoA to acetyl
- Cofactor: lipoic acid (not vitamin-derived) & coenzyme A (pantothenic acid/vitamin B5)
E3, dihydrolipoyl dehydrogenase
- Reduces NAD+ to NADH
- Cofactor: NAD+ (niacin/vitamin B3) & FAD (riboflavin/vitamin B2)
Lipoic acid is only cofactor for PDC that is not vitamin-derived
CLINICAL CORRELATION
PDC-based pathology
- Deficiencies in vitamins or PDC cofactors produce initial neurological/muscular symptoms
- Acetyl CoA, major product of the PDC catalyzed reaction.
- NADH, product of PDC and citric acid cycle.
Covalent modification
PDH kinase – adds an inhibitory phosphate to PDC
- Activated by: ATP, Acetyl CoA and NADH
- Inhibited by: CoA, Pyruvate and NAD+
PDH phosphatase – removes inhibitory phosphate from PDC
- Activate PDC by removing inhibitory phosphate
- Activated by insulin and free calcium in the muscle
PDC-based pathology
- Neurological symptoms: brain cells rely on citric acid cycle for ATP
- Muscular symptoms: dysfunctional PDC produces lactic acidosis
Thiamine deficiency
- Cofactor of E1 of PDC
- CNS problems: brain cells cannot produce ATP
- Results in a syndrome called Wernicke's encephalopathy
Arsenic and mercury poisoning
- Inhibit PDC
- Van Gogh (arsenic-based paint) & "mad hatters" (mercury-treated animal furs)