Describe the pyruvate dehydrogenase complex with its components, coenzymes and regulation. Explain its metabolic significance.

Definition and Importance

• Site — mitochondrial matrix
• It is irreversible — the single most important consequence being that fatty acids can never be converted to glucose
• It is the gateway linking glycolysis to the TCA cycle

Components

Steps

Decarboxylation — pyruvate + TPP → hydroxyethyl-TPP + CO2 → Oxidation — transferred to lipoamide as acetyl group → Transfer — acetyl group to CoA → acetyl-CoA → Reoxidation — reduced lipoamide → FAD → FADH2 → NAD+ → NADH

Regulation

A. Covalent modification — the chief mechanism

B. Product inhibition

• Acetyl-CoA and NADH inhibit the complex directly
• This is why β-oxidation of fatty acids switches off PDH — it floods the cell with acetyl-CoA and NADH, sparing glucose

Metabolic Significance

• Commits carbohydrate carbon irreversibly to oxidation or fat synthesis
• Its irreversibility is why acetyl-CoA is not glucogenic
• Ca2+ activation couples muscle contraction to fuel oxidation
• In the fed state insulin activates it → glucose is oxidised or converted to fat
• In fasting it is switched off → pyruvate is diverted to gluconeogenesis instead of being wasted

Related Complexes

• α-Ketoglutarate dehydrogenase of the TCA cycle and the branched-chain α-keto acid dehydrogenase use the same five coenzymes and the same mechanism
• Hence thiamine deficiency affects all three, and arsenite inhibits all three by binding lipoamide

Energetics and Position in Metabolism

• It is the only route by which carbohydrate carbon can enter the TCA cycle
• Because it is irreversible, carbohydrate can make fat but fat cannot make carbohydrate — one of the most consequential facts in metabolism

Fate of Acetyl-coa

• Acetyl-CoA is the central junction of metabolism — every major fuel converges on it, and several biosynthetic routes leave from it

Applied Aspects

• Thiamine deficiency → PDH cannot function → pyruvate and lactate accumulate → lactic acidosis, and the brain is deprived of acetyl-CoA. This underlies Wernicke encephalopathy and beri-beri
• Give thiamine before glucose in an alcoholic or malnourished patient — a glucose load consumes the last thiamine and can precipitate Wernicke encephalopathy
• PDH deficiency (inherited) — congenital lactic acidosis with neurological damage; treated with a ketogenic diet, which bypasses the block
• Arsenic poisoning — arsenite binds the sulphydryl groups of lipoamide → inhibits PDH; treated with BAL (dimercaprol)
• Dichloroacetate inhibits PDH kinase, keeping the complex active; used experimentally in congenital lactic acidosis
• Leigh syndrome — a mitochondrial encephalopathy in which PDH deficiency is one recognised cause