Branch point between glycolytic endpoint and TCA / fermentation / gluconeogenesis. Three fates: (1) pyruvate dehydrogenase (PDH) → acetyl-CoA (mitochondrial, irreversible; the gateway to TCA + fatty acid synthesis); (2) lactate dehydrogenase (LDH) → lactate (cytosolic; regenerates NAD+ in anaerobic conditions or in Warburg-effect tumors; type A tissues = muscle/liver, type B = heart); (3) pyruvate carboxylase → oxaloacetate (anaplerotic; mitochondrial; gluconeogenesis entry). PDH deficiency is the most common congenital lactic acidosis; thiamine deficiency (Wernicke-Korsakoff) presents partly as PDH dysfunction (TPP cofactor). Dichloroacetate (DCA) activates PDH and is investigated for MELAS + congenital lactic acidosis.
Organ Systems
endocrine
musculoskeletal
nervous
Pathway Steps
pyruvate → acetyl-coa — via PDH complex (E1 + E2 + E3 + TPP + lipoamide + FAD + NAD cofactors). Pyruvate dehydrogenase irreversibly commits carbohydrate carbon to oxidation/lipogenesis, needing five cofactors (thiamine/TPP, lipoate, FAD, NAD, CoA). It is inhibited by acetyl-CoA/NADH and by PDK phosphorylation (fasting); thiamine deficiency (beriberi/Wernicke) cripples it.
pyruvate → lactate — via LDH (regenerates NAD+; anaerobic / Warburg effect). Lactate dehydrogenase regenerates NAD⁺ to sustain glycolysis when oxygen/mitochondria are limiting (exercise, anaerobic tissue, the Warburg effect). Lactate is not waste — it shuttles between tissues (Cori cycle, lactate shuttle) as fuel and gluconeogenic substrate.
pyruvate → oxaloacetate — via pyruvate carboxylase (biotin; mitochondrial; anaplerotic). Pyruvate carboxylase (biotin-dependent, acetyl-CoA-activated) replenishes TCA oxaloacetate (anaplerosis) and is the first committed step of gluconeogenesis — favored in fasting when fat-derived acetyl-CoA accumulates.
Known Modulators
pyruvate (substrate) — central metabolic hub: PDH/PC/LDH/ALT branches