pyruvaatdehydrogenasecomplex

Pyruvate dehydrogenase refers to a mitochondrial enzyme complex (in eukaryotes) or a cytosolic complex in many bacteria that catalyzes the oxidative decarboxylation of pyruvate to acetyl‑CoA, linking glycolysis to the citric acid cycle. The reaction also generates NADH and carbon dioxide, with acetyl‑CoA entering the tricarboxylic acid cycle for further energy production or biosynthetic processes. In mammals, the enzyme operates in the mitochondrial matrix; in bacteria it is typically cytosolic.

The pyruvate dehydrogenase (PDH) complex is a multi‑enzyme assembly composed mainly of three catalytic components: E1 (pyruvate dehydrogenase), E2 (dihydrolipoamide acetyltransferase), and E3 (dihydrolipoamide dehydrogenase). It requires several cofactors: thiamine pyrophosphate (TPP) bound to E1, lipoic acid on E2, flavin adenine dinucleotide (FAD) on E3, NAD+, and CoA. The mechanism begins with decarboxylation of pyruvate by E1, transfer of the resulting hydroxyethyl group to the lipoamide arm of E2, formation of acetyl‑CoA from the acetyl group and CoA, and reoxidation of lipoamide by E3 with FAD and NAD+ as electron carriers.

Regulation is tightly controlled by covalent and allosteric mechanisms. PDH kinase (PDK) phosphorylates and inactivates E1, while PDH phosphatase (PDP) removes the phosphate to activate the complex. Energy status signals—high ATP, NADH, and acetyl‑CoA inhibit PDH; high ADP or pyruvate levels activate it. Defects in PDH activity can cause metabolic disorders, including lactic acidosis and neurodevelopmental issues, and the pathway is a focus of metabolic research and therapeutic strategies such as dietary interventions.