Pyruvatoxidation

Pyruvate oxidation, also known as the pyruvate dehydrogenase reaction, is the oxidative decarboxylation of pyruvate to acetyl-CoA with concomitant production of carbon dioxide and NADH. This reaction links glycolysis, which occurs in the cytosol, to the citric acid cycle in the mitochondria, and it is a central control point in cellular respiration. In eukaryotes, it is carried out by the mitochondrial pyruvate dehydrogenase complex (PDC); in many prokaryotes the analogous reaction occurs in the cytosol.

The pyruvate dehydrogenase complex is a large multienzyme assembly comprising three catalytic components: E1 (pyruvate dehydrogenase), E2 (dihydrolipoyl transacetylase), and E3 (dihydrolipoyl dehydrogenase). E1 decarboxylates pyruvate and transfers the resulting acetyl group to a lipoamide arm on E2. The acetyl group is then transferred to CoA to form acetyl-CoA. E3 reoxidizes the reduced lipoamide, passing electrons to NAD+, which becomes NADH. Essential cofactors include thiamine pyrophosphate (TPP), lipoic acid, FAD, and NAD+.

Inputs and outputs include pyruvate, NAD+, and CoA as substrates; products are acetyl-CoA, CO2, and NADH. The reaction is effectively irreversible under cellular conditions and supplies acetyl groups for the citric acid cycle, where the acetyl moiety combines with oxaloacetate to form citrate.

Regulation of the PDC integrates cellular energy status. PDH kinases phosphorylate and inactivate the complex, while PDH phosphatases activate it by dephosphorylation. Activation is promoted by pyruvate, NAD+, and ADP, whereas inhibition occurs with high NADH, high acetyl-CoA, and high ATP. Clinically, PDH deficiency or thiamine (TPP) deficiency can disrupt acetyl-CoA production and energy metabolism.