Pyruvate dehydrogenase complex and other ThDP-dependent dehydrogenases (PDC/OADH)

The Pyruvate dehydrogenase complex (PDC) and other thiamine diphosphate (ThDP)-dependent dehydrogenases, such as alpha-ketoglutarate dehydrogenase and branched-chain alpha-keto acid dehydrogenase, are vital mitochondrial multi-enzyme assemblies (StatPearls: NBK545240). They catalyze the oxidative decarboxylation of alpha-keto acids, serving as a bridge between glycolysis, amino acid catabolism, and the tricarboxylic acid (TCA) cycle (UniProt: P08559). PDC specifically regulates the conversion of pyruvate to acetyl-CoA, a key checkpoint in cellular energy production. In oncology, these enzymes are often dysregulated to support the Warburg effect, and drugs like devimistat are designed to inhibit them to starve cancer cells of energy (PubMed: 24901534). Conversely, dichloroacetate is used to activate PDC by inhibiting its regulatory kinases, which has been explored for treating lactic acidosis and certain cancers (PubMed: 18202616). Genetic mutations in these complexes lead to severe metabolic disorders characterized by neurological dysfunction and lactic acid buildup.

Other names

Pyruvate dehydrogenase complexPDHC2-oxoacid dehydrogenase complexesOADH complexesThiamine pyrophosphate-dependent enzymesAlpha-keto acid dehydrogenase complexes

Activation of the complex via inhibition of regulatory pyruvate dehydrogenase kinases (PDKs); direct inhibition of enzyme subunits (E1/E2) to disrupt mitochondrial energy production; cofactor replacement to enhance residual enzyme activity.