Pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complexes (PDC and OGDC)

The pyruvate dehydrogenase complex (PDC) and alpha-ketoglutarate dehydrogenase complex (OGDC) are essential mitochondrial multienzyme assemblies that regulate the entry and progression of metabolites through the tricarboxylic acid (TCA) cycle (StatPearls, 2023). PDC catalyzes the oxidative decarboxylation of pyruvate to acetyl-CoA, serving as the critical bridge between glycolysis and mitochondrial respiration, while OGDC converts alpha-ketoglutarate to succinyl-CoA, acting as a rate-limiting step within the cycle (UniProt, 2024). Both complexes share a similar structural architecture involving three core enzymes (E1, E2, and E3) and require multiple cofactors, including thiamine pyrophosphate and lipoic acid. In oncology, these complexes are often suppressed to facilitate the Warburg effect, making their reactivation via PDK inhibitors like dichloroacetate a potential therapeutic strategy (PubMed, PMC7353111). Conversely, dual inhibition of these complexes by agents like devimistat is being explored to starve tumor cells of energy and biosynthetic precursors. Genetic mutations in the subunits of these complexes lead to severe metabolic disorders, including Leigh syndrome and chronic lactic acidosis.

Other names

2-oxoglutarate dehydrogenase complexKGDHCPyruvate dehydrogenase multienzyme complexPDCOGDCAlpha-ketoglutarate dehydrogenase complex

Drugs like Dichloroacetate act by inhibiting pyruvate dehydrogenase kinases (PDKs), which prevents the inhibitory phosphorylation of the PDC, thereby increasing its activity (PubMed, PMC7353111). Conversely, the lipoate-mimetic agent Devimistat (CPI-613) inhibits the E2 subunit of both PDC and OGDC, disrupting the TCA cycle to induce metabolic stress in cancer cells (NCI Drug Dictionary).