Pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase (PDH complex (PDHc) and KGDH complex (KGDHc))

Pyruvate dehydrogenase complex (PDHc) and alpha-ketoglutarate dehydrogenase complex (KGDHc) are large mitochondrial enzyme complexes that catalyze rate-limiting steps in central carbon metabolism. PDHc links glycolysis to the Krebs (citric acid) cycle by converting pyruvate to acetyl-CoA, whereas KGDHc catalyzes the conversion of alpha-ketoglutarate to succinyl-CoA within the Krebs cycle. Both complexes consist of multiple subunits and require several vitamin-derived cofactors (thiamine, lipoic acid, FAD, NAD+). Dynamic regulation by kinases, phosphatases, and redox modifications integrates their activity with cellular energy and redox status. Dysfunction or genetic deficiency causes severe impairment of energy metabolism and may result in lactic acidosis, neurologic deficits, or contribute to the pathology of cancer, heart disease, and fatty liver disease. Both are being explored as drug targets, especially via modulation of their regulation for therapeutic benefit in metabolic and mitochondrial disorders[1][2][3][5]. Note: Structurally and functionally, PDH complex and KGDH complex are distinct entities and should not be combined as a single curatable "target." Both, however, are evolutionarily related and share several mechanistic features[1][5].

Other names

PDHPDHcKGDHKGDHc2-oxoglutarate dehydrogenase complexOGDH complex

Inhibition of kinase (activates complex, increases flux into Krebs cycle); Cofactor supplementation (thiamine, lipoic acid, etc.); Covalent modification (deglutathionylation, denitrosylation)