PDHA1

PDHA1 encodes the somatic form of the pyruvate dehydrogenase E1 component subunit alpha (E1alpha), a mitochondrial matrix protein. Together with PDHB (E1beta) it assembles into the alpha2-beta2 heterotetrameric E1 component of the pyruvate dehydrogenase complex (PDC), the multienzyme assembly (E1, E2/DLAT, E3/DLD, plus the E3-binding protein) that catalyzes the committed, rate-limiting oxidative decarboxylation of pyruvate to acetyl-CoA and CO2 with reduction of NAD+ to NADH. The E1 alpha subunit carries the thiamine pyrophosphate (TPP)- and Mg2+-dependent active site and performs two consecutive steps: TPP-dependent decarboxylation of pyruvate to a hydroxyethyl-TPP intermediate, and reductive acetylation of the lipoyl group covalently attached to the E2 lipoyl domains. By converting pyruvate to acetyl-CoA, PDC forms the metabolic gateway that links cytoplasmic glycolysis to the mitochondrial tricarboxylic acid (TCA) cycle and lipogenesis. Enzyme activity is switched off by phosphorylation of conserved serine residues on E1alpha (Ser-232, Ser-293, Ser-300; sites 3, 1, 2) by pyruvate dehydrogenase kinases (PDKs) and switched back on by dephosphorylation by pyruvate dehydrogenase phosphatases (PDPs). The gene is X-linked, and pathogenic variants cause pyruvate dehydrogenase E1-alpha deficiency, the most common cause of PDC deficiency, presenting with primary lactic acidosis and neurological disease (including Leigh syndrome).

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

An entry matches when ClinGen's MONDO disease is the entry's own disease term, a subtype term, or an exact-match mapping. An amber status marks an entry ClinGen supports the gene for (Definitive, Strong or Moderate) whose own record does not type it. A Limited, Disputed or Refuted tier on such an entry is not a gap.