Dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex (DLAT)

The Pyruvate dehydrogenase complex E2 subunit, also known as dihydrolipoyllysine-residue acetyltransferase (DLAT), is a core enzymatic component of the mitochondrial pyruvate dehydrogenase complex (PDC) (UniProt: P10515). It plays a vital role in aerobic respiration by catalyzing the conversion of pyruvate into acetyl-CoA, effectively linking glycolysis to the tricarboxylic acid (TCA) cycle (PubMed: 23543447). Structurally, the E2 subunit forms the scaffold of the complex and utilizes a lipoic acid cofactor to transfer acetyl groups between active sites. In clinical medicine, PDC-E2 is most recognized as the primary autoantigen in Primary Biliary Cholangitis (PBC), where anti-mitochondrial antibodies (AMA) target this protein, leading to the autoimmune destruction of small bile ducts (PubMed: 28803133). Beyond autoimmunity, DLAT is an emerging target in oncology, as certain cancer cells rely on PDC activity for metabolic flexibility. Drugs like devimistat (CPI-613) inhibit E2 to disrupt mitochondrial metabolism in tumor cells (ClinicalTrials.gov: NCT03504423). Genetic mutations in the DLAT gene can also lead to pyruvate dehydrogenase deficiency, a condition characterized by lactic acidosis and severe neurological dysfunction (NCBI Gene: 1737). Overall, the E2 subunit is a critical metabolic node with significant implications in autoimmune, genetic, and neoplastic diseases.

Other names

PDC-E2Dihydrolipoamide S-acetyltransferaseDLTAE2 component of pyruvate dehydrogenase complexM2 autoantigen

The E2 subunit catalyzes the transfer of an acetyl group from the lipoyl group of the enzyme to coenzyme A (CoA), producing acetyl-CoA and leaving a reduced dihydrolipoyl group (PubMed: 23543447). This reaction is part of the multi-step oxidative decarboxylation of pyruvate. Drugs like devimistat act by mimicking the lipoate cofactor, leading to the inhibition of the E2 and E3 subunits within the complex (ClinicalTrials.gov: NCT03504423).