Dihydrolipoyl transacylase (E2) (E2)

The E2 subunit, or dihydrolipoyl transacylase, is a fundamental enzymatic component of the three major mitochondrial alpha-keto acid dehydrogenase complexes: the pyruvate dehydrogenase complex (PDC), the alpha-ketoglutarate dehydrogenase complex (KGDHC), and the branched-chain alpha-keto acid dehydrogenase complex (BCKDC) [UniProt P10515, P36957]. These complexes are essential for aerobic metabolism, catalyzing the oxidative decarboxylation of alpha-keto acids to produce acyl-CoA and NADH, thereby linking glycolysis and amino acid catabolism to the tricarboxylic acid (TCA) cycle [StatPearls, NBK547674]. The E2 subunit is unique for its use of a covalently bound lipoic acid cofactor, which facilitates the transfer of acyl groups between the E1 and E3 subunits of the complex [Wikipedia, Dihydrolipoyl transacetylase]. In clinical pathology, the E2 subunit of PDC (PDC-E2) is the primary autoantigen targeted by anti-mitochondrial antibodies (AMAs) in patients with primary biliary cholangitis (PBC) [NIH, NIDDK]. Furthermore, the E2 subunits of PDC and KGDHC have become significant therapeutic targets in oncology; the small molecule devimistat (CPI-613) acts as a lipoate analog to inhibit these enzymes, selectively disrupting the mitochondrial metabolism of cancer cells to induce apoptosis [NCI Drug Dictionary]. Genetic mutations in the various E2 subunits can lead to severe metabolic disorders, such as maple syrup urine disease (DBT deficiency) or Leigh syndrome (DLAT deficiency) [PubMed, PMID: 22134488].

Other names

Dihydrolipoyl transacetylaseDihydrolipoyl lysine-residue succinyltransferaseDihydrolipoyl lysine-residue acetyltransferaseDLATDLSTDBTPDC-E2OGDC-E2BCKDC-E2

Inhibition of the lipoate-dependent transacylase activity within mitochondrial dehydrogenase complexes, which prevents the conversion of alpha-keto acids to acyl-CoA, thereby disrupting the TCA cycle and inducing metabolic stress and apoptosis in susceptible cells [NCI Drug Dictionary, PubMed PMID: 24513127].