Dihydrolipoyl transacetylase (Pyruvate dehydrogenase complex component E2) (DLAT)

The Pyruvate dehydrogenase complex component E2 (PDC-E2), also known as dihydrolipoyl transacetylase, is a core enzyme within the mitochondrial pyruvate dehydrogenase complex (UniProt: P10515). It plays a vital role in cellular respiration by catalyzing the conversion of pyruvate into acetyl-CoA, bridging glycolysis and the citric acid cycle (StatPearls: Pyruvate Dehydrogenase). The lipoic acid cofactor is covalently bound to a lysine residue on the E2 subunit, forming a lipoyl-lysine domain that functions as a swinging arm to shuttle reaction intermediates between active sites (PubMed: 11096111). This specific lipoyl domain is the immunodominant epitope targeted by anti-mitochondrial antibodies (AMAs) in patients with Primary Biliary Cholangitis (PBC), a chronic autoimmune liver disease (PubMed: 28533316). In PBC, the immune system mistakenly attacks the biliary epithelial cells that express this complex, leading to progressive bile duct destruction. Additionally, the sulfhydryl groups of the lipoic acid cofactor are highly sensitive to heavy metals like arsenic and mercury, which bind and inhibit the enzyme, causing metabolic failure and lactic acidosis (PubChem: Arsenic). Therapeutic interventions include the use of ursodeoxycholic acid and obeticholic acid to manage PBC progression, while chelating agents like dimercaprol are used to treat heavy metal toxicity by restoring cofactor availability.

Other names

PDC-E2Dihydrolipoamide acetyltransferaseM2 mitochondrial antigenPyruvate dehydrogenase complex E2 subunitLipoyl-lysine domain

Inhibition of enzyme activity through covalent binding of heavy metals to the lipoyl-lysine cofactor, or autoimmune recognition of the lipoyl domain leading to biliary cell destruction.