Dihydrolipoyl transacetylase (DLAT) (DLAT)

Dihydrolipoyl transacetylase (DLAT), also known as the E2 component of the pyruvate dehydrogenase complex (PDC), is a mitochondrial enzyme essential for the conversion of pyruvate into acetyl-CoA, linking glycolysis to the tricarboxylic acid (TCA) cycle (UniProt P10515). The lipoate-binding domain of DLAT is a critical functional unit that covalently binds lipoic acid, facilitating the transfer of acetyl groups via a swinging-arm mechanism (PubMed: 10601298). This domain is clinically significant as the primary autoantigen in Primary Biliary Cholangitis (PBC), where it is targeted by antimitochondrial antibodies (AMA-M2) (StatPearls: NBK459209). In oncology, DLAT is a therapeutic target for drugs like devimistat (CPI-613), which inhibits the PDC to disrupt the altered mitochondrial metabolism of cancer cells (PubMed: 24613413). Genetic mutations in the DLAT gene lead to pyruvate dehydrogenase deficiency, a condition characterized by lactic acidosis and severe neurological dysfunction (NCBI Gene: 1737). Proper functioning of this domain is vital for cellular energy homeostasis, and its disruption is a hallmark of various metabolic and autoimmune pathologies.

Other names

Pyruvate dehydrogenase complex component E2PDC-E2Dihydrolipoamide S-acetyltransferaseM2 autoantigen70 kDa mitochondrial autoantigen

DLAT functions as the structural core of the pyruvate dehydrogenase complex and catalyzes the thioester exchange reaction that transfers an acetyl group from dihydrolipoamide to coenzyme A (CoA) (UniProt P10515). Therapeutic agents like devimistat inhibit this process by mimicking the lipoate cofactor, leading to the inactivation of the complex and subsequent metabolic exhaustion in tumor cells (PubMed: 24613413).