Dihydrolipoyl transacetylase (E2 subunit of pyruvate dehydrogenase complex) (DLAT)

The pyruvate dehydrogenase complex E2 subunit, specifically its lipoamide arm, is a critical component of the mitochondrial machinery responsible for converting pyruvate into acetyl-CoA [1]. This subunit, known as dihydrolipoyl transacetylase (DLAT), utilizes a flexible lipoyl domain that shuttles acetyl groups between the E1 and E3 subunits of the complex [2]. The lipoamide arm consists of a lipoic acid moiety covalently bound to a lysine residue, which undergoes a cycle of reduction and acylation during catalysis. In clinical medicine, the E2 lipoamide arm is most notable as the primary autoantigen in Primary Biliary Cholangitis (PBC), where the immune system generates anti-mitochondrial antibodies (AMA) against the lipoylated domain [2]. Beyond its role in autoimmunity, the E2 subunit is a target for novel cancer therapeutics like devimistat (CPI-613), which mimics the lipoate intermediate to selectively inhibit mitochondrial metabolism in tumor cells [3]. Arsenic compounds also exert toxicity by binding to the thiol groups of the lipoamide arm, effectively inactivating the complex. Mutations in the DLAT gene lead to pyruvate dehydrogenase deficiency, characterized by lactic acidosis and severe neurological impairment [4]. Understanding the structural dynamics of the lipoamide arm is essential for developing metabolic inhibitors and diagnostic tools for autoimmune liver diseases.

Other names

Dihydrolipoamide S-acetyltransferasePDC-E2M2 autoantigenPyruvate dehydrogenase complex component E2

Inhibition of the lipoamide-dependent enzyme activity by mimicking or binding to the lipoyl group, thereby disrupting the conversion of pyruvate to acetyl-CoA and impairing mitochondrial respiration [3].