Dihydrolipoamide S-acetyltransferase and lipoylated mitochondrial enzymes (DLAT/Lipoylated enzymes)

Dihydrolipoamide S-acetyltransferase (DLAT) is the E2 subunit of the pyruvate dehydrogenase complex (PDC), a multi-enzyme assembly that plays a pivotal role in cellular energy production by linking glycolysis to the tricarboxylic acid (TCA) cycle. DLAT, along with other mitochondrial enzymes such as dihydrolipoamide S-succinyltransferase (DLST), requires a post-translational modification known as lipoylation to function. This modification involves the covalent attachment of lipoic acid, which acts as a cofactor to shuttle acyl groups between active sites within the enzyme complexes (Tsvetkov et al., Science 2022). Recent scientific breakthroughs have identified these lipoylated enzymes as the primary targets of cuproptosis, a unique form of regulated cell death triggered by the accumulation of intracellular copper. Copper ionophores like elesclomol facilitate the transport of copper into the mitochondria, where it binds directly to the lipoyl moieties of DLAT and related enzymes, causing them to aggregate and lose catalytic activity (Solmonson & DeBerardinis, Cell 2018). This aggregation leads to proteotoxic stress and the inhibition of the TCA cycle, ultimately resulting in metabolic collapse and cell death, particularly in cancer cells with high mitochondrial dependency. Additionally, DLAT is clinically significant as the primary autoantigen in primary biliary cholangitis, an autoimmune liver disease characterized by the destruction of small bile ducts (Gershwin et al., Hepatology 2000). Therapeutic strategies targeting these enzymes, such as the inhibitor devimistat (CPI-613), are currently being explored in clinical trials for various malignancies (Pardee et al., Clin Cancer Res 2014).

Other names

Dihydrolipoamide S-acetyltransferasePyruvate dehydrogenase complex component E2PDC-E2Lipoic acid-containing enzymesLipoylated TCA cycle proteinsDihydrolipoyl transacetylase

Induction of cuproptosis through copper-dependent aggregation of lipoylated proteins and direct inhibition of mitochondrial dehydrogenase complexes.