Dihydrolipoyllysine-residue succinyltransferase (DLST) (DLST)

Dihydrolipoyllysine-residue succinyltransferase (DLST) is the E2 subunit of the mitochondrial alpha-ketoglutarate dehydrogenase complex (KGDHC), a rate-limiting enzyme in the tricarboxylic acid (TCA) cycle (UniProt: P36957). It contains a critical lipoate-binding domain that facilitates the transfer of a succinyl group to coenzyme A, producing succinyl-CoA and reduced dihydrolipoamide. This enzymatic step is vital for maintaining cellular energy levels and metabolic flux. Reduced activity of DLST and the KGDHC complex has been extensively documented in neurodegenerative conditions such as Alzheimer's disease, where it contributes to metabolic failure (PubMed: 11015565). Conversely, in certain cancers, DLST is upregulated to support increased metabolic demands, making it a viable therapeutic target. The drug devimistat (CPI-613) acts as a lipoate analog that selectively inhibits DLST, thereby disrupting the TCA cycle and inducing apoptosis in cancer cells (PubMed: 29909986). Furthermore, germline mutations in the DLST gene have been identified as a cause of hereditary paraganglioma and pheochromocytoma, underscoring its significance in tumor biology (PubMed: 30545852).

Other names

E2 component of the alpha-ketoglutarate dehydrogenase complexDihydrolipoyl transsuccinylaseDLTS2-oxoglutarate dehydrogenase complex component E2Mitochondrial E2 lipoate-binding domain

Devimistat (CPI-613) acts as a lipoate analog that selectively inhibits the E2 subunit (DLST) of the alpha-ketoglutarate dehydrogenase complex, leading to the disruption of the TCA cycle and mitochondrial energy production in cancer cells.