Dihydrolipoamide S-succinyltransferase (DLST) (DLST)

Dihydrolipoamide S-succinyltransferase (DLST) is the E2 subunit and structural core of the mitochondrial alpha-ketoglutarate dehydrogenase complex (KGDHC), a rate-limiting enzyme in the tricarboxylic acid (TCA) cycle [Medlink, 2024; PubMed, 2022]. It catalyzes the conversion of alpha-ketoglutarate to succinyl-CoA, a critical step for energy production and biosynthetic precursor generation [Medlink, 2024; GeneCards]. Beyond its metabolic role, DLST is involved in cellular redox sensing and the post-translational modification of proteins via succinylation [PubMed, 2022; PubMed, 2017]. In oncology, DLST is often overexpressed in MYC-driven cancers like T-cell acute lymphoblastic leukemia and neuroblastoma, where it supports the high metabolic demands of tumor cells [PubMed, 2017; PubMed, 2021]. It is also genetically linked to neurodegenerative conditions such as Alzheimer's disease and certain hereditary paraganglioma syndromes [GeneCards; PubMed, 2021]. Therapeutic targeting of DLST, notably by the lipoate analog devimistat (CPI-613), exploits the enzyme's redox-sensitive lipoate residues to induce mitochondrial oxidative stress and inhibit tumor growth [PubMed, 2014].

Other names

Alpha-ketoglutarate dehydrogenase complex E2 subunitDihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrialOGDC-E2KGD2DLTS2-oxoglutarate dehydrogenase complex component E2

Devimistat (CPI-613) inhibits the alpha-ketoglutarate dehydrogenase complex by inducing a burst of mitochondrial reactive oxygen species (ROS) from the E3 subunit, which leads to the inhibitory redox modification (e.g., glutathionylation) of the lipoate residues on the DLST (E2) subunit [PubMed, 2014; PubMed, 2022].