Dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial (DLST)

Dihydrolipoyllysine-residue succinyltransferase (DLST) is a critical enzyme that serves as the E2 component of the mitochondrial 2-oxoglutarate dehydrogenase (alpha-ketoglutarate dehydrogenase) complex (UniProt P36957). It plays a central role in the tricarboxylic acid (TCA) cycle by catalyzing the conversion of alpha-ketoglutarate to succinyl-CoA, a pivotal step for cellular energy production and the generation of biosynthetic precursors. In recent years, DLST has emerged as a significant therapeutic target in oncology, particularly in MYC-driven cancers such as T-cell acute lymphoblastic leukemia and neuroblastoma, where its upregulation supports the high metabolic demands of rapidly proliferating cells (PubMed: 28622514, 31515472). Inhibition of DLST or its mRNA expression leads to the depletion of TCA cycle intermediates, resulting in mitochondrial dysfunction and cell death. While direct inhibitors like Devimistat (CPI-613) target the enzyme complex, experimental approaches using RNA interference (siRNA) or antisense oligonucleotides specifically target DLST mRNA to suppress its expression. Beyond cancer, mutations or deficiencies in DLST have been linked to neurodegenerative conditions like Alzheimer's disease and certain hereditary paragangliomas (PubMed: 32029884). As a therapeutic target, DLST offers a strategy to exploit the metabolic vulnerabilities of high-grade tumors, though its central role in normal metabolism necessitates careful consideration of systemic toxicity.

Other names

Dihydrolipoyl transsuccinylaseE2KDLTS2-oxoglutarate dehydrogenase complex component E2DLST mRNA

Inhibition of the alpha-ketoglutarate dehydrogenase complex, leading to disruption of the mitochondrial tricarboxylic acid (TCA) cycle and induction of metabolic stress.