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Dihydrolipoamide S-succinyltransferase (DLST)
- Target
- DLST
- Molecular classification
- Enzyme, 2-oxoacid dehydrogenase family, Mitochondrial enzyme
01
Overview
Dihydrolipoamide S-succinyltransferase (DLST) is the E2 core enzyme component of the mitochondrial 2-oxoglutarate dehydrogenase complex, a multisubunit enzyme that catalyzes a key step in the tricarboxylic acid (TCA) cycle—the conversion of 2-oxoglutarate (alpha-ketoglutarate) to succinyl-CoA and carbon dioxide[3][2]. DLST functions as a transferase, mediating the transfer of succinyl groups from coenzyme A to specific lysine residues. This enzyme is essential for mitochondrial energy production and cellular metabolism. Disruptions in DLST function have been implicated in certain hereditary cancer syndromes (e.g., pheochromocytoma/paraganglioma) and possibly neurodegenerative disorders[3][7]. In addition to its essential mitochondrial role, a nuclear subfraction of the 2-oxoglutarate dehydrogenase complex, including DLST, is involved in histone succinylation, suggesting an additional regulatory role in chromatin modification[3].
- Other names
- Dihydrolipoyllysine-residue succinyltransferaseKGD2OGDC-E2DLTSDihydrolipoamide S-succinyltransferase (E2 component of 2-oxo-glutarate complex)2-oxoglutarate dehydrogenase complex component E2E2KPGL7PPGL7
02
Mechanism of action
Inhibition blunts the TCA cycle by blocking conversion of 2-oxoglutarate to succinyl-CoA, reducing cellular energy production
03
Biological functions
Catalyzes the transfer of succinyl groups within the 2-oxoglutarate dehydrogenase complexConverts 2-oxoglutarate to succinyl-CoA and CO₂ in the tricarboxylic acid (TCA) cycleProvides succinyl-CoA for histone succinylation in the nucleus in cooperation with the histone acetyltransferase KAT2A[3]
04
Disease associations
Cancer (including paraganglioma and pheochromocytoma syndromes)Neurodegenerative disease (potential associations with Alzheimer's disease risk)Metabolic disorders[3][7]
05
Safety considerations
Targeting DLST systemically can lead to severe impairment of mitochondrial energy metabolism, resulting in lactic acidosis and organ dysfunctionInhibition may be cytotoxic to most cell types due to the central metabolic role of DLST in the TCA cycle[3]
06
Interacting drugs
No direct, FDA-approved drugs targeting DLST are known; inhibition of the 2-oxoglutarate dehydrogenase complex (containing DLST) can occur secondarily with some metabolic poisons (e.g., arsenic trioxide, which targets lipoamide-containing enzymes in general)
07
Biomarkers
Mutations in DLST may serve as biomarkers for paraganglioma-pheochromocytoma syndromes[3]Altered activity may be a marker in some metabolic or neurodegenerative diseases[7]
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