Succinyl-CoA synthetase (SCS)

Succinyl-CoA synthetase (SCS), also known as succinate-CoA ligase, is a key mitochondrial enzyme complex that facilitates the reversible interconversion of succinyl-CoA and succinate [2, 7, 10]. It plays a unique role in the citric acid cycle as the only enzyme that generates a nucleoside triphosphate (ATP or GTP) through substrate-level phosphorylation, a process that can occur independently of oxygen [2, 11, 13]. The enzyme functions as a heterodimer composed of a catalytic alpha subunit (SUCLG1) and one of two beta subunits (SUCLA2 for ADP or SUCLG2 for GTP), which determine its nucleotide specificity and direct its tissue-specific metabolic priorities [7, 13, 18]. Beyond energy production, SCS is essential for maintaining mitochondrial DNA (mtDNA) integrity, supporting heme biosynthesis, and managing ketone body metabolism [10, 11, 13]. Genetic deficiencies in SCS subunits are linked to severe mitochondrial DNA depletion syndromes and encephalomyopathies, often presenting with symptoms like methylmalonic aciduria and neurodevelopmental regression in early childhood [7, 9, 11]. Recent studies have also highlighted its role in oncology, where altered SCS activity leads to abnormal protein succinylation and metabolic reprogramming that contributes to tumor growth and metastasis [1, 2, 5]. While clinical therapies are limited, oral succinic acid is sometimes utilized to bypass metabolic blocks in deficient patients, and experimental inhibitors like LY266500 are used in research to study its potential as a therapeutic target in parasites and cancer cells [4, 6, 16].

Other names

Succinate-CoA ligaseSuccinate thiokinaseSuccinyl-CoA ligaseSuccinyl coenzyme A synthetaseSUCLSUCLG1SUCLA2SUCLG2ADP-forming succinate-CoA ligaseGTP-forming succinate-CoA ligase

Substrate-level phosphorylation