succinylCoAksi

Succinyl-CoA synthetase, also known as succinate thiokinase, is a mitochondrial enzyme of the citric acid cycle (Krebs cycle). It catalyzes the conversion of succinyl-CoA to succinate while transferring a phosphate group to a nucleotide triphosphate, yielding either GTP or ATP. The overall reaction is generally described as succinyl-CoA + Pi + GDP (or ADP) ⇌ succinate + CoA + GTP (or ATP), with the exact nucleotide produced depending on the enzyme isoform present in the organism or tissue.

In the mitochondrion, succinyl-CoA synthetase operates at one of the few steps in the cycle that generates a high-energy phosphate bond through substrate-level phosphorylation. This provides a direct link between the catabolic flow of carbon and the cellular nucleotide economy, contributing to the cellular energy pool without relying on oxidative phosphorylation alone. The enzyme also helps regulate the balance of intermediates in the TCA cycle and participates in broader metabolic networks through its product, succinate.

The enzyme exists as distinct heteromeric complexes encoded by different nuclear genes. In mammals, two main mitochondrial isoforms are described: a GTP-forming complex (composed of SUCLG1 with SUCLA2) and an ATP-forming complex (composed of SUCLG1 with SUCLG2). The alpha subunit (SUCLG1) is shared, whereas the beta subunits determine the nucleotide produced. Similar enzymes are conserved across bacteria and eukaryotes, reflecting the evolutionary importance of substrate-level phosphorylation in energy metabolism.

Genetic defects in SUCLG1, SUCLA2, or SUCLG2 can lead to mitochondrial disease phenotypes, including hypotonia, developmental delay, and lactic acidosis, sometimes with mtDNA depletion.