Glutamate–cysteine ligase catalytic subunit (GCLC)

Glutamate–cysteine ligase catalytic subunit (GCLC) is the essential enzyme subunit that catalyzes the first and rate-limiting step in the biosynthesis of glutathione (GSH), combining glutamate and cysteine in an ATP-dependent reaction[1][3]. GCLC, together with the regulatory glutamate–cysteine ligase modifier subunit (GCLM), forms the glutamate–cysteine ligase holoenzyme, which is responsible for cellular glutathione production. Adequate GSH is critical for detoxification of reactive oxygen species and maintenance of redox equilibrium. Dysregulation or mutation of this enzyme has been linked to increased susceptibility to oxidative damage, multiple human pathologies including cancer, neurodegeneration, metabolic, and respiratory diseases, and can confer resistance to chemotherapeutic agents through enhanced antioxidant capacity. Pharmacologic inhibition of GCLC (e.g., with buthionine sulfoximine) is an established research tool for studying glutathione-dependent processes and modulating cellular sensitivity to oxidative damage[1][3].

Other names

γ-glutamylcysteine synthetase catalytic subunitGamma-glutamylcysteine synthetase catalytic subunitGCL catalytic subunitGCLc

Inhibition of GCLC leads to decreased glutathione synthesis, lowering cellular antioxidant capacity and increasing sensitivity to oxidative or chemotherapeutic stress[1][3]. Some drugs act as competitive inhibitors at the glutamate binding site or by covalent modification.