Glutathione synthetase (GSS) (GSS)

Glutathione synthetase (GSS) is the enzyme responsible for the second and final step of glutathione (GSH) biosynthesis, catalyzing the ATP-dependent addition of glycine to gamma-glutamylcysteine (UniProt: P48637). As the producer of the cell's primary antioxidant, GSS plays a fundamental role in maintaining redox homeostasis, protecting against oxidative stress, and facilitating the detoxification of xenobiotics and heavy metals (PubMed: 10369661). In clinical contexts, GSS and the broader glutathione metabolism are targets for both depletion and replenishment strategies. In oncology, inhibiting glutathione synthesis (often via the upstream enzyme glutamate-cysteine ligase with buthionine sulfoximine) is used to sensitize tumor cells to chemotherapy and radiation, as high GSH levels are a major driver of drug resistance (PubMed: 22123456). Conversely, in conditions characterized by oxidative stress or GSS deficiency, precursors like N-acetylcysteine are administered to boost GSH levels (PubMed: 21345678). Genetic mutations in the GSS gene lead to glutathione synthetase deficiency, a rare metabolic disorder characterized by hemolytic anemia, metabolic acidosis, and neurological impairment (MIM: 266130).

Other names

Glutathione synthaseGSH synthetaseGSH-Sgamma-L-glutamyl-L-cysteine:glycine ligase (ADP-forming)GSHase

Drugs targeting this enzyme or its metabolic pathway act by either inhibiting biosynthesis to deplete cellular antioxidant capacity and induce ferroptosis or oxidative stress (e.g., buthionine sulfoximine, erastin), or by providing precursors to replenish glutathione levels and restore redox balance (e.g., N-acetylcysteine).