Glutathione synthetase

Glutathione synthetase (GSS) catalyzes the ATP-dependent synthesis of glutathione (GSH) from gamma-glutamylcysteine and glycine (UniProt: P48637). GSH is the predominant intracellular thiol and serves critical roles in cellular protection against oxidative damage, detoxification of foreign compounds, and as a cofactor for multiple enzymes. The protein also participates in ophthalmate biosynthesis in hepatocytes.

GSS deficiency causes rare autosomal recessive disorders including glutathione synthetase deficiency (GSSD, MIM 266130), characterized by severe 5-oxoproline excretion, metabolic acidosis, hemolytic anemia, and CNS damage, and the milder congenital non-spherocytic hemolytic anemia type 6 (CNSHA6, MIM 231900) (UniProt: P48637). These genetic conditions highlight the critical importance of GSH synthesis for neurological and hematological function.

GSS is downregulated in Alzheimer's disease brain tissue compared to age-matched controls (Chaparral AD proteomics), with a mean log2 fold-change of −0.394 across post-mortem samples analyzed by TMT-labeled proteomics. This reduction may reflect diminished antioxidant capacity in AD pathology, consistent with the established role of oxidative stress in neurodegeneration.