Glutathione synthetase

spinqualitylabelsall models Human glutathione synthetase complex with glutathione, ADP, sulfate and Mg+2 ions (2hgs) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Function Glutathione synthetase (GSS) is an ATP-dependent enzyme which catalyzes the condensation of γ-glutamylcysteine and glycine to glutathione. GSS is part of the glutathione biosynthesis pathway. Glutathione Synthetases are a class of enzymes that work catalyze the chemical reaction ATP + γ-L-glutamyl-L-cysteine + glycine ↔ ADP + phosphate + glutathione Human Glutathione Synthase participates in glutamate metabolism and glutathione metabolism; its three substrates are ATP, gamma-L-glutamyl-L-cysteine, and glycine. Its three products are ADP, phosphate, and glutathione. At least one compound, Phosphinate, is known to inhibit this enzyme. The enzyme is also a member of the ATP-Grasp family of proteins, so its method of binding is similar to others in the ATP-Grasp family. However, it lacks significant sequence identity with other members of the family, even though its structure is circular permutation of other known structures in the family. Role in Human Disease This enzyme's action produces glutathione, a vital and abundant tripeptide that is found in most living cells. In humans, mutations to hGS can lead to lowered levels of glutathione, causing a range of disease states. Lowered levels of glutathione have been associated with diseases such as human immunodeficiency, hepatitis C, type II diabetes, ulcerative colitis, idiopathic pulmonary fibrosis, adult respiratory distress syndrome, and cataracts. Common Mutations Mutation Structural Effect Recombinant Protein Activity Arg125Cys γ-glutamyl cysteine binding ↓ Asp219Gly γ-glutamyl cysteine binding ↓ Asp219Ala γ-glutamyl cysteine binding Not Studied Leu254Arg γ-glutamyl cysteine binding Not Studied Arg267Trp γ-glutamyl cysteine binding ↓ Tyr270Cys γ-glutamyl cysteine binding ↓ Tyr270His γ-glutamyl cysteine binding ↓ Leu286Gln γ-glutamyl cysteine binding Not Studied Asp469Glu γ-glutamyl cysteine binding Not Studied Gly464Val glycine binding Not Studied Leu188Pro ATP binding ↓ Ala26Asp disrupts dimer ↓ Val380 Glu381 deletion misfolding insoluble Pro314Leu None obvious, polymorphism? normal Arg283Cys disulfide formation ↓ Arg330Cys None obvious, polymorphism? Not Studied Structural highlights GSS active site is situated at one edge of a parallel β sheet. Water molecules are shown as red spheres.

3D structures of glutathione synthetase

Updated on 21-July-2025

8fbz - hGSS (mutant) – human 2hgs - hGSS + glutathione + ADP
5oes – GSS + ADP – potato
1m0t – yGSS – yeast
1m0w - yGSS + γ-glutamyl-cysteine + AMP-PNP
3ln6 – GSS – Streptococcus agalactiae
3ln7 – GSS – Pasteurella multocida
2wyo - GSS + glutathione – Trypanosoma brucei
1glv, 2glt, 1gsh – EcGSS – Escherichia coli
1gsa – EcGSS + glutathione + ADP

Reference

Created with the participation of John Mazella.

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Alexander Berchansky, Michal Harel, Joel L. Sussman