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 + gamma-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[1]
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[2]
| 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
|
3D structures of glutathione synthetase
1glv, 2glt, 1gsh – EcGSS – Escherichia coli
1m0t – yGSS – yeast
3ln6 – GSS – Streptococcus agalactiae
3ln7 – GSS – Pasteurella multocida
2wyo - GSS + glutathione – Trypanosoma brucei
1gsa – EcGSS + glutathione + ADP
2hgs - GSS + glutathione + ADP – human
1m0w - yGSS + γ-glutamyl-cysteine + AMP-PNP
