glutathione synthase


Summary: One of the enzymes active in the gamma-glutamyl cycle. It catalyzes the synthesis of glutathione from gamma-glutamylcysteine and glycine in the presence of ATP with the formation of ADP and orthophosphate. EC

Top Publications

  1. Zhou X, Vaziri N, Wang X, Silva F, Laszik Z. Nitric oxide synthase expression in hypertension induced by inhibition of glutathione synthase. J Pharmacol Exp Ther. 2002;300:762-7 pubmed
    ..Instead, it is associated with and perhaps partially related to enhanced renal NO inactivation by ROS and diminished NO bioavailability. ..
  2. Townsend D, Tew K, Tapiero H. The importance of glutathione in human disease. Biomed Pharmacother. 2003;57:145-55 pubmed
    ..Polymorphic expression of enzymes involved in GSH homeostasis influences susceptibility and progression of these conditions. This review provides an overview of the biological importance of GSH at the level of the cell and organism. ..
  3. Njalsson R, Ristoff E, Carlsson K, Winkler A, Larsson A, Norgren S. Genotype, enzyme activity, glutathione level, and clinical phenotype in patients with glutathione synthetase deficiency. Hum Genet. 2005;116:384-9 pubmed
    ..The type of mutation involved can, to some extent, predict a mild versus a more severe phenotype. ..
  4. Polekhina G, Board P, Gali R, Rossjohn J, Parker M. Molecular basis of glutathione synthetase deficiency and a rare gene permutation event. EMBO J. 1999;18:3204-13 pubmed
    ..Mutations that lead to GS deficiency have been mapped onto the structure, providing a molecular basis for understanding their effects. ..
  5. Jez J, Cahoon R. Kinetic mechanism of glutathione synthetase from Arabidopsis thaliana. J Biol Chem. 2004;279:42726-31 pubmed
    ..Overall, these observations are consistent with a random Ter-reactant mechanism for the eukaryotic GS in which the binding order of certain substrates is kinetically preferred for catalysis. ..
  6. Gogos A, Shapiro L. Large conformational changes in the catalytic cycle of glutathione synthase. Structure. 2002;10:1669-76 pubmed
    b>Glutathione synthase catalyzes the final ATP-dependent step in glutathione biosynthesis, the formation of glutathione from gamma-glutamylcysteine and glycine...
  7. Yamaguchi H, Kato H, Hata Y, Nishioka T, Kimura A, Oda J, et al. Three-dimensional structure of the glutathione synthetase from Escherichia coli B at 2.0 A resolution. J Mol Biol. 1993;229:1083-100 pubmed
    ..The ATP binding site is surrounded by two sets of the structural motif that belong to those respective domains. Each motif consists of an anti-parallel beta-sheet and a glycine-rich loop. ..
  8. Njalsson R, Carlsson K, Winkler A, Larsson A, Norgren S. Diagnostics in patients with glutathione synthetase deficiency but without mutations in the exons of the GSS gene. Hum Mutat. 2003;22:497 pubmed
    ..Thus, we conclude that in the investigation of patients with glutathione synthetase deficiency, and probably other genetic diseases as well, it might be time saving to initiate mutation analysis with sequencing of mRNA. ..
  9. Dalton T, Chen Y, Schneider S, Nebert D, Shertzer H. Genetically altered mice to evaluate glutathione homeostasis in health and disease. Free Radic Biol Med. 2004;37:1511-26 pubmed
    ..This review focuses on the regulation of GSH homeostasis and, specifically, the new GSH-deficient mouse models that have been developed. These models will improve our understanding of the role of GSH in animal and human diseases. ..

More Information


  1. Shi Z, Habib G, Rhead W, Gahl W, He X, Sazer S, et al. Mutations in the glutathione synthetase gene cause 5-oxoprolinuria. Nat Genet. 1996;14:361-5 pubmed
    ..Our data provide the first molecular genetic analysis of 5-oxoprolinuria and demonstrate that GSS deficiency with oxoprolinuria and GSS deficiency without 5-oxoprolinuria are caused by mutations in the same gene. ..
  2. Lu S. Regulation of glutathione synthesis. Mol Aspects Med. 2009;30:42-59 pubmed publisher
    ..These include diabetes mellitus, pulmonary fibrosis, cholestatic liver injury, endotoxemia and drug-resistant tumor cells. Manipulation of the GSH synthetic capacity is an important target in the treatment of many of these disorders. ..
  3. Frendo P, Jimenez M, Mathieu C, Duret L, Gallesi D, Van de Sype G, et al. A Medicago truncatula homoglutathione synthetase is derived from glutathione synthetase by gene duplication. Plant Physiol. 2001;126:1706-15 pubmed
    ..Analysis of the structure of gshs1 and gshs2 genes shows they are both present in a cluster and in the same orientation in the M. truncatula genome, suggesting that the duplication of gshs1 and gshs2 occurred via a tandem duplication. ..
  4. Phlippen N, Hoffmann K, Fischer R, Wolf K, Zimmermann M. The glutathione synthetase of Schizosaccharomyces pombe is synthesized as a homodimer but retains full activity when present as a heterotetramer. J Biol Chem. 2003;278:40152-61 pubmed
    ..This also showed normal levels of glutathione synthetase activity. These data provide novel insight into the mechanisms of protein folding and the structure and evolution of the glutathione synthetase family. ..
  5. Grant C, MacIver F, Dawes I. Glutathione synthetase is dispensable for growth under both normal and oxidative stress conditions in the yeast Saccharomyces cerevisiae due to an accumulation of the dipeptide gamma-glutamylcysteine. Mol Biol Cell. 1997;8:1699-707 pubmed
    ..We suggest that this function may be the detoxification of harmful intermediates that are generated during normal cellular metabolism. ..
  6. Hara T, Kato H, Katsube Y, Oda J. A pseudo-michaelis quaternary complex in the reverse reaction of a ligase: structure of Escherichia coli B glutathione synthetase complexed with ADP, glutathione, and sulfate at 2.0 A resolution. Biochemistry. 1996;35:11967-74 pubmed
    ..Functional aspects of the active site architecture in the substrate-binding form are discussed. ..
  7. Al Lahham A, Rohde V, Heim P, Leuchter R, Veeck J, Wunderlich C, et al. Biosynthesis of phytochelatins in the fission yeast. Phytochelatin synthesis: a second role for the glutathione synthetase gene of Schizosaccharomyces pombe. Yeast. 1999;15:385-96 pubmed
    ..The sequence has been submitted to EMBL, Accession No. Y08414. ..
  8. Huang C, He W, Meister A, Anderson M. Amino acid sequence of rat kidney glutathione synthetase. Proc Natl Acad Sci U S A. 1995;92:1232-6 pubmed
  9. Ristoff E, Hebert C, Njalsson R, Norgren S, Rooyackers O, Larsson A. Glutathione synthetase deficiency: is gamma-glutamylcysteine accumulation a way to cope with oxidative stress in cells with insufficient levels of glutathione?. J Inherit Metab Dis. 2002;25:577-84 pubmed
    ..7-51.4), we propose that the cultured fibroblasts may have a mechanism to regulate in a coordinated way the levels of GSH and gamma-GC; for instance, by both compounds acting as feedback inhibitors of gamma-GC synthetase. ..
  10. Pasternak M, Lim B, Wirtz M, Hell R, Cobbett C, Meyer A. Restricting glutathione biosynthesis to the cytosol is sufficient for normal plant development. Plant J. 2008;53:999-1012 pubmed
  11. Ristoff E, Mayatepek E, Larsson A. Long-term clinical outcome in patients with glutathione synthetase deficiency. J Pediatr. 2001;139:79-84 pubmed
    ..Our results indicate that early supplementation with vitamins C and E may improve the long-term clinical outcome. ..
  12. Mayatepek E. 5-Oxoprolinuria in patients with and without defects in the gamma-glutamyl cycle. Eur J Pediatr. 1999;158:221-5 pubmed
    ..However, several other inborn errors of metabolism and pathophysiological conditions must be taken into account when discovering 5-oxoprolinuria. ..
  13. Okumura N, Masamoto K, Wada H. The gshB gene in the cyanobacterium Synechococcus sp. PCC 7942 encodes a functional glutathione synthetase. Microbiology. 1997;143 ( Pt 9):2883-90 pubmed
    ..These findings demonstrate that the gshB gene of Synechococcus sp. PCC 7942 is a structural gene for glutathione synthetase and is involved in the biosynthesis of glutathione. ..
  14. Dinescu A, Anderson M, Cundari T. Catalytic loop motion in human glutathione synthetase: A molecular modeling approach. Biochem Biophys Res Commun. 2007;353:450-6 pubmed
    ..Additionally, this research identifies important amino acid residues and explains their function within the catalytic loops of hGS. ..
  15. Ristoff E, Burstedt M, Larsson A, Wachtmeister L. Progressive retinal dystrophy in two sisters with glutathione synthetase (GS) deficiency. J Inherit Metab Dis. 2007;30:102 pubmed
    ..If this is the case, the redox state in the retina should be a potentially useful therapeutic target to prevent reduced visual function and blindness. ..
  16. Meister A, Anderson M. Glutathione. Annu Rev Biochem. 1983;52:711-60 pubmed
  17. Gali R, Board P. Sequencing and expression of a cDNA for human glutathione synthetase. Biochem J. 1995;310 ( Pt 1):353-8 pubmed
  18. Skipsey M, Davis B, Edwards R. Diversification in substrate usage by glutathione synthetases from soya bean (Glycine max), wheat (Triticum aestivum) and maize (Zea mays). Biochem J. 2005;391:567-74 pubmed publisher
    ..Our results suggest that plant GSs are capable of producing a diverse range of glutathione homologues depending on the availability of the acyl acceptor...
  19. Beutler E, Moroose R, Kramer L, Gelbart T, Forman L. Gamma-glutamylcysteine synthetase deficiency and hemolytic anemia. Blood. 1990;75:271-3 pubmed
    ..This leads us to conclude that either the occurrence of neurologic symptoms in the other reported family was a chance association or that the clinical expression of this rare defect is pleomorphic. ..
  20. Wachter A, Wolf S, Steininger H, Bogs J, Rausch T. Differential targeting of GSH1 and GSH2 is achieved by multiple transcription initiation: implications for the compartmentation of glutathione biosynthesis in the Brassicaceae. Plant J. 2005;41:15-30 pubmed
    ..The implications of the results for the compartmentation and regulation of GSH synthesis are discussed. ..
  21. DeLeve L. Effect of decreased glutathione levels in hereditary glutathione synthetase deficiency on dibromoethane-induced genotoxicity in human fibroblasts. Mutat Res. 1997;389:291-7 pubmed
    ..Inhibition of cell proliferation was similar in the glutathione-deficient and normal fibroblasts. In conclusion, low endogenous glutathione levels are protective against dibromoethane-induced genotoxicity in human fibroblasts. ..
  22. Gopal S, Borovok I, Ofer A, Yanku M, Cohen G, Goebel W, et al. A multidomain fusion protein in Listeria monocytogenes catalyzes the two primary activities for glutathione biosynthesis. J Bacteriol. 2005;187:3839-47 pubmed publisher
  23. Matamoros M, Clemente M, Sato S, Asamizu E, Tabata S, Ramos J, et al. Molecular analysis of the pathway for the synthesis of thiol tripeptides in the model legume Lotus japonicus. Mol Plant Microbe Interact. 2003;16:1039-46 pubmed publisher
    ..This strongly suggests an important role of GSH in the rhizobia-legume symbiosis...
  24. Iwata C, Wang X, Uchida K, Nakanishi N, Hattori Y. Buthionine sulfoximine causes endothelium dependent hyper-relaxation and hypoadiponectinemia. Life Sci. 2007;80:873-8 pubmed
  25. Gupta S, Srivastava A, Banu N. Setaria cervi: kinetic studies of filarial glutathione synthetase by high performance liquid chromatography. Exp Parasitol. 2005;111:137-41 pubmed
    ..The effect of various amino acids was studied on enzyme activity at 1mM concentration. L-cystine caused a significant enzyme inhibition of 11%. Preincubation with N-ethylmaleimide also resulted in significant inhibition of GS activity. ..
  26. Frendo P, Harrison J, Norman C, Hernández Jiménez M, Van de Sype G, Gilabert A, et al. Glutathione and homoglutathione play a critical role in the nodulation process of Medicago truncatula. Mol Plant Microbe Interact. 2005;18:254-9 pubmed
    ..In conclusion, GSH and hGSH appear to be essential for proper development of the root nodules during the symbiotic interaction. ..
  27. Whitin J, Cohen H. Disorders of respiratory burst termination. Hematol Oncol Clin North Am. 1988;2:289-99 pubmed
    ..Further investigations on the mechanisms of inactivation of the NADPH oxidase are warranted in order to gain a greater understanding of this important regulating mechanism. ..
  28. Herrera K, Cahoon R, Kumaran S, Jez J. Reaction mechanism of glutathione synthetase from Arabidopsis thaliana: site-directed mutagenesis of active site residues. J Biol Chem. 2007;282:17157-65 pubmed
    ..thaliana GS and the Arg-132 and Arg-454 mutants also suggest distinct mechanistic roles for these residues. Based on these results, a catalytic mechanism for the eukaryotic GS is proposed. ..
  29. Kim S, Shin Y, Kim K, Park E, Sa J, Lim C. Regulation of the gene encoding glutathione synthetase from the fission yeast. J Biochem Mol Biol. 2003;36:326-31 pubmed
    ..It was also induced by L-buthionine-(S,R)-sulfoximine, a specific inhibitor of gamma-glutamylcysteine synthetase (GCS). We also found that the expression of the S. pombe GS gene is regulated by the Atf1-Spc1-Wis1 signal pathway. ..
  30. Carney Almroth B, Albertsson E, Sturve J, Förlin L. Oxidative stress, evident in antioxidant defences and damage products, in rainbow trout caged outside a sewage treatment plant. Ecotoxicol Environ Saf. 2008;70:370-8 pubmed publisher
    ..Antioxidant enzymes showed no clear-cut response. Additionally, older pollutants that have been present in down stream sediment for decades had no effects on the parameters measured here. ..
  31. Bardag Gorce F, Oliva J, Lin A, Li J, French B, French S. Proteasome inhibitor up regulates liver antioxidative enzymes in rat model of alcoholic liver disease. Exp Mol Pathol. 2011;90:123-30 pubmed publisher
    ..In conclusion, proteasome inhibitor treatment used at a non toxic low dose has potential protective effects against oxidative stress due to chronic ethanol feeding. ..
  32. Njalsson R, Carlsson K, Olin B, Carlsson B, Whitbread L, Polekhina G, et al. Kinetic properties of missense mutations in patients with glutathione synthetase deficiency. Biochem J. 2000;349:275-9 pubmed
    ..Thus our data indicate that different mutations can affect the catalytic capacity of GS by decreasing substrate affinity, maximal velocity or enzyme stability. ..
  33. Wang C, Oliver D. Cloning of the cDNA and genomic clones for glutathione synthetase from Arabidopsis thaliana and complementation of a gsh2 mutant in fission yeast. Plant Mol Biol. 1996;31:1093-104 pubmed
    ..Since the Arabidopsis cDNA was under control of a thiamine-repressible promoter, growth of the transformed yeast on thiamine-free medium increased expression of the cDNA resulting in increases in cadmium resistance. ..
  34. Shi Z, Carter B, Habib G, He X, Sazer S, Lebovitz R, et al. A single mouse glutathione synthetase gene encodes six mRNAs with different 5' ends. Arch Biochem Biophys. 1996;331:215-24 pubmed
    ..In liver only type A1 GSH syn RNA is detectable, while in kidney 90% of GSH syn RNA is type A1 and types B and C account for about 10%. ..
  35. Nakamura Y, Dubick M, Omaye S. Modulation of oxidative stress by ?-glutamylcysteine (GGC) and conjugated linoleic acid (CLA) isomer mixture in human umbilical vein endothelial cells. Food Chem Toxicol. 2012;50:1854-9 pubmed publisher
  36. Chen Y, Tuan H, Tien C, Lo W, Liang H, Hu Y. Augmented biosynthesis of cadmium sulfide nanoparticles by genetically engineered Escherichia coli. Biotechnol Prog. 2009;25:1260-6 pubmed publisher
    ..Additionally, E. coli-based biosynthesis offers a more energy-efficient and eco-friendly method as opposed to chemical processes requiring high temperature and toxic solvents. ..
  37. Armenian P, Gerona R, Blanc P, Wu A, Mookherjee S. 5-oxoprolinemia causing elevated anion gap metabolic acidosis in the setting of acetaminophen use. J Emerg Med. 2012;43:54-7 pubmed publisher
    ..The ED differential diagnosis of AG metabolic acidosis in chronic APAP overuse, especially with concomitant nutritional compromise, should include 5-oxoprolinemia. ..
  38. Amicarelli F, Colafarina S, Cattani F, Cimini A, Di Ilio C, Ceru M, et al. Scavenging system efficiency is crucial for cell resistance to ROS-mediated methylglyoxal injury. Free Radic Biol Med. 2003;35:856-71 pubmed
    ..These data emphasize the pivotal role of antioxidant and detoxifying systems in determining the grade of sensitivity of cells to methylglyoxal. ..
  39. Faucet Marquis V, Pont F, Størmer F, Rizk T, Castegnaro M, Pfohl Leszkowicz A. Evidence of a new dechlorinated ochratoxin A derivative formed in opossum kidney cell cultures after pretreatment by modulators of glutathione pathways: correlation with DNA-adduct formation. Mol Nutr Food Res. 2006;50:530-42 pubmed
    ..Ochratoxin B (OTB), open-ring ochratoxin A (OP-OA), 4 hydroxylated OTA, 10 hydroxylated OTA, OTA without phenylalanine, OTB without phenylalanine, and a dechlorinated OTA metabolite could be identified by nano-ESI-IT-MS. ..
  40. Raftos J, Dwarte T, Luty A, Willcock C. Direct measurement of the rate of glutathione synthesis in 1-chloro-2,4-dinitrobenzene treated human erythrocytes. Redox Rep. 2006;11:9-14 pubmed
    ..Application of this direct method for measuring glutathione synthesis will increase understanding of the interactions of effectors that determine glutathione levels in RBCs under various physiological and pathological conditions. ..
  41. Kowara R, Karaczyn A, Cheng R, Salnikow K, Kasprzak K. Microarray analysis of altered gene expression in murine fibroblasts transformed by nickel(II) to nickel(II)-resistant malignant phenotype. Toxicol Appl Pharmacol. 2005;205:1-10 pubmed
  42. Brüggemann L, Groenendaal F, Ristoff E, Larsson A, Duran M, van Lier J, et al. Glutathione synthetase deficiency associated with antenatal cerebral bleeding. J Inherit Metab Dis. 2004;27:275-6 pubmed
    ..We present a newborn with glutathione synthetase deficiency and intracranial haemorrhages. Because the latter are rare in term newborns a possible relationship with glutathione synthetase deficiency will be discussed. ..
  43. Chuang J, Chang T, Liu H. Glutathione depletion-induced apoptosis of Ha-ras-transformed NIH3T3 cells can be prevented by melatonin. Oncogene. 2003;22:1349-57 pubmed
    ..Cotreatment of ras-related cancer cells with melatonin and BSO stops cell growth as well as apoptosis. Whether these cancer cells will undergo further regression or become recurrent merits investigation. ..
  44. Rappa G, Gamcsik M, Mitina R, Baum C, Fodstad O, Lorico A. Retroviral transfer of MRP1 and gamma-glutamyl cysteine synthetase modulates cell sensitivity to L-buthionine-S,R-sulphoximine (BSO): new rationale for the use of BSO in cancer therapy. Eur J Cancer. 2003;39:120-8 pubmed
    ..These data, and in particular the elevated single-agent cytotoxicity of BSO, provide a new rationale for the use of BSO in the treatment of MRP1-overexpressing tumours. ..
  45. Copley S, Dhillon J. Lateral gene transfer and parallel evolution in the history of glutathione biosynthesis genes. Genome Biol. 2002;3:research0025 pubmed
    ..The eukaryotic glutathione synthetase did not evolve directly from the bacterial glutathione synthetase. ..
  46. Fan C, Moews P, Shi Y, Walsh C, Knox J. A common fold for peptide synthetases cleaving ATP to ADP: glutathione synthetase and D-alanine:d-alanine ligase of Escherichia coli. Proc Natl Acad Sci U S A. 1995;92:1172-6 pubmed
  47. Rathinam M, Watts L, Stark A, Mahimainathan L, Stewart J, Schenker S, et al. Astrocyte control of fetal cortical neuron glutathione homeostasis: up-regulation by ethanol. J Neurochem. 2006;96:1289-300 pubmed
  48. Lee T, Yang H, Whang J, Lu S. Cloning and characterization of the human glutathione synthetase 5'-flanking region. Biochem J. 2005;390:521-8 pubmed
    ..In summary, two NFE2 sites in the human GSS promoter play important roles in the basal expression of GSS and, similar to the GCL subunits, the human GSS gene expression is also regulated by Nrf2. ..
  49. Yang H, Magilnick N, Xia M, Lu S. Effects of hepatocyte growth factor on glutathione synthesis, growth, and apoptosis is cell density-dependent. Exp Cell Res. 2008;314:398-412 pubmed
    ..The increase in cell GSH under low cell density allows HGF to exert its full mitogenic effect but is not necessary for its anti-apoptotic effect. ..
  50. Hiratake J. [Probing the structure and function of enzymes by using transition-state analogues]. Seikagaku. 2002;74:38-42 pubmed
  51. Habenicht A, Hille S, Knochel W. Molecular cloning of the large subunit of glutathione synthetase from Xenopus laevis embryos. Biochim Biophys Acta. 1993;1174:295-8 pubmed
    ..Transcripts are also detected in various adult tissues suggesting an ubiquitous distribution of the corresponding protein. ..
  52. Stout J, De Vos D, Vergauwen B, Savvides S. Glutathione biosynthesis in bacteria by bifunctional GshF is driven by a modular structure featuring a novel hybrid ATP-grasp fold. J Mol Biol. 2012;416:486-94 pubmed publisher
    ..Comparison of the two GshF structures and mapping of structure-function relationships reveal that the bifunctional GshF structural platform operates as a dynamic dimeric assembly. ..
  53. Wang B, Hom G, Zhou S, Guo M, Li B, Yang J, et al. The oxidized thiol proteome in aging and cataractous mouse and human lens revealed by ICAT labeling. Aging Cell. 2017;16:244-261 pubmed publisher
    ..Enzymes with oxidized cysteine at critical sites include GAPDH (hGAPDH, Cys247), glutathione synthase (hGSS, Cys294), aldehyde dehydrogenase (hALDH1A1, Cys126 and Cys186), sorbitol dehydrogenase (hSORD, Cys140,..