ID   GSHB_HUMAN              Reviewed;         474 AA.
AC   P48637; B2R697; B6F210; E1P5P9; Q4TTD9;
DT   01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
DT   01-FEB-1996, sequence version 1.
DT   04-NOV-2026, entry version 229.
DE   RecName: Full=Glutathione synthetase {ECO:0000303|PubMed:7646467};
DE            Short=GSH synthetase;
DE            Short=GSH-S;
DE            EC=6.3.2.3 {ECO:0000269|PubMed:7646467, ECO:0000269|PubMed:9215686};
DE   AltName: Full=Glutathione synthase;
GN   Name=GSS {ECO:0000312|HGNC:HGNC:4624};
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, CATALYTIC ACTIVITY, AND
RP   SUBUNIT.
RC   TISSUE=Brain;
RX   PubMed=7646467; DOI=10.1042/bj3100353;
RA   Gali R.R., Board P.G.;
RT   "Sequencing and expression of a cDNA for human glutathione synthetase.";
RL   Biochem. J. 310:353-358(1995).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX   PubMed=19672693; DOI=10.1007/s11033-009-9675-3;
RA   Uchida M., Sugaya M., Kanamaru T., Hisatomi H.;
RT   "Alternative RNA splicing in expression of the glutathione synthetase gene
RT   in human cells.";
RL   Mol. Biol. Rep. 37:2105-2109(2010).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC   TISSUE=Kidney;
RA   Shi Z.-Z., Galang R.L., Habib G.M., Lebovitz R.M., Lieberman M.W.;
RL   Submitted (AUG-1995) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT GLU-437.
RC   TISSUE=Substantia nigra;
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS GLN-236 AND GLU-437.
RG   NIEHS SNPs program;
RL   Submitted (MAY-2005) to the EMBL/GenBank/DDBJ databases.
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=11780052; DOI=10.1038/414865a;
RA   Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R.,
RA   Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L.,
RA   Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P.,
RA   Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J., Buck D., Burrill W.D.,
RA   Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G.,
RA   Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E.,
RA   Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D.,
RA   Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P.,
RA   Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E.,
RA   Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J.,
RA   Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D.,
RA   Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S.,
RA   Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D.,
RA   Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A.,
RA   Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T.,
RA   Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I.,
RA   Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M.,
RA   Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D.,
RA   Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M.,
RA   Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A.,
RA   Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L.,
RA   Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L.,
RA   Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J.;
RT   "The DNA sequence and comparative analysis of human chromosome 20.";
RL   Nature 414:865-871(2001).
RN   [7]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN   [8]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Lung;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [9]
RP   PROTEIN SEQUENCE OF 26-34; 113-125; 142-158; 222-230; 254-267; 274-283;
RP   294-305; 419-434 AND 453-474, AND IDENTIFICATION BY MASS SPECTROMETRY.
RC   TISSUE=Fetal brain cortex;
RA   Lubec G., Chen W.-Q., Sun Y.;
RL   Submitted (DEC-2008) to UniProtKB.
RN   [10]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP   METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP   [LARGE SCALE ANALYSIS].
RX   PubMed=19413330; DOI=10.1021/ac9004309;
RA   Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT   "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT   refined SCX-based approach.";
RL   Anal. Chem. 81:4493-4501(2009).
RN   [11]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA   Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [12]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP   METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP   [LARGE SCALE ANALYSIS].
RX   PubMed=22223895; DOI=10.1074/mcp.m111.015131;
RA   Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T.,
RA   Giglione C.;
RT   "Comparative large-scale characterisation of plant vs. mammal proteins
RT   reveals similar and idiosyncratic N-alpha acetylation features.";
RL   Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012).
RN   [13]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-415, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Erythroleukemia;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [14]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-415, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA   Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA   Ye M., Zou H.;
RT   "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT   phosphoproteome.";
RL   J. Proteomics 96:253-262(2014).
RN   [15]
RP   X-RAY CRYSTALLOGRAPHY IN COMPLEX WITH ADP AND GLUTATHIONE, FUNCTION,
RP   COFACTOR, AND SUBUNIT.
RX   PubMed=10369661; DOI=10.1093/emboj/18.12.3204;
RA   Polekhina G., Board P.G., Gali R.R., Rossjohn J., Parker M.W.;
RT   "Molecular basis of glutathione synthetase deficiency and a rare gene
RT   permutation event.";
RL   EMBO J. 18:3204-3213(1999).
RN   [16]
RP   VARIANTS GSSD CYS-125; TRP-267 AND CYS-283, VARIANT CNSHA6 GLY-219, VARIANT
RP   LEU-314, AND INVOLVEMENT IN CNSHA6.
RX   PubMed=8896573; DOI=10.1038/ng1196-361;
RA   Shi Z.-Z., Habib G.M., Rhead W.J., Gahl W.A., He X., Sazer S.,
RA   Lieberman M.W.;
RT   "Mutations in the glutathione synthetase gene cause 5-oxoprolinuria.";
RL   Nat. Genet. 14:361-365(1996).
RN   [17]
RP   VARIANTS GSSD ASP-26; PRO-188; ARG-254; TRP-267; CYS-270; HIS-270; CYS-283;
RP   VAL-464 AND GLU-469, VARIANTS CNSHA6 GLY-219; GLN-286 AND CYS-330,
RP   CHARACTERIZATION OF VARIANTS GSSD PRO-188; CYS-270; HIS-270 AND CYS-283,
RP   FUNCTION, CATALYTIC ACTIVITY, AND PATHWAY.
RX   PubMed=9215686; DOI=10.1093/hmg/6.7.1147;
RA   Dahl N., Pigg M., Ristoff E., Gali R., Carlsson B., Mannervik B.,
RA   Larsson A., Board P.;
RT   "Missense mutations in the human glutathione synthetase gene result in
RT   severe metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and
RT   neurological dysfunction.";
RL   Hum. Mol. Genet. 6:1147-1152(1997).
RN   [18]
RP   VARIANTS CNSHA6 GLY-219 AND PRO-301.
RX   PubMed=27581854; DOI=10.1542/peds.2015-4324;
RA   Signolet I., Chenouard R., Oca F., Barth M., Reynier P., Denis M.C.,
RA   Simard G.;
RT   "Recurrent isolated neonatal hemolytic anemia: think about glutathione
RT   synthetase deficiency.";
RL   Pediatrics 138:0-0(2016).
CC   -!- FUNCTION: Catalyzes the production of glutathione from gamma-
CC       glutamylcysteine and glycine in an ATP-dependent manner
CC       (PubMed:7646467, PubMed:9215686). Glutathione (gamma-
CC       glutamylcysteinylglycine, GSH) is the most abundant intracellular thiol
CC       in living aerobic cells and is required for numerous processes
CC       including the protection of cells against oxidative damage, amino acid
CC       transport, the detoxification of foreign compounds, the maintenance of
CC       protein sulfhydryl groups in a reduced state and acts as a cofactor for
CC       a number of enzymes (PubMed:10369661). Participates in ophthalmate
CC       biosynthesis in hepatocytes (By similarity).
CC       {ECO:0000250|UniProtKB:P51855, ECO:0000269|PubMed:7646467,
CC       ECO:0000269|PubMed:9215686, ECO:0000303|PubMed:10369661}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=gamma-L-glutamyl-L-cysteine + glycine + ATP = glutathione +
CC         ADP + phosphate + H(+); Xref=Rhea:RHEA:13557, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:57305,
CC         ChEBI:CHEBI:57925, ChEBI:CHEBI:58173, ChEBI:CHEBI:456216; EC=6.3.2.3;
CC         Evidence={ECO:0000269|PubMed:7646467, ECO:0000269|PubMed:9215686};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:13558;
CC         Evidence={ECO:0000269|PubMed:9215686};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=gamma-L-glutamyl-(2S)-2-aminobutanoate + glycine + ATP =
CC         ophthalmate + ADP + phosphate + H(+); Xref=Rhea:RHEA:72075,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474,
CC         ChEBI:CHEBI:57305, ChEBI:CHEBI:189406, ChEBI:CHEBI:189750,
CC         ChEBI:CHEBI:456216; Evidence={ECO:0000250|UniProtKB:P51855};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:72076;
CC         Evidence={ECO:0000250|UniProtKB:P51855};
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC         Evidence={ECO:0000269|PubMed:10369661};
CC       Note=Binds 1 Mg(2+) ion per subunit. {ECO:0000269|PubMed:10369661};
CC   -!- PATHWAY: Sulfur metabolism; glutathione biosynthesis; glutathione from
CC       L-cysteine and L-glutamate: step 2/2. {ECO:0000305|PubMed:9215686}.
CC   -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:10369661,
CC       ECO:0000269|PubMed:7646467}.
CC   -!- INTERACTION:
CC       P48637; P48637: GSS; NbExp=8; IntAct=EBI-2969145, EBI-2969145;
CC       P48637; P54274: TERF1; NbExp=2; IntAct=EBI-2969145, EBI-710997;
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=P48637-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=P48637-2; Sequence=VSP_047617;
CC   -!- DISEASE: Glutathione synthetase deficiency (GSSD) [MIM:266130]: An
CC       autosomal recessive disorder characterized by massive urinary excretion
CC       of 5-oxoproline, metabolic acidosis, hemolytic anemia, and central
CC       nervous system damage. {ECO:0000269|PubMed:27581854,
CC       ECO:0000269|PubMed:8896573, ECO:0000269|PubMed:9215686}. Note=The
CC       disease is caused by variants affecting the gene represented in this
CC       entry.
CC   -!- DISEASE: Anemia, congenital, non-spherocytic hemolytic, 6 (CNSHA6)
CC       [MIM:231900]: A mild form of glutathione synthetase deficiency,
CC       resulting in hemolytic anemia. Affected individuals do not have
CC       neurologic abnormalities. CNSHA6 inheritance is autosomal recessive.
CC       {ECO:0000269|PubMed:27581854, ECO:0000269|PubMed:8896573,
CC       ECO:0000269|PubMed:9215686}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry.
CC   -!- MISCELLANEOUS: [Isoform 2]: Detected in colon, kidney, lung, liver,
CC       placenta, peripheral blood and uterus, but not in heart, skeletal
CC       muscle and spleen. {ECO:0000305}.
CC   -!- SIMILARITY: Belongs to the eukaryotic GSH synthase family.
CC       {ECO:0000305}.
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DR   EMBL; L42531; AAA69492.1; -; mRNA.
DR   EMBL; AB459500; BAG75452.1; -; mRNA.
DR   EMBL; U34683; AAB62390.1; -; mRNA.
DR   EMBL; AK312492; BAG35394.1; -; mRNA.
DR   EMBL; DQ074975; AAY57328.1; -; Genomic_DNA.
DR   EMBL; AL133324; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471077; EAW76239.1; -; Genomic_DNA.
DR   EMBL; CH471077; EAW76240.1; -; Genomic_DNA.
DR   EMBL; BC007927; AAH07927.1; -; mRNA.
DR   CCDS; CCDS13245.1; -. [P48637-1]
DR   PIR; S56748; S56748.
DR   RefSeq; NP_000169.1; NM_000178.4. [P48637-1]
DR   RefSeq; NP_001309423.1; NM_001322494.1. [P48637-1]
DR   RefSeq; NP_001309424.1; NM_001322495.1. [P48637-1]
DR   PDB; 2HGS; X-ray; 2.10 A; A=1-474.
DR   PDB; 8FBZ; X-ray; 1.59 A; A/B=1-474.
DR   AlphaFoldDB; P48637; -.
DR   MDposit; P48637; -.
DR   SMR; P48637; -.
DR   BioGRID; 109192; 58.
DR   FunCoup; P48637; 1365.
DR   IntAct; P48637; 13.
DR   NDEx; IQUERY-CP-GSS; 7 NDEx IQuery Curated Pathways.
DR   STRING; 9606.ENSP00000495750; -.
DR   BindingDB; P48637; -.
DR   ChEMBL; CHEMBL6066521; -.
DR   DrugBank; DB06151; Acetylcysteine.
DR   DrugBank; DB09130; Copper.
DR   DrugBank; DB00151; Cysteine.
DR   DrugBank; DB03408; gamma-Glutamylcysteine.
DR   DrugBank; DB00143; Glutathione.
DR   DrugBank; DB00145; Glycine.
DR   DrugBank; DB04395; Phosphoaminophosphonic Acid-Adenylate Ester.
DR   DrugCentral; P48637; -.
DR   iPTMnet; P48637; -.
DR   PhosphoSitePlus; P48637; -.
DR   BioMuta; GSS; -.
DR   DMDM; 1346191; -.
DR   OGP; P48637; -.
DR   REPRODUCTION-2DPAGE; IPI00010706; -.
DR   CPTAC; CPTAC-210; -.
DR   CPTAC; CPTAC-211; -.
DR   jPOST; P48637; -.
DR   MassIVE; P48637; -.
DR   PaxDb; 9606-ENSP00000495750; -.
DR   PeptideAtlas; P48637; -.
DR   ProteomicsDB; 55917; -. [P48637-1]
DR   ProteomicsDB; 6247; -.
DR   Pumba; P48637; -.
DR   Antibodypedia; 25920; 531 antibodies from 38 providers.
DR   DNASU; 2937; -.
DR   Ensembl; ENST00000451957.2; ENSP00000407517.2; ENSG00000100983.13. [P48637-2]
DR   Ensembl; ENST00000643188.1; ENSP00000493903.1; ENSG00000100983.13. [P48637-1]
DR   Ensembl; ENST00000644793.1; ENSP00000495750.1; ENSG00000100983.13. [P48637-1]
DR   Ensembl; ENST00000646735.1; ENSP00000493763.1; ENSG00000100983.13. [P48637-2]
DR   Ensembl; ENST00000651619.1; ENSP00000498303.1; ENSG00000100983.13. [P48637-1]
DR   Ensembl; ENST00000854975.1; ENSP00000525034.1; ENSG00000100983.13. [P48637-1]
DR   Ensembl; ENST00000854981.1; ENSP00000525040.1; ENSG00000100983.13. [P48637-1]
DR   Ensembl; ENST00000854982.1; ENSP00000525041.1; ENSG00000100983.13. [P48637-1]
DR   Ensembl; ENST00000961051.1; ENSP00000631110.1; ENSG00000100983.13. [P48637-1]
DR   GeneID; 2937; -.
DR   KEGG; hsa:2937; -.
DR   MANE-Select; ENST00000651619.1; ENSP00000498303.1; NM_000178.4; NP_000169.1.
DR   UCSC; uc010zuo.3; human. [P48637-1]
DR   AGR; HGNC:4624; -.
DR   ClinPGx; PA29015; -.
DR   CTD; 2937; -.
DR   DisGeNET; 2937; -.
DR   GeneCards; GSS; -.
DR   HGNC; HGNC:4624; GSS.
DR   HPA; ENSG00000100983; Low tissue specificity.
DR   MalaCards; GSS; -.
DR   MIM; 231900; phenotype.
DR   MIM; 266130; phenotype.
DR   MIM; 601002; gene.
DR   OpenTargets; ENSG00000100983; -.
DR   Orphanet; 289846; Glutathione synthetase deficiency with 5-oxoprolinuria.
DR   Orphanet; 289849; Glutathione synthetase deficiency without 5-oxoprolinuria.
DR   VEuPathDB; HostDB:ENSG00000100983; -.
DR   eggNOG; KOG0021; Eukaryota.
DR   GeneTree; ENSGT00390000013764; -.
DR   HOGENOM; CLU_025152_2_1_1; -.
DR   InParanoid; P48637; -.
DR   OMA; AAGWKAM; -.
DR   OrthoDB; 2020073at2759; -.
DR   PAN-GO; P48637; 3 GO annotations based on evolutionary models.
DR   PhylomeDB; P48637; -.
DR   BioCyc; MetaCyc:HS02174-MONOMER; -.
DR   BRENDA; 6.3.2.3; 2681.
DR   PathwayCommons; P48637; -.
DR   Reactome; R-HSA-174403; Glutathione synthesis and recycling.
DR   Reactome; R-HSA-5579006; Defective GSS causes GSS deficiency.
DR   SABIO-RK; P48637; -.
DR   SignaLink; P48637; -.
DR   SIGNOR; P48637; -.
DR   UniPathway; UPA00142; UER00210.
DR   Agora; ENSG00000100983; -.
DR   BioGRID-ORCS; 2937; 41 hits in 1177 CRISPR screens.
DR   ChiTaRS; GSS; human.
DR   EvolutionaryTrace; P48637; -.
DR   GenomeRNAi; 2937; -.
DR   Pharos; P48637; Tbio.
DR   PRO; PR:P48637; -.
DR   Proteomes; UP000005640; Chromosome 20.
DR   RNAct; P48637; protein.
DR   Bgee; ENSG00000100983; Expressed in frontal pole and 206 other cell types or tissues.
DR   ExpressionAtlas; P48637; baseline and differential.
DR   GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR   GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR   GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR   GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR   GO; GO:0043295; F:glutathione binding; IDA:UniProtKB.
DR   GO; GO:0004363; F:glutathione synthase activity; IDA:UniProtKB.
DR   GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR   GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB.
DR   GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR   GO; GO:0006520; P:amino acid metabolic process; TAS:ProtInc.
DR   GO; GO:0006750; P:glutathione biosynthetic process; IMP:FlyBase.
DR   GO; GO:0007399; P:nervous system development; TAS:ProtInc.
DR   GO; GO:0006979; P:response to oxidative stress; TAS:ProtInc.
DR   CDD; cd00228; eu-GS; 1.
DR   FunFam; 3.30.1490.50:FF:000001; Glutathione synthetase; 1.
DR   FunFam; 3.30.1490.80:FF:000004; Glutathione synthetase; 1.
DR   FunFam; 3.40.50.1760:FF:000003; Glutathione synthetase; 1.
DR   Gene3D; 3.30.1490.50; -; 1.
DR   Gene3D; 3.30.1490.80; -; 1.
DR   Gene3D; 3.30.470.20; ATP-grasp fold, B domain; 1.
DR   Gene3D; 3.40.50.1760; Glutathione synthase, substrate-binding domain superfamily, eukaryotic; 1.
DR   Gene3D; 1.10.1080.10; Glutathione Synthetase, Chain A, domain 3; 1.
DR   InterPro; IPR005615; Glutathione_synthase.
DR   InterPro; IPR014042; Glutathione_synthase_a-hlx.
DR   InterPro; IPR014709; Glutathione_synthase_C_euk.
DR   InterPro; IPR014049; Glutathione_synthase_N_euk.
DR   InterPro; IPR037013; GSH-S_sub-bd_sf.
DR   InterPro; IPR004887; GSH_synth_subst-bd.
DR   InterPro; IPR016185; PreATP-grasp_dom_sf.
DR   NCBIfam; TIGR01986; glut_syn_euk; 1.
DR   PANTHER; PTHR11130; GLUTATHIONE SYNTHETASE; 1.
DR   PANTHER; PTHR11130:SF0; GLUTATHIONE SYNTHETASE; 1.
DR   Pfam; PF03917; GSH_synth_ATP; 1.
DR   Pfam; PF03199; GSH_synthase; 1.
DR   PIRSF; PIRSF001558; GSHase; 1.
DR   SUPFAM; SSF56059; Glutathione synthetase ATP-binding domain-like; 1.
DR   SUPFAM; SSF52440; PreATP-grasp domain; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Alternative splicing; ATP-binding;
KW   Direct protein sequencing; Disease variant; Glutathione biosynthesis;
KW   Hereditary hemolytic anemia; Ligase; Magnesium; Metal-binding;
KW   Nucleotide-binding; Phosphoprotein; Proteomics identification;
KW   Reference proteome.
FT   INIT_MET        1
FT                   /note="Removed"
FT                   /evidence="ECO:0007744|PubMed:19413330,
FT                   ECO:0007744|PubMed:22223895"
FT   CHAIN           2..474
FT                   /note="Glutathione synthetase"
FT                   /id="PRO_0000211260"
FT   BINDING         125
FT                   /ligand="substrate"
FT   BINDING         144
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT   BINDING         144
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT   BINDING         146
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT   BINDING         148..151
FT                   /ligand="substrate"
FT   BINDING         214..216
FT                   /ligand="substrate"
FT   BINDING         220
FT                   /ligand="substrate"
FT   BINDING         267..270
FT                   /ligand="substrate"
FT   BINDING         305
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT   BINDING         364..373
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT   BINDING         368
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT   BINDING         375
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT   BINDING         398..401
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT   BINDING         425
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT   BINDING         450
FT                   /ligand="substrate"
FT   BINDING         452
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT   BINDING         458
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT   BINDING         461..462
FT                   /ligand="substrate"
FT   MOD_RES         2
FT                   /note="N-acetylalanine"
FT                   /evidence="ECO:0007744|PubMed:19413330,
FT                   ECO:0007744|PubMed:22223895"
FT   MOD_RES         415
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163,
FT                   ECO:0007744|PubMed:24275569"
FT   VAR_SEQ         93..203
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:19672693"
FT                   /id="VSP_047617"
FT   VARIANT         26
FT                   /note="A -> D (in GSSD; dbSNP:rs759253242)"
FT                   /evidence="ECO:0000269|PubMed:9215686"
FT                   /id="VAR_003602"
FT   VARIANT         125
FT                   /note="R -> C (in GSSD)"
FT                   /evidence="ECO:0000269|PubMed:8896573"
FT                   /id="VAR_090059"
FT   VARIANT         188
FT                   /note="L -> P (in GSSD; 100-fold decreased glutathione
FT                   synthase activity)"
FT                   /evidence="ECO:0000269|PubMed:9215686"
FT                   /id="VAR_003603"
FT   VARIANT         219
FT                   /note="D -> A (in GSSD; dbSNP:rs28938472)"
FT                   /evidence="ECO:0000269|PubMed:9215686"
FT                   /id="VAR_003604"
FT   VARIANT         219
FT                   /note="D -> G (in CNSHA6; dbSNP:rs28938472)"
FT                   /evidence="ECO:0000269|PubMed:27581854,
FT                   ECO:0000269|PubMed:8896573, ECO:0000269|PubMed:9215686"
FT                   /id="VAR_003605"
FT   VARIANT         236
FT                   /note="R -> Q (in dbSNP:rs34239729)"
FT                   /evidence="ECO:0000269|Ref.5"
FT                   /id="VAR_025047"
FT   VARIANT         254
FT                   /note="L -> R (in GSSD)"
FT                   /evidence="ECO:0000269|PubMed:9215686"
FT                   /id="VAR_003606"
FT   VARIANT         267
FT                   /note="R -> W (in GSSD; dbSNP:rs121909308)"
FT                   /evidence="ECO:0000269|PubMed:8896573,
FT                   ECO:0000269|PubMed:9215686"
FT                   /id="VAR_003607"
FT   VARIANT         270
FT                   /note="Y -> C (in GSSD; 100-fold decreased glutathione
FT                   synthase activity; dbSNP:rs1325986563)"
FT                   /evidence="ECO:0000269|PubMed:9215686"
FT                   /id="VAR_003608"
FT   VARIANT         270
FT                   /note="Y -> H (in GSSD; 100-fold decreased glutathione
FT                   synthase activity)"
FT                   /evidence="ECO:0000269|PubMed:9215686"
FT                   /id="VAR_003609"
FT   VARIANT         283
FT                   /note="R -> C (in GSSD; 10-fold decreased glutathione
FT                   synthase activity; dbSNP:rs121909309)"
FT                   /evidence="ECO:0000269|PubMed:8896573,
FT                   ECO:0000269|PubMed:9215686"
FT                   /id="VAR_003610"
FT   VARIANT         286
FT                   /note="L -> Q (in CNSHA6; uncertain significance;
FT                   dbSNP:rs1296000099)"
FT                   /evidence="ECO:0000269|PubMed:9215686"
FT                   /id="VAR_003611"
FT   VARIANT         301
FT                   /note="L -> P (in CNSHA6)"
FT                   /evidence="ECO:0000269|PubMed:27581854"
FT                   /id="VAR_078567"
FT   VARIANT         314
FT                   /note="P -> L"
FT                   /evidence="ECO:0000269|PubMed:8896573"
FT                   /id="VAR_090060"
FT   VARIANT         330
FT                   /note="R -> C (in CNSHA6; uncertain significance;
FT                   dbSNP:rs148640446)"
FT                   /evidence="ECO:0000269|PubMed:9215686"
FT                   /id="VAR_003612"
FT   VARIANT         437
FT                   /note="K -> E (in dbSNP:rs34852238)"
FT                   /evidence="ECO:0000269|PubMed:14702039, ECO:0000269|Ref.5"
FT                   /id="VAR_025048"
FT   VARIANT         464
FT                   /note="G -> V (in GSSD)"
FT                   /evidence="ECO:0000269|PubMed:9215686"
FT                   /id="VAR_003613"
FT   VARIANT         469
FT                   /note="D -> E (in GSSD; dbSNP:rs1419704426)"
FT                   /evidence="ECO:0000269|PubMed:9215686"
FT                   /id="VAR_003614"
FT   HELIX           6..8
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   HELIX           12..28
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   STRAND          32..34
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   STRAND          43..47
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   STRAND          50..53
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   STRAND          55..57
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   HELIX           59..80
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   HELIX           83..96
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   HELIX           98..113
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   STRAND          118..132
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   STRAND          134..136
FT                   /evidence="ECO:0007829|PDB:2HGS"
FT   STRAND          138..146
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   HELIX           153..156
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   HELIX           160..169
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   HELIX           173..178
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   HELIX           184..199
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   STRAND          205..209
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   HELIX           217..228
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   TURN            229..231
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   STRAND          234..237
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   HELIX           239..245
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   STRAND          246..248
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   STRAND          254..256
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   STRAND          259..268
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   HELIX           272..274
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   HELIX           277..288
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   STRAND          289..294
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   HELIX           297..302
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   HELIX           305..310
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   HELIX           316..320
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   HELIX           325..333
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   STRAND          338..340
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   STRAND          342..344
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   HELIX           345..356
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   HELIX           358..360
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   STRAND          361..365
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   STRAND          369..371
FT                   /evidence="ECO:0007829|PDB:2HGS"
FT   HELIX           376..386
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   HELIX           390..394
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   STRAND          395..399
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   STRAND          406..411
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   STRAND          419..435
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   STRAND          438..454
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   STRAND          462..469
FT                   /evidence="ECO:0007829|PDB:8FBZ"
FT   STRAND          471..473
FT                   /evidence="ECO:0007829|PDB:8FBZ"
SQ   SEQUENCE   474 AA;  52385 MW;  3C25EF7072EFE058 CRC64;
     MATNWGSLLQ DKQQLEELAR QAVDRALAEG VLLRTSQEPT SSEVVSYAPF TLFPSLVPSA
     LLEQAYAVQM DFNLLVDAVS QNAAFLEQTL SSTIKQDDFT ARLFDIHKQV LKEGIAQTVF
     LGLNRSDYMF QRSADGSPAL KQIEINTISA SFGGLASRTP AVHRHVLSVL SKTKEAGKIL
     SNNPSKGLAL GIAKAWELYG SPNALVLLIA QEKERNIFDQ RAIENELLAR NIHVIRRTFE
     DISEKGSLDQ DRRLFVDGQE IAVVYFRDGY MPRQYSLQNW EARLLLERSH AAKCPDIATQ
     LAGTKKVQQE LSRPGMLEML LPGQPEAVAR LRATFAGLYS LDVGEEGDQA IAEALAAPSR
     FVLKPQREGG GNNLYGEEMV QALKQLKDSE ERASYILMEK IEPEPFENCL LRPGSPARVV
     QCISELGIFG VYVRQEKTLV MNKHVGHLLR TKAIEHADGG VAAGVAVLDN PYPV
//