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Protein

Glutathione synthetase

Gene

GSS

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Catalytic activityi

ATP + gamma-L-glutamyl-L-cysteine + glycine = ADP + phosphate + glutathione.

Cofactori

Mg2+1 PublicationNote: Binds 1 Mg2+ ion per subunit.1 Publication

Pathwayi: glutathione biosynthesis

This protein is involved in step 2 of the subpathway that synthesizes glutathione from L-cysteine and L-glutamate.
Proteins known to be involved in the 2 steps of the subpathway in this organism are:
  1. Glutamate--cysteine ligase catalytic subunit (GCLC), Glutamate--cysteine ligase regulatory subunit (GCLM)
  2. Glutathione synthetase (GSS), Glutathione synthetase (HEL-S-64p), Glutathione synthetase, Glutathione synthetase (GSS), Glutathione synthetase
This subpathway is part of the pathway glutathione biosynthesis, which is itself part of Sulfur metabolism.
View all proteins of this organism that are known to be involved in the subpathway that synthesizes glutathione from L-cysteine and L-glutamate, the pathway glutathione biosynthesis and in Sulfur metabolism.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei125Substrate1
Metal bindingi144Magnesium1
Binding sitei144ATP1
Metal bindingi146Magnesium1
Binding sitei220Substrate1
Binding sitei305ATP1
Metal bindingi368Magnesium1
Binding sitei375ATP1
Binding sitei425ATP1
Binding sitei450Substrate1
Binding sitei452ATP1
Binding sitei458ATP; via carbonyl oxygen1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi364 – 373ATP10
Nucleotide bindingi398 – 401ATP4

GO - Molecular functioni

  • ATP binding Source: UniProtKB
  • glutathione binding Source: UniProtKB
  • glutathione synthase activity Source: GO_Central
  • identical protein binding Source: IntAct
  • magnesium ion binding Source: UniProtKB
  • protein homodimerization activity Source: UniProtKB

GO - Biological processi

Keywordsi

Molecular functionLigase
Biological processGlutathione biosynthesis
LigandATP-binding, Magnesium, Metal-binding, Nucleotide-binding

Enzyme and pathway databases

BioCyciMetaCyc:HS02174-MONOMER
BRENDAi6.3.2.3 2681
ReactomeiR-HSA-174403 Glutathione synthesis and recycling
R-HSA-5579006 Defective GSS causes Glutathione synthetase deficiency (GSS deficiency)
SABIO-RKiP48637
UniPathwayi
UPA00142;UER00210

Names & Taxonomyi

Protein namesi
Recommended name:
Glutathione synthetase (EC:6.3.2.3)
Short name:
GSH synthetase
Short name:
GSH-S
Alternative name(s):
Glutathione synthase
Gene namesi
Name:GSS
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 20

Organism-specific databases

EuPathDBiHostDB:ENSG00000100983.9
HGNCiHGNC:4624 GSS
MIMi601002 gene
neXtProtiNX_P48637

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Pathology & Biotechi

Involvement in diseasei

Glutathione synthetase deficiency (GSS deficiency)3 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionSevere form characterized by an increased rate of hemolysis and defective function of the central nervous system.
See also OMIM:266130
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_00360226A → D in GSS deficiency. Corresponds to variant dbSNP:rs759253242Ensembl.1
Natural variantiVAR_003603188L → P in GSS deficiency; 100-fold reduction of activity. 1
Natural variantiVAR_003604219D → A in GSS deficiency. 1
Natural variantiVAR_003605219D → G in GSS deficiency. 2 PublicationsCorresponds to variant dbSNP:rs28938472EnsemblClinVar.1
Natural variantiVAR_003606254L → R in GSS deficiency. 1
Natural variantiVAR_003607267R → W in GSS deficiency. 1 PublicationCorresponds to variant dbSNP:rs121909308EnsemblClinVar.1
Natural variantiVAR_003608270Y → C in GSS deficiency; 100-fold reduction of activity. 1
Natural variantiVAR_003609270Y → H in GSS deficiency; 100-fold reduction of activity. 1
Natural variantiVAR_003610283R → C in GSS deficiency; 10-fold reduction of activity. 1 PublicationCorresponds to variant dbSNP:rs121909309EnsemblClinVar.1
Natural variantiVAR_003611286L → Q in GSS deficiency. 1
Natural variantiVAR_078567301L → P in GSS deficiency. 1 Publication1
Natural variantiVAR_003612330R → C in GSS deficiency. Corresponds to variant dbSNP:rs148640446Ensembl.1
Natural variantiVAR_003613464G → V in GSS deficiency. 1
Natural variantiVAR_003614469D → E in GSS deficiency. 1
Glutathione synthetase deficiency of erythrocytes (GLUSYNDE)
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionMild form causing hemolytic anemia.
See also OMIM:231900

Keywords - Diseasei

Disease mutation, Hereditary hemolytic anemia

Organism-specific databases

DisGeNETi2937
MalaCardsiGSS
MIMi231900 phenotype
266130 phenotype
OpenTargetsiENSG00000100983
Orphaneti289846 Glutathione synthetase deficiency with 5-oxoprolinuria
289849 Glutathione synthetase deficiency without 5-oxoprolinuria
PharmGKBiPA29015

Chemistry databases

DrugBankiDB06151 Acetylcysteine
DB03408 gamma-Glutamylcysteine
DB00143 Glutathione
DB00145 Glycine
DB00151 L-Cysteine
DB04395 Phosphoaminophosphonic Acid-Adenylate Ester

Polymorphism and mutation databases

BioMutaiGSS
DMDMi1346191

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedCombined sources
ChainiPRO_00002112602 – 474Glutathione synthetaseAdd BLAST473

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylalanineCombined sources1
Modified residuei415PhosphoserineCombined sources1

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiP48637
PaxDbiP48637
PeptideAtlasiP48637
PRIDEiP48637
ProteomicsDBi55917

2D gel databases

OGPiP48637
REPRODUCTION-2DPAGEiIPI00010706

PTM databases

iPTMnetiP48637
PhosphoSitePlusiP48637

Expressioni

Gene expression databases

BgeeiENSG00000100983 Expressed in 234 organ(s), highest expression level in cerebral cortex
CleanExiHS_GSS
ExpressionAtlasiP48637 baseline and differential
GenevisibleiP48637 HS

Organism-specific databases

HPAiHPA054508
HPA059315

Interactioni

Subunit structurei

Homodimer.1 Publication

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi109192, 27 interactors
IntActiP48637, 3 interactors
MINTiP48637
STRINGi9606.ENSP00000216951

Structurei

Secondary structure

1474
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliP48637
SMRiP48637
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP48637

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni148 – 151Substrate binding4
Regioni214 – 216Substrate binding3
Regioni267 – 270Substrate binding4
Regioni461 – 462Substrate binding2

Sequence similaritiesi

Belongs to the eukaryotic GSH synthase family.Curated

Phylogenomic databases

eggNOGiKOG0021 Eukaryota
ENOG410XPHH LUCA
GeneTreeiENSGT00390000013764
HOGENOMiHOG000172641
HOVERGENiHBG002458
InParanoidiP48637
KOiK21456
OMAiFRSDYMV
OrthoDBiEOG091G05V8
PhylomeDBiP48637
TreeFamiTF105187

Family and domain databases

CDDicd00228 eu-GS, 1 hit
Gene3Di1.10.1080.10, 2 hits
3.30.1490.50, 1 hit
3.30.1490.80, 3 hits
3.40.50.1760, 1 hit
InterProiView protein in InterPro
IPR005615 Glutathione_synthase
IPR014042 Glutathione_synthase_a-hlx
IPR014709 Glutathione_synthase_C_euk
IPR014049 Glutathione_synthase_N_euk
IPR037013 GSH-S_sub-bd_sf
IPR004887 GSH_synth_subst-bd
IPR016185 PreATP-grasp_dom_sf
PANTHERiPTHR11130 PTHR11130, 1 hit
PfamiView protein in Pfam
PF03917 GSH_synth_ATP, 1 hit
PF03199 GSH_synthase, 1 hit
PIRSFiPIRSF001558 GSHase, 1 hit
SUPFAMiSSF52440 SSF52440, 1 hit
TIGRFAMsiTIGR01986 glut_syn_euk, 1 hit

Sequences (2+)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

This entry has 2 described isoforms and 12 potential isoforms that are computationally mapped.iShow all

Isoform 1 (identifier: P48637-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide
        10         20         30         40         50
MATNWGSLLQ DKQQLEELAR QAVDRALAEG VLLRTSQEPT SSEVVSYAPF
60 70 80 90 100
TLFPSLVPSA LLEQAYAVQM DFNLLVDAVS QNAAFLEQTL SSTIKQDDFT
110 120 130 140 150
ARLFDIHKQV LKEGIAQTVF LGLNRSDYMF QRSADGSPAL KQIEINTISA
160 170 180 190 200
SFGGLASRTP AVHRHVLSVL SKTKEAGKIL SNNPSKGLAL GIAKAWELYG
210 220 230 240 250
SPNALVLLIA QEKERNIFDQ RAIENELLAR NIHVIRRTFE DISEKGSLDQ
260 270 280 290 300
DRRLFVDGQE IAVVYFRDGY MPRQYSLQNW EARLLLERSH AAKCPDIATQ
310 320 330 340 350
LAGTKKVQQE LSRPGMLEML LPGQPEAVAR LRATFAGLYS LDVGEEGDQA
360 370 380 390 400
IAEALAAPSR FVLKPQREGG GNNLYGEEMV QALKQLKDSE ERASYILMEK
410 420 430 440 450
IEPEPFENCL LRPGSPARVV QCISELGIFG VYVRQEKTLV MNKHVGHLLR
460 470
TKAIEHADGG VAAGVAVLDN PYPV
Length:474
Mass (Da):52,385
Last modified:February 1, 1996 - v1
Checksum:i3C25EF7072EFE058
GO
Isoform 2 (identifier: P48637-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     93-203: Missing.

Note: Detected in colon, kidney, lung, liver, placenta, peripheral blood and uterus, but not in heart, skeletal muscle and spleen.
Show »
Length:363
Mass (Da):40,349
Checksum:i931DA0F137EE1634
GO

Computationally mapped potential isoform sequencesi

There are 12 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
A0A2R8Y430A0A2R8Y430_HUMAN
Glutathione synthetase
GSS
450Annotation score:
A0A2R8Y5T7A0A2R8Y5T7_HUMAN
Glutathione synthetase
GSS
360Annotation score:
A0A0S2Z4J7A0A0S2Z4J7_HUMAN
Glutathione synthetase isoform 2
GSS
132Annotation score:
A0A2R8Y7I7A0A2R8Y7I7_HUMAN
Glutathione synthetase
GSS
155Annotation score:
A0A2R8Y6Q7A0A2R8Y6Q7_HUMAN
Glutathione synthetase
GSS
169Annotation score:
A0A2R8Y446A0A2R8Y446_HUMAN
Glutathione synthetase
GSS
124Annotation score:
A0A2R8Y790A0A2R8Y790_HUMAN
Glutathione synthetase
GSS
112Annotation score:
A0A2R8YF34A0A2R8YF34_HUMAN
Glutathione synthetase
GSS
134Annotation score:
A0A2R8Y4V9A0A2R8Y4V9_HUMAN
Glutathione synthetase
GSS
97Annotation score:
A0A2R8Y6Y6A0A2R8Y6Y6_HUMAN
Glutathione synthetase
GSS
81Annotation score:
There are more potential isoformsShow all

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_00360226A → D in GSS deficiency. Corresponds to variant dbSNP:rs759253242Ensembl.1
Natural variantiVAR_003603188L → P in GSS deficiency; 100-fold reduction of activity. 1
Natural variantiVAR_003604219D → A in GSS deficiency. 1
Natural variantiVAR_003605219D → G in GSS deficiency. 2 PublicationsCorresponds to variant dbSNP:rs28938472EnsemblClinVar.1
Natural variantiVAR_025047236R → Q1 PublicationCorresponds to variant dbSNP:rs34239729Ensembl.1
Natural variantiVAR_003606254L → R in GSS deficiency. 1
Natural variantiVAR_003607267R → W in GSS deficiency. 1 PublicationCorresponds to variant dbSNP:rs121909308EnsemblClinVar.1
Natural variantiVAR_003608270Y → C in GSS deficiency; 100-fold reduction of activity. 1
Natural variantiVAR_003609270Y → H in GSS deficiency; 100-fold reduction of activity. 1
Natural variantiVAR_003610283R → C in GSS deficiency; 10-fold reduction of activity. 1 PublicationCorresponds to variant dbSNP:rs121909309EnsemblClinVar.1
Natural variantiVAR_003611286L → Q in GSS deficiency. 1
Natural variantiVAR_078567301L → P in GSS deficiency. 1 Publication1
Natural variantiVAR_003612330R → C in GSS deficiency. Corresponds to variant dbSNP:rs148640446Ensembl.1
Natural variantiVAR_025048437K → E2 PublicationsCorresponds to variant dbSNP:rs34852238Ensembl.1
Natural variantiVAR_003613464G → V in GSS deficiency. 1
Natural variantiVAR_003614469D → E in GSS deficiency. 1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_04761793 – 203Missing in isoform 2. 1 PublicationAdd BLAST111

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L42531 mRNA Translation: AAA69492.1
AB459500 mRNA Translation: BAG75452.1
U34683 mRNA Translation: AAB62390.1
AK312492 mRNA Translation: BAG35394.1
DQ074975 Genomic DNA Translation: AAY57328.1
AL133324 Genomic DNA No translation available.
CH471077 Genomic DNA Translation: EAW76239.1
CH471077 Genomic DNA Translation: EAW76240.1
BC007927 mRNA Translation: AAH07927.1
CCDSiCCDS13245.1 [P48637-1]
PIRiS56748
RefSeqiNP_000169.1, NM_000178.3 [P48637-1]
NP_001309423.1, NM_001322494.1 [P48637-1]
NP_001309424.1, NM_001322495.1 [P48637-1]
UniGeneiHs.82327

Genome annotation databases

EnsembliENST00000216951; ENSP00000216951; ENSG00000100983 [P48637-1]
ENST00000451957; ENSP00000407517; ENSG00000100983 [P48637-2]
ENST00000643188; ENSP00000493903; ENSG00000100983 [P48637-1]
ENST00000644793; ENSP00000495750; ENSG00000100983 [P48637-1]
ENST00000646735; ENSP00000493763; ENSG00000100983 [P48637-2]
GeneIDi2937
KEGGihsa:2937
UCSCiuc010zuo.3 human [P48637-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Cross-referencesi

Web resourcesi

NIEHS-SNPs

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L42531 mRNA Translation: AAA69492.1
AB459500 mRNA Translation: BAG75452.1
U34683 mRNA Translation: AAB62390.1
AK312492 mRNA Translation: BAG35394.1
DQ074975 Genomic DNA Translation: AAY57328.1
AL133324 Genomic DNA No translation available.
CH471077 Genomic DNA Translation: EAW76239.1
CH471077 Genomic DNA Translation: EAW76240.1
BC007927 mRNA Translation: AAH07927.1
CCDSiCCDS13245.1 [P48637-1]
PIRiS56748
RefSeqiNP_000169.1, NM_000178.3 [P48637-1]
NP_001309423.1, NM_001322494.1 [P48637-1]
NP_001309424.1, NM_001322495.1 [P48637-1]
UniGeneiHs.82327

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2HGSX-ray2.10A1-474[»]
ProteinModelPortaliP48637
SMRiP48637
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi109192, 27 interactors
IntActiP48637, 3 interactors
MINTiP48637
STRINGi9606.ENSP00000216951

Chemistry databases

DrugBankiDB06151 Acetylcysteine
DB03408 gamma-Glutamylcysteine
DB00143 Glutathione
DB00145 Glycine
DB00151 L-Cysteine
DB04395 Phosphoaminophosphonic Acid-Adenylate Ester

PTM databases

iPTMnetiP48637
PhosphoSitePlusiP48637

Polymorphism and mutation databases

BioMutaiGSS
DMDMi1346191

2D gel databases

OGPiP48637
REPRODUCTION-2DPAGEiIPI00010706

Proteomic databases

EPDiP48637
PaxDbiP48637
PeptideAtlasiP48637
PRIDEiP48637
ProteomicsDBi55917

Protocols and materials databases

DNASUi2937
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000216951; ENSP00000216951; ENSG00000100983 [P48637-1]
ENST00000451957; ENSP00000407517; ENSG00000100983 [P48637-2]
ENST00000643188; ENSP00000493903; ENSG00000100983 [P48637-1]
ENST00000644793; ENSP00000495750; ENSG00000100983 [P48637-1]
ENST00000646735; ENSP00000493763; ENSG00000100983 [P48637-2]
GeneIDi2937
KEGGihsa:2937
UCSCiuc010zuo.3 human [P48637-1]

Organism-specific databases

CTDi2937
DisGeNETi2937
EuPathDBiHostDB:ENSG00000100983.9
GeneCardsiGSS
HGNCiHGNC:4624 GSS
HPAiHPA054508
HPA059315
MalaCardsiGSS
MIMi231900 phenotype
266130 phenotype
601002 gene
neXtProtiNX_P48637
OpenTargetsiENSG00000100983
Orphaneti289846 Glutathione synthetase deficiency with 5-oxoprolinuria
289849 Glutathione synthetase deficiency without 5-oxoprolinuria
PharmGKBiPA29015
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0021 Eukaryota
ENOG410XPHH LUCA
GeneTreeiENSGT00390000013764
HOGENOMiHOG000172641
HOVERGENiHBG002458
InParanoidiP48637
KOiK21456
OMAiFRSDYMV
OrthoDBiEOG091G05V8
PhylomeDBiP48637
TreeFamiTF105187

Enzyme and pathway databases

UniPathwayi
UPA00142;UER00210

BioCyciMetaCyc:HS02174-MONOMER
BRENDAi6.3.2.3 2681
ReactomeiR-HSA-174403 Glutathione synthesis and recycling
R-HSA-5579006 Defective GSS causes Glutathione synthetase deficiency (GSS deficiency)
SABIO-RKiP48637

Miscellaneous databases

ChiTaRSiGSS human
EvolutionaryTraceiP48637
GenomeRNAii2937
PROiPR:P48637
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000100983 Expressed in 234 organ(s), highest expression level in cerebral cortex
CleanExiHS_GSS
ExpressionAtlasiP48637 baseline and differential
GenevisibleiP48637 HS

Family and domain databases

CDDicd00228 eu-GS, 1 hit
Gene3Di1.10.1080.10, 2 hits
3.30.1490.50, 1 hit
3.30.1490.80, 3 hits
3.40.50.1760, 1 hit
InterProiView protein in InterPro
IPR005615 Glutathione_synthase
IPR014042 Glutathione_synthase_a-hlx
IPR014709 Glutathione_synthase_C_euk
IPR014049 Glutathione_synthase_N_euk
IPR037013 GSH-S_sub-bd_sf
IPR004887 GSH_synth_subst-bd
IPR016185 PreATP-grasp_dom_sf
PANTHERiPTHR11130 PTHR11130, 1 hit
PfamiView protein in Pfam
PF03917 GSH_synth_ATP, 1 hit
PF03199 GSH_synthase, 1 hit
PIRSFiPIRSF001558 GSHase, 1 hit
SUPFAMiSSF52440 SSF52440, 1 hit
TIGRFAMsiTIGR01986 glut_syn_euk, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiGSHB_HUMAN
AccessioniPrimary (citable) accession number: P48637
Secondary accession number(s): B2R697
, B6F210, E1P5P9, Q4TTD9
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1996
Last sequence update: February 1, 1996
Last modified: September 12, 2018
This is version 188 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome
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Main funding by: National Institutes of Health

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