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P48506 (GSH1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 131. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Glutamate--cysteine ligase catalytic subunit

EC=6.3.2.2
Alternative name(s):
GCS heavy chain
Gamma-ECS
Gamma-glutamylcysteine synthetase
Gene names
Name:GCLC
Synonyms:GLCL, GLCLC
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length637 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Catalytic activity

ATP + L-glutamate + L-cysteine = ADP + phosphate + gamma-L-glutamyl-L-cysteine.

Enzyme regulation

Feedback inhibition by glutathione.

Pathway

Sulfur metabolism; glutathione biosynthesis; glutathione from L-cysteine and L-glutamate: step 1/2.

Subunit structure

Heterodimer of a catalytic heavy chain and a regulatory light chain.

Involvement in disease

Hemolytic anemia due to gamma-glutamylcysteine synthetase deficiency (HAGGSD) [MIM:230450]: A disease characterized by hemolytic anemia, glutathione deficiency, myopathy, late-onset spinocerebellar degeneration, and peripheral neuropathy.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.6 Ref.10 Ref.11

Sequence similarities

Belongs to the glutamate--cysteine ligase type 3 family.

Ontologies

Keywords
   Biological processGlutathione biosynthesis
   Coding sequence diversityPolymorphism
   DiseaseDisease mutation
Hereditary hemolytic anemia
   LigandATP-binding
Nucleotide-binding
   Molecular functionLigase
   PTMAcetylation
Phosphoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processL-ascorbic acid metabolic process

Inferred from electronic annotation. Source: Ensembl

apoptotic mitochondrial changes

Inferred from electronic annotation. Source: Ensembl

cell redox homeostasis

Inferred from direct assay PubMed 10439045. Source: UniProtKB

cellular nitrogen compound metabolic process

Traceable author statement. Source: Reactome

cysteine metabolic process

Inferred from direct assay PubMed 2294991. Source: UniProtKB

glutamate metabolic process

Inferred from direct assay Ref.11PubMed 2294991. Source: UniProtKB

glutathione biosynthetic process

Inferred from direct assay PubMed 10395918PubMed 8104187. Source: UniProtKB

glutathione derivative biosynthetic process

Traceable author statement. Source: Reactome

negative regulation of apoptotic process

Inferred from direct assay PubMed 10439045. Source: UniProtKB

negative regulation of extrinsic apoptotic signaling pathway

Inferred from electronic annotation. Source: Ensembl

negative regulation of neuron apoptotic process

Inferred from electronic annotation. Source: Ensembl

negative regulation of protein ubiquitination

Inferred from electronic annotation. Source: Ensembl

negative regulation of transcription, DNA-templated

Inferred from direct assay PubMed 10439045. Source: UniProtKB

positive regulation of proteasomal ubiquitin-dependent protein catabolic process

Inferred from electronic annotation. Source: Ensembl

regulation of blood vessel size

Inferred from mutant phenotype PubMed 12598062. Source: UniProtKB

regulation of mitochondrial depolarization

Inferred from electronic annotation. Source: Ensembl

response to arsenic-containing substance

Inferred from electronic annotation. Source: Ensembl

response to heat

Inferred from direct assay PubMed 8104187. Source: UniProtKB

response to hormone

Inferred from direct assay PubMed 8104187. Source: UniProtKB

response to nitrosative stress

Inferred from electronic annotation. Source: Ensembl

response to oxidative stress

Inferred from direct assay PubMed 10395918PubMed 11972604. Source: UniProtKB

small molecule metabolic process

Traceable author statement. Source: Reactome

sulfur amino acid metabolic process

Traceable author statement. Source: Reactome

xenobiotic metabolic process

Traceable author statement. Source: Reactome

   Cellular_componentcytoplasm

Inferred from Biological aspect of Ancestor. Source: RefGenome

cytosol

Traceable author statement. Source: Reactome

glutamate-cysteine ligase complex

Inferred from electronic annotation. Source: Ensembl

   Molecular_functionADP binding

Inferred from direct assay PubMed 24639. Source: UniProtKB

ATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

coenzyme binding

Inferred from physical interaction Ref.7PubMed 9841880. Source: UniProtKB

glutamate binding

Inferred from direct assay PubMed 9841880. Source: UniProtKB

glutamate-cysteine ligase activity

Inferred from direct assay PubMed 11972604PubMed 8104187. Source: UniProtKB

magnesium ion binding

Inferred from direct assay PubMed 24639. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 637637Glutamate--cysteine ligase catalytic subunit
PRO_0000192563

Amino acid modifications

Modified residue11N-acetylmethionine Ref.8
Modified residue51Phosphoserine Ref.8
Modified residue81Phosphoserine Ref.8

Natural variations

Natural variant551L → S.
Corresponds to variant rs2066512 [ dbSNP | Ensembl ].
VAR_014884
Natural variant1271R → C in HAGGSD. Ref.11
VAR_021110
Natural variant1581P → L in HAGGSD. Ref.10
VAR_015403
Natural variant3701H → L in HAGGSD. Ref.6
VAR_013514
Natural variant4621P → S. Ref.2
Corresponds to variant rs17883718 [ dbSNP | Ensembl ].
VAR_021100

Sequences

Sequence LengthMass (Da)Tools
P48506 [UniParc].

Last modified January 23, 2007. Version 2.
Checksum: 511F33F106A15504

FASTA63772,766
        10         20         30         40         50         60 
MGLLSQGSPL SWEETKRHAD HVRRHGILQF LHIYHAVKDR HKDVLKWGDE VEYMLVSFDH 

        70         80         90        100        110        120 
ENKKVRLVLS GEKVLETLQE KGERTNPNHP TLWRPEYGSY MIEGTPGQPY GGTMSEFNTV 

       130        140        150        160        170        180 
EANMRKRRKE ATSILEENQA LCTITSFPRL GCPGFTLPEV KPNPVEGGAS KSLFFPDEAI 

       190        200        210        220        230        240 
NKHPRFSTLT RNIRHRRGEK VVINVPIFKD KNTPSPFIET FTEDDEASRA SKPDHIYMDA 

       250        260        270        280        290        300 
MGFGMGNCCL QVTFQACSIS EARYLYDQLA TICPIVMALS AASPFYRGYV SDIDCRWGVI 

       310        320        330        340        350        360 
SASVDDRTRE ERGLEPLKNN NYRISKSRYD SIDSYLSKCG EKYNDIDLTI DKEIYEQLLQ 

       370        380        390        400        410        420 
EGIDHLLAQH VAHLFIRDPL TLFEEKIHLD DANESDHFEN IQSTNWQTMR FKPPPPNSDI 

       430        440        450        460        470        480 
GWRVEFRPME VQLTDFENSA YVVFVVLLTR VILSYKLDFL IPLSKVDENM KVAQKRDAVL 

       490        500        510        520        530        540 
QGMFYFRKDI CKGGNAVVDG CGKAQNSTEL AAEEYTLMSI DTIINGKEGV FPGLIPILNS 

       550        560        570        580        590        600 
YLENMEVDVD TRCSILNYLK LIKKRASGEL MTVARWMREF IANHPDYKQD SVITDEMNYS 

       610        620        630 
LILKCNQIAN ELCECPELLG SAFRKVKYSG SKTDSSN 

« Hide

References

« Hide 'large scale' references
[1]"Cloning and nucleotide sequence of a full-length cDNA for human liver gamma-glutamylcysteine synthetase."
Gipp J.J., Chang C., Mulcahy R.T.
Biochem. Biophys. Res. Commun. 185:29-35(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Liver.
[2]NIEHS SNPs program
Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT SER-462.
[3]"The DNA sequence and analysis of human chromosome 6."
Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., Andrews T.D. expand/collapse author list , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S.
Nature 425:805-811(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Hippocampus and Testis.
[5]"Identification of a putative antioxidant response element in the 5'-flanking region of the human gamma-glutamylcysteine synthetase heavy subunit gene."
Mulcahy R.T., Gipp J.J.
Biochem. Biophys. Res. Commun. 209:227-233(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-27.
Tissue: Foreskin fibroblast.
[6]"The molecular basis of a case of gamma-glutamylcysteine synthetase deficiency."
Beutler E., Gelbart T., Kondo T., Matsunaga A.T.
Blood 94:2890-2894(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 341-440, VARIANT HAGGSD LEU-370.
[7]"Expression and purification of human gamma-glutamylcysteine synthetase."
Misra I., Griffith O.W.
Protein Expr. Purif. 13:268-276(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: CHARACTERIZATION.
[8]"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis."
Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.
Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-5 AND SER-8, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[9]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[10]"A missense mutation in the heavy subunit of gamma-glutamylcysteine synthetase gene causes hemolytic anemia."
Ristoff E., Augustson C., Geissler J., de Rijk T., Carlsson K., Luo J.-L., Andersson K., Weening R.S., van Zwieten R., Larsson A., Roos D.
Blood 95:2193-2196(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT HAGGSD LEU-158.
[11]"A novel missense mutation in the gamma-glutamylcysteine synthetase catalytic subunit gene causes both decreased enzymatic activity and glutathione production."
Hamilton D., Wu J.H., Alaoui-Jamali M., Batist G.
Blood 102:725-730(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT HAGGSD CYS-127.
+Additional computationally mapped references.

Web resources

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
M90656 mRNA. Translation: AAA58499.1.
AY780794 Genomic DNA. Translation: AAV31778.1.
AL033397 Genomic DNA. No translation available.
BC022487 mRNA. Translation: AAH22487.1.
BC039894 mRNA. Translation: AAH39894.1.
L39773 Genomic DNA. Translation: AAC41751.1.
AF118846 Genomic DNA. Translation: AAD18031.1.
PIRJH0611.
RefSeqNP_001184044.1. NM_001197115.1.
NP_001489.1. NM_001498.3.
UniGeneHs.654465.

3D structure databases

ProteinModelPortalP48506.
SMRP48506. Positions 2-610.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid108991. 7 interactions.
IntActP48506. 2 interactions.
STRING9606.ENSP00000229416.

Chemistry

BindingDBP48506.
ChEMBLCHEMBL4055.
DrugBankDB00151. L-Cysteine.
DB00142. L-Glutamic Acid.

PTM databases

PhosphoSiteP48506.

Polymorphism databases

DMDM1346190.

Proteomic databases

PaxDbP48506.
PeptideAtlasP48506.
PRIDEP48506.

Protocols and materials databases

DNASU2729.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000229416; ENSP00000229416; ENSG00000001084.
ENST00000514004; ENSP00000421908; ENSG00000001084.
GeneID2729.
KEGGhsa:2729.
UCSCuc003pbv.1. human.

Organism-specific databases

CTD2729.
GeneCardsGC06M053409.
HGNCHGNC:4311. GCLC.
HPACAB009569.
HPA036359.
HPA036360.
MIM230450. phenotype.
606857. gene+phenotype.
neXtProtNX_P48506.
Orphanet33574. Gamma-glutamylcysteine synthetase deficiency.
PharmGKBPA28612.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG269969.
HOGENOMHOG000199354.
HOVERGENHBG005924.
InParanoidP48506.
KOK11204.
OMARWMREFI.
OrthoDBEOG7B8S3B.
PhylomeDBP48506.
TreeFamTF105644.

Enzyme and pathway databases

BioCycMetaCyc:ENSG00000001084-MONOMER.
BRENDA6.3.2.2. 2681.
ReactomeREACT_111217. Metabolism.
UniPathwayUPA00142; UER00209.

Gene expression databases

ArrayExpressP48506.
BgeeP48506.
CleanExHS_GCLC.
GenevestigatorP48506.

Family and domain databases

InterProIPR004308. GCS.
[Graphical view]
PANTHERPTHR11164. PTHR11164. 1 hit.
PfamPF03074. GCS. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSGCLC. human.
GeneWikiGCLC.
GenomeRNAi2729.
NextBio10756.
PMAP-CutDBP48506.
PROP48506.
SOURCESearch...

Entry information

Entry nameGSH1_HUMAN
AccessionPrimary (citable) accession number: P48506
Secondary accession number(s): Q14399
Entry history
Integrated into UniProtKB/Swiss-Prot: February 1, 1996
Last sequence update: January 23, 2007
Last modified: April 16, 2014
This is version 131 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PATHWAY comments

Index of metabolic and biosynthesis pathways

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 6

Human chromosome 6: entries, gene names and cross-references to MIM