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P48506

- GSH1_HUMAN

UniProt

P48506 - GSH1_HUMAN

Protein

Glutamate--cysteine ligase catalytic subunit

Gene

GCLC

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 136 (01 Oct 2014)
      Sequence version 2 (23 Jan 2007)
      Previous versions | rss
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    Functioni

    Catalytic activityi

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

    Enzyme regulationi

    Feedback inhibition by glutathione.

    Pathwayi

    GO - Molecular functioni

    1. ADP binding Source: UniProtKB
    2. ATP binding Source: UniProtKB-KW
    3. coenzyme binding Source: UniProtKB
    4. glutamate binding Source: UniProtKB
    5. glutamate-cysteine ligase activity Source: UniProtKB
    6. magnesium ion binding Source: UniProtKB

    GO - Biological processi

    1. apoptotic mitochondrial changes Source: Ensembl
    2. cell redox homeostasis Source: UniProtKB
    3. cellular nitrogen compound metabolic process Source: Reactome
    4. cysteine metabolic process Source: UniProtKB
    5. glutamate metabolic process Source: UniProtKB
    6. glutathione biosynthetic process Source: UniProtKB
    7. glutathione derivative biosynthetic process Source: Reactome
    8. L-ascorbic acid metabolic process Source: Ensembl
    9. negative regulation of apoptotic process Source: UniProtKB
    10. negative regulation of extrinsic apoptotic signaling pathway Source: Ensembl
    11. negative regulation of neuron apoptotic process Source: Ensembl
    12. negative regulation of protein ubiquitination Source: Ensembl
    13. negative regulation of transcription, DNA-templated Source: UniProtKB
    14. positive regulation of proteasomal ubiquitin-dependent protein catabolic process Source: Ensembl
    15. regulation of blood vessel size Source: UniProtKB
    16. regulation of mitochondrial depolarization Source: Ensembl
    17. response to arsenic-containing substance Source: Ensembl
    18. response to heat Source: UniProtKB
    19. response to hormone Source: UniProtKB
    20. response to nitrosative stress Source: Ensembl
    21. response to oxidative stress Source: UniProtKB
    22. small molecule metabolic process Source: Reactome
    23. sulfur amino acid metabolic process Source: Reactome
    24. xenobiotic metabolic process Source: Reactome

    Keywords - Molecular functioni

    Ligase

    Keywords - Biological processi

    Glutathione biosynthesis

    Keywords - Ligandi

    ATP-binding, Nucleotide-binding

    Enzyme and pathway databases

    BioCyciMetaCyc:ENSG00000001084-MONOMER.
    BRENDAi6.3.2.2. 2681.
    ReactomeiREACT_115639. Sulfur amino acid metabolism.
    REACT_6960. Glutathione synthesis and recycling.
    UniPathwayiUPA00142; UER00209.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Glutamate--cysteine ligase catalytic subunit (EC:6.3.2.2)
    Alternative name(s):
    GCS heavy chain
    Gamma-ECS
    Gamma-glutamylcysteine synthetase
    Gene namesi
    Name:GCLC
    Synonyms:GLCL, GLCLC
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 6

    Organism-specific databases

    HGNCiHGNC:4311. GCLC.

    Subcellular locationi

    GO - Cellular componenti

    1. cytoplasm Source: RefGenome
    2. cytosol Source: Reactome
    3. glutamate-cysteine ligase complex Source: Ensembl

    Pathology & Biotechi

    Involvement in diseasei

    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.3 Publications
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti127 – 1271R → C in HAGGSD. 1 Publication
    VAR_021110
    Natural varianti158 – 1581P → L in HAGGSD. 1 Publication
    VAR_015403
    Natural varianti370 – 3701H → L in HAGGSD. 1 Publication
    VAR_013514

    Keywords - Diseasei

    Disease mutation, Hereditary hemolytic anemia

    Organism-specific databases

    MIMi230450. phenotype.
    606857. gene+phenotype.
    Orphaneti33574. Gamma-glutamylcysteine synthetase deficiency.
    PharmGKBiPA28612.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 637637Glutamate--cysteine ligase catalytic subunitPRO_0000192563Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei1 – 11N-acetylmethionine1 Publication
    Modified residuei5 – 51Phosphoserine1 Publication
    Modified residuei8 – 81Phosphoserine1 Publication

    Keywords - PTMi

    Acetylation, Phosphoprotein

    Proteomic databases

    MaxQBiP48506.
    PaxDbiP48506.
    PeptideAtlasiP48506.
    PRIDEiP48506.

    PTM databases

    PhosphoSiteiP48506.

    Miscellaneous databases

    PMAP-CutDBP48506.

    Expressioni

    Gene expression databases

    ArrayExpressiP48506.
    BgeeiP48506.
    CleanExiHS_GCLC.
    GenevestigatoriP48506.

    Organism-specific databases

    HPAiCAB009569.
    HPA036359.
    HPA036360.

    Interactioni

    Subunit structurei

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

    Protein-protein interaction databases

    BioGridi108991. 7 interactions.
    IntActiP48506. 2 interactions.
    STRINGi9606.ENSP00000229416.

    Structurei

    3D structure databases

    ProteinModelPortaliP48506.
    SMRiP48506. Positions 2-610.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Sequence similaritiesi

    Phylogenomic databases

    eggNOGiNOG269969.
    HOGENOMiHOG000199354.
    HOVERGENiHBG005924.
    InParanoidiP48506.
    KOiK11204.
    OMAiRWMREFI.
    OrthoDBiEOG7B8S3B.
    PhylomeDBiP48506.
    TreeFamiTF105644.

    Family and domain databases

    InterProiIPR004308. GCS.
    [Graphical view]
    PANTHERiPTHR11164. PTHR11164. 1 hit.
    PfamiPF03074. GCS. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    P48506-1 [UniParc]FASTAAdd to Basket

    « Hide

    MGLLSQGSPL SWEETKRHAD HVRRHGILQF LHIYHAVKDR HKDVLKWGDE    50
    VEYMLVSFDH ENKKVRLVLS GEKVLETLQE KGERTNPNHP TLWRPEYGSY 100
    MIEGTPGQPY GGTMSEFNTV EANMRKRRKE ATSILEENQA LCTITSFPRL 150
    GCPGFTLPEV KPNPVEGGAS KSLFFPDEAI NKHPRFSTLT RNIRHRRGEK 200
    VVINVPIFKD KNTPSPFIET FTEDDEASRA SKPDHIYMDA MGFGMGNCCL 250
    QVTFQACSIS EARYLYDQLA TICPIVMALS AASPFYRGYV SDIDCRWGVI 300
    SASVDDRTRE ERGLEPLKNN NYRISKSRYD SIDSYLSKCG EKYNDIDLTI 350
    DKEIYEQLLQ EGIDHLLAQH VAHLFIRDPL TLFEEKIHLD DANESDHFEN 400
    IQSTNWQTMR FKPPPPNSDI GWRVEFRPME VQLTDFENSA YVVFVVLLTR 450
    VILSYKLDFL IPLSKVDENM KVAQKRDAVL QGMFYFRKDI CKGGNAVVDG 500
    CGKAQNSTEL AAEEYTLMSI DTIINGKEGV FPGLIPILNS YLENMEVDVD 550
    TRCSILNYLK LIKKRASGEL MTVARWMREF IANHPDYKQD SVITDEMNYS 600
    LILKCNQIAN ELCECPELLG SAFRKVKYSG SKTDSSN 637
    Length:637
    Mass (Da):72,766
    Last modified:January 23, 2007 - v2
    Checksum:i511F33F106A15504
    GO

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti55 – 551L → S.
    Corresponds to variant rs2066512 [ dbSNP | Ensembl ].
    VAR_014884
    Natural varianti127 – 1271R → C in HAGGSD. 1 Publication
    VAR_021110
    Natural varianti158 – 1581P → L in HAGGSD. 1 Publication
    VAR_015403
    Natural varianti370 – 3701H → L in HAGGSD. 1 Publication
    VAR_013514
    Natural varianti462 – 4621P → S.1 Publication
    Corresponds to variant rs17883718 [ dbSNP | Ensembl ].
    VAR_021100

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    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.
    CCDSiCCDS4952.1.
    PIRiJH0611.
    RefSeqiNP_001184044.1. NM_001197115.1.
    NP_001489.1. NM_001498.3.
    UniGeneiHs.654465.

    Genome annotation databases

    EnsembliENST00000229416; ENSP00000229416; ENSG00000001084.
    ENST00000514004; ENSP00000421908; ENSG00000001084.
    GeneIDi2729.
    KEGGihsa:2729.
    UCSCiuc003pbv.1. human.

    Polymorphism databases

    DMDMi1346190.

    Keywords - Coding sequence diversityi

    Polymorphism

    Cross-referencesi

    Web resourcesi

    NIEHS-SNPs

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    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 .
    CCDSi CCDS4952.1.
    PIRi JH0611.
    RefSeqi NP_001184044.1. NM_001197115.1.
    NP_001489.1. NM_001498.3.
    UniGenei Hs.654465.

    3D structure databases

    ProteinModelPortali P48506.
    SMRi P48506. Positions 2-610.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 108991. 7 interactions.
    IntActi P48506. 2 interactions.
    STRINGi 9606.ENSP00000229416.

    Chemistry

    BindingDBi P48506.
    ChEMBLi CHEMBL4055.
    DrugBanki DB00151. L-Cysteine.
    DB00142. L-Glutamic Acid.

    PTM databases

    PhosphoSitei P48506.

    Polymorphism databases

    DMDMi 1346190.

    Proteomic databases

    MaxQBi P48506.
    PaxDbi P48506.
    PeptideAtlasi P48506.
    PRIDEi P48506.

    Protocols and materials databases

    DNASUi 2729.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000229416 ; ENSP00000229416 ; ENSG00000001084 .
    ENST00000514004 ; ENSP00000421908 ; ENSG00000001084 .
    GeneIDi 2729.
    KEGGi hsa:2729.
    UCSCi uc003pbv.1. human.

    Organism-specific databases

    CTDi 2729.
    GeneCardsi GC06M053409.
    HGNCi HGNC:4311. GCLC.
    HPAi CAB009569.
    HPA036359.
    HPA036360.
    MIMi 230450. phenotype.
    606857. gene+phenotype.
    neXtProti NX_P48506.
    Orphaneti 33574. Gamma-glutamylcysteine synthetase deficiency.
    PharmGKBi PA28612.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi NOG269969.
    HOGENOMi HOG000199354.
    HOVERGENi HBG005924.
    InParanoidi P48506.
    KOi K11204.
    OMAi RWMREFI.
    OrthoDBi EOG7B8S3B.
    PhylomeDBi P48506.
    TreeFami TF105644.

    Enzyme and pathway databases

    UniPathwayi UPA00142 ; UER00209 .
    BioCyci MetaCyc:ENSG00000001084-MONOMER.
    BRENDAi 6.3.2.2. 2681.
    Reactomei REACT_115639. Sulfur amino acid metabolism.
    REACT_6960. Glutathione synthesis and recycling.

    Miscellaneous databases

    ChiTaRSi GCLC. human.
    GeneWikii GCLC.
    GenomeRNAii 2729.
    NextBioi 10756.
    PMAP-CutDB P48506.
    PROi P48506.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi P48506.
    Bgeei P48506.
    CleanExi HS_GCLC.
    Genevestigatori P48506.

    Family and domain databases

    InterProi IPR004308. GCS.
    [Graphical view ]
    PANTHERi PTHR11164. PTHR11164. 1 hit.
    Pfami PF03074. GCS. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    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.
      , 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. 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.

    Entry informationi

    Entry nameiGSH1_HUMAN
    AccessioniPrimary (citable) accession number: P48506
    Secondary accession number(s): Q14399
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: February 1, 1996
    Last sequence update: January 23, 2007
    Last modified: October 1, 2014
    This is version 136 of the entry and version 2 of the sequence. [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

    Complete proteome, Reference proteome

    Documents

    1. Human chromosome 6
      Human chromosome 6: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PATHWAY comments
      Index of metabolic and biosynthesis pathways
    6. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3