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P48506

- GSH1_HUMAN

UniProt

P48506 - GSH1_HUMAN

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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

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
Complete GO annotation...

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
Complete GO annotation...

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

BgeeiP48506.
CleanExiHS_GCLC.
ExpressionAtlasiP48506. baseline and differential.
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.
GeneTreeiENSGT00390000011908.
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

        10         20         30         40         50
MGLLSQGSPL SWEETKRHAD HVRRHGILQF LHIYHAVKDR HKDVLKWGDE
60 70 80 90 100
VEYMLVSFDH ENKKVRLVLS GEKVLETLQE KGERTNPNHP TLWRPEYGSY
110 120 130 140 150
MIEGTPGQPY GGTMSEFNTV EANMRKRRKE ATSILEENQA LCTITSFPRL
160 170 180 190 200
GCPGFTLPEV KPNPVEGGAS KSLFFPDEAI NKHPRFSTLT RNIRHRRGEK
210 220 230 240 250
VVINVPIFKD KNTPSPFIET FTEDDEASRA SKPDHIYMDA MGFGMGNCCL
260 270 280 290 300
QVTFQACSIS EARYLYDQLA TICPIVMALS AASPFYRGYV SDIDCRWGVI
310 320 330 340 350
SASVDDRTRE ERGLEPLKNN NYRISKSRYD SIDSYLSKCG EKYNDIDLTI
360 370 380 390 400
DKEIYEQLLQ EGIDHLLAQH VAHLFIRDPL TLFEEKIHLD DANESDHFEN
410 420 430 440 450
IQSTNWQTMR FKPPPPNSDI GWRVEFRPME VQLTDFENSA YVVFVVLLTR
460 470 480 490 500
VILSYKLDFL IPLSKVDENM KVAQKRDAVL QGMFYFRKDI CKGGNAVVDG
510 520 530 540 550
CGKAQNSTEL AAEEYTLMSI DTIINGKEGV FPGLIPILNS YLENMEVDVD
560 570 580 590 600
TRCSILNYLK LIKKRASGEL MTVARWMREF IANHPDYKQD SVITDEMNYS
610 620 630
LILKCNQIAN ELCECPELLG SAFRKVKYSG SKTDSSN
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:
EMBLi
GenBanki
DDBJi
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:
EMBLi
GenBanki
DDBJi
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.
DB00163. Vitamin E.

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.
GeneTreei ENSGT00390000011908.
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

Bgeei P48506.
CleanExi HS_GCLC.
ExpressionAtlasi P48506. baseline and differential.
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

« Hide 'large scale' publications
  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 29, 2014
This is version 137 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