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Protein

Glutamate--cysteine ligase catalytic subunit

Gene

GCLC

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: 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

  • ADP binding Source: UniProtKB
  • ATP binding Source: UniProtKB-KW
  • coenzyme binding Source: UniProtKB
  • glutamate binding Source: UniProtKB
  • glutamate-cysteine ligase activity Source: UniProtKB
  • magnesium ion binding Source: UniProtKB

GO - Biological processi

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_268321. Defective GCLC causes Hemolytic anemia due to gamma-glutamylcysteine synthetase deficiency (HAGGSD).
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 Componenti: Chromosome 6

Organism-specific databases

HGNCiHGNC:4311. GCLC.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Pathology & Biotechi

Involvement in diseasei

Hemolytic anemia due to gamma-glutamylcysteine synthetase deficiency (HAGGSD)3 Publications

The disease is caused by mutations affecting the gene represented in this entry.

Disease descriptionA disease characterized by hemolytic anemia, glutathione deficiency, myopathy, late-onset spinocerebellar degeneration, and peripheral neuropathy.

See also OMIM:230450
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.

Chemistry

DrugBankiDB00151. L-Cysteine.
DB00163. Vitamin E.

Polymorphism and mutation databases

BioMutaiGCLC.
DMDMi1346190.

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. 8 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

        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.
GeneIDi2729.
KEGGihsa:2729.
UCSCiuc003pbv.1. human.

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.
CCDSiCCDS4952.1.
PIRiJH0611.
RefSeqiNP_001184044.1. NM_001197115.1.
NP_001489.1. NM_001498.3.
UniGeneiHs.654465.

3D structure databases

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

Protein-protein interaction databases

BioGridi108991. 8 interactions.
IntActiP48506. 2 interactions.
STRINGi9606.ENSP00000229416.

Chemistry

BindingDBiP48506.
ChEMBLiCHEMBL4055.
DrugBankiDB00151. L-Cysteine.
DB00163. Vitamin E.

PTM databases

PhosphoSiteiP48506.

Polymorphism and mutation databases

BioMutaiGCLC.
DMDMi1346190.

Proteomic databases

MaxQBiP48506.
PaxDbiP48506.
PeptideAtlasiP48506.
PRIDEiP48506.

Protocols and materials databases

DNASUi2729.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

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

Organism-specific databases

CTDi2729.
GeneCardsiGC06M053409.
HGNCiHGNC:4311. GCLC.
HPAiCAB009569.
HPA036359.
HPA036360.
MIMi230450. phenotype.
606857. gene+phenotype.
neXtProtiNX_P48506.
Orphaneti33574. Gamma-glutamylcysteine synthetase deficiency.
PharmGKBiPA28612.
GenAtlasiSearch...

Phylogenomic databases

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

Enzyme and pathway databases

UniPathwayiUPA00142; UER00209.
BioCyciMetaCyc:ENSG00000001084-MONOMER.
BRENDAi6.3.2.2. 2681.
ReactomeiREACT_115639. Sulfur amino acid metabolism.
REACT_268321. Defective GCLC causes Hemolytic anemia due to gamma-glutamylcysteine synthetase deficiency (HAGGSD).
REACT_6960. Glutathione synthesis and recycling.

Miscellaneous databases

ChiTaRSiGCLC. human.
GeneWikiiGCLC.
GenomeRNAii2729.
NextBioi10756.
PMAP-CutDBP48506.
PROiP48506.
SOURCEiSearch...

Gene expression databases

BgeeiP48506.
CleanExiHS_GCLC.
ExpressionAtlasiP48506. baseline and differential.
GenevestigatoriP48506.

Family and domain databases

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

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. "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome."
    Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., Ye M., Zou H.
    J. Proteomics 96:253-262(2014) [PubMed] [Europe PMC] [Abstract]
    Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Liver.
  11. "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.
  12. "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: April 29, 2015
This is version 142 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

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.