P48506 (GSH1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	637 AA.
Sequence status	Complete.
Protein existence	Evidence 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 process	Glutathione biosynthesis
Coding sequence diversity	Polymorphism
Disease	Disease mutation Hereditary hemolytic anemia
Ligand	ATP-binding Nucleotide-binding
Molecular function	Ligase
PTM	Acetylation Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	L-ascorbic acid metabolic process Inferred from electronic annotation. Source: Compara cell redox homeostasis Inferred from direct assay PubMed 10439045. Source: UniProtKB 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 negative regulation of apoptotic process Inferred from direct assay PubMed 10439045. Source: UniProtKB negative regulation of neuron apoptotic process Inferred from electronic annotation. Source: Compara negative regulation of protein ubiquitination Inferred from electronic annotation. Source: Compara negative regulation of transcription, DNA-dependent Inferred from direct assay PubMed 10439045. Source: UniProtKB positive regulation of proteasomal ubiquitin-dependent protein catabolic process Inferred from electronic annotation. Source: Compara regulation of blood vessel size Inferred from mutant phenotype PubMed 12598062. Source: UniProtKB regulation of mitochondrial depolarization Inferred from electronic annotation. Source: Compara response to arsenic-containing substance Inferred from electronic annotation. Source: Compara response to heat Inferred from direct assay PubMed 8104187. Source: UniProtKB response to hormone stimulus Inferred from direct assay PubMed 8104187. Source: UniProtKB response to nitrosative stress Inferred from electronic annotation. Source: Compara response to oxidative stress Inferred from direct assay PubMed 10395918PubMed 11972604. Source: UniProtKB xenobiotic metabolic process Traceable author statement. Source: Reactome
Cellular_component	cytosol Traceable author statement. Source: Reactome glutamate-cysteine ligase complex Inferred from electronic annotation. Source: Compara
Molecular_function	ADP 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 key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 637	637	Glutamate--cysteine ligase catalytic subunit		PRO_0000192563
Amino acid modifications
	Modified residue	1	1	N-acetylmethionine Ref.8
	Modified residue	5	1	Phosphoserine Ref.8
	Modified residue	8	1	Phosphoserine Ref.8
Natural variations
	Natural variant	55	1	L → S. Corresponds to variant rs2066512 [ dbSNP | Ensembl ].		VAR_014884
	Natural variant	127	1	R → C in HAGGSD. Ref.11		VAR_021110
	Natural variant	158	1	P → L in HAGGSD. Ref.10		VAR_015403
	Natural variant	370	1	H → L in HAGGSD. Ref.6		VAR_013514
	Natural variant	462	1	P → S. Ref.2 Corresponds to variant rs17883718 [ dbSNP | Ensembl ].		VAR_021100

Sequences

	Sequence		Length	Mass (Da)
	P48506 [UniParc]. Last modified January 23, 2007. Version 2. Checksum: 511F33F106A15504	FASTA	637	72,766
	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

References

	« Hide 'large scale' referencesShow '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. , 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, MASS SPECTROMETRY. 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

NIEHS-SNPs

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.
IPI	IPI00215768.
PIR	JH0611.
RefSeq	NP_001184044.1. NM_001197115.1. NP_001489.1. NM_001498.3.
UniGene	Hs.654465.
3D structure databases
ProteinModelPortal	P48506.
ModBase	Search...
Protein-protein interaction databases
IntAct	P48506. 2 interactions.
STRING	9606.ENSP00000229416.
PTM databases
PhosphoSite	P48506.
Polymorphism databases
DMDM	1346190.
Proteomic databases
PaxDb	P48506.
PeptideAtlas	P48506.
PRIDE	P48506.
Protocols and materials databases
DNASU	2729.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000229416; ENSP00000229416; ENSG00000001084. ENST00000514004; ENSP00000421908; ENSG00000001084.
GeneID	2729.
KEGG	hsa:2729.
UCSC	uc003pbv.1. human.
Organism-specific databases
CTD	2729.
GeneCards	GC06M053409.
HGNC	HGNC:4311. GCLC.
HPA	CAB009569. HPA036359. HPA036360.
MIM	230450. phenotype. 606857. gene+phenotype.
neXtProt	NX_P48506.
Orphanet	33574. Gamma-glutamylcysteine synthetase deficiency.
PharmGKB	PA28612.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG269969.
HOGENOM	HOG000199354.
HOVERGEN	HBG005924.
InParanoid	P48506.
KO	K11204.
OMA	GILQFLH.
OrthoDB	EOG47M1XB.
PhylomeDB	P48506.
Enzyme and pathway databases
BioCyc	MetaCyc:ENSG00000001084-MONOMER.
BRENDA	6.3.2.2. 2681.
Reactome	REACT_111217. Metabolism.
UniPathway	UPA00142; UER00209.
Gene expression databases
ArrayExpress	P48506.
Bgee	P48506.
CleanEx	HS_GCLC.
Genevestigator	P48506.
GermOnline	ENSG00000001084. Homo sapiens.
Family and domain databases
InterPro	IPR004308. GCS. [Graphical view]
PANTHER	PTHR11164. PTHR11164. 1 hit.
Pfam	PF03074. GCS. 1 hit. [Graphical view]
ProtoNet	Search...
Other
BindingDB	P48506.
ChEMBL	CHEMBL4055.
ChiTaRS	GCLC. human.
DrugBank	DB00151. L-Cysteine. DB00142. L-Glutamic Acid.
GenomeRNAi	2729.
NextBio	10756.
PMAP-CutDB	P48506.
SOURCE	Search...

Entry information

Entry name

GSH1_HUMAN

Accession

Primary (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:	May 1, 2013
This is version 122 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.