Reviewed, UniProtKB/Swiss-Prot P48506 (GSH1_HUMAN)

Names and origin

Protein names

Recommended name:
    Glutamate--cysteine ligase catalytic subunit
    EC=6.3.2.2
Alternative name(s):
    Gamma-glutamylcysteine synthetase
    Gamma-ECS
    GCS heavy chain

Gene names

Name:	GCLC
Synonyms:	GLCL, GLCLC

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	637 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
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	Defects in GCLC are the cause of hemolytic anemia [MIM:230450]. Ref.6 Ref.9 Ref.10
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
Technical term	Complete proteome
Gene Ontology (GO)
Biological process	anti-apoptosis Inferred from direct assay. Source: UniProtKB cell redox homeostasis Inferred from direct assay. Source: UniProtKB cysteine metabolic process Inferred from direct assay. Source: UniProtKB glutamate metabolic process Ref.10 Inferred from direct assay. Source: UniProtKB glutathione biosynthetic process Ref.10 Inferred from direct assay. Source: UniProtKB negative regulation of transcription Inferred from direct assay. Source: UniProtKB regulation of blood vessel size Inferred from mutant phenotype. Source: UniProtKB response to heat Inferred from direct assay. Source: UniProtKB response to hormone stimulus Inferred from direct assay. Source: UniProtKB response to oxidative stress Inferred from direct assay. Source: UniProtKB
Molecular function	ADP binding Inferred from direct assay. Source: UniProtKB ATP binding Inferred from electronic annotation. Source: UniProtKB-KW coenzyme binding Ref.7 Inferred from physical interaction. Source: UniProtKB glutamate binding Inferred from direct assay. Source: UniProtKB glutamate-cysteine ligase activity Inferred from direct assay. Source: UniProtKB magnesium ion binding Inferred from direct assay. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Initiator methionine	1	1	Removed Probable
	Chain	2 – 637	636	Glutamate--cysteine ligase catalytic subunit		PRO_0000192563
Natural variations
	Natural variant	55	1	L → S: dbSNP rs2066512.		VAR_014884
	Natural variant	127	1	R → C in hemolytic anemia. Ref.10		VAR_021110
	Natural variant	158	1	P → L in hemolytic anemia. Ref.9		VAR_015403
	Natural variant	370	1	H → L in hemolytic anemia. Ref.6		VAR_013514
	Natural variant	462	1	P → S: dbSNP rs17883718. Ref.2		VAR_021100

Sequences

	Sequence		Length	Mass (Da)
	P48506-1 [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: 1350904] [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: 14574404] [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: 15489334] [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: 7726839] [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: 10515893] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 341-440, VARIANT HEMOLYTIC ANEMIA LEU-370.
[7]	"Expression and purification of human gamma-glutamylcysteine synthetase." Misra I., Griffith O.W. Protein Expr. Purif. 13:268-276(1998) [PubMed: 9675072] [Abstract] Cited for: CHARACTERIZATION.
[8]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[9]	"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: 10733484] [Abstract] Cited for: VARIANT HEMOLYTIC ANEMIA LEU-158.
[10]	"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: 12663448] [Abstract] Cited for: VARIANT HEMOLYTIC ANEMIA CYS-127.
+	Additional computationally mapped references.

Web resources

NIEHS-SNPs

Cross-references

Sequence databases
EMBLGenBankDDBJ	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_001489.1.
UniGene	Hs.654465
3D structure databases
ModBase	Search...
Protein-protein interaction databases
STRING	P48506.
PTM databases
PhosphoSite	P48506.
Proteomic databases
PeptideAtlas	P48506.
PRIDE	P48506.
Genome annotation databases
Ensembl	ENST00000229416; ENSP00000229416; ENSG00000001084; Homo sapiens. [Genome view]
GeneID	2729.
KEGG	hsa:2729.
UCSC	uc003pbw.1. human.
Organism-specific databases
CTD	2729.
GeneCards	GC06M053470.
H-InvDB	HIX0025084.
HGNC	HGNC:4311. GCLC.
HPA	CAB009569.
MIM	230450. phenotype. 606857. gene+phenotype.
Orphanet	33574. Gamma-glutamylcysteine synthetase deficiency.
PharmGKB	PA28612.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	P48506.
HOVERGEN	P48506.
OMA	DNMRKRR
OrthoDB	EOG9M94BX
Enzyme and pathway databases
BRENDA	6.3.2.2. 247.
Reactome	REACT_13433. Biological oxidations.
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. GCS. 1 hit.
Pfam	PF03074. GCS. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
DrugBank	DB00151. L-Cysteine. DB00142. L-Glutamic Acid.
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:	November 24, 2009
This is version 88 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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.