Full text data of GCLC
GCLC
(GLCL, GLCLC)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Glutamate--cysteine ligase catalytic subunit; 6.3.2.2 (GCS heavy chain; Gamma-ECS; Gamma-glutamylcysteine synthetase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Glutamate--cysteine ligase catalytic subunit; 6.3.2.2 (GCS heavy chain; Gamma-ECS; Gamma-glutamylcysteine synthetase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00215768
IPI00215768 Glutamate-cysteine liGase, catalytic subunit Feedback inhibition by glutathione, ATP + L-glutamate + L-cysteine = ADP + phosphate + gamma-L-glutamyl-L-cysteine, GSH biosynthesis first step soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
IPI00215768 Glutamate-cysteine liGase, catalytic subunit Feedback inhibition by glutathione, ATP + L-glutamate + L-cysteine = ADP + phosphate + gamma-L-glutamyl-L-cysteine, GSH biosynthesis first step soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
UniProt
P48506
ID GSH1_HUMAN Reviewed; 637 AA.
AC P48506; Q14399;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 2.
DT 22-JAN-2014, entry version 128.
DE RecName: Full=Glutamate--cysteine ligase catalytic subunit;
DE EC=6.3.2.2;
DE AltName: Full=GCS heavy chain;
DE AltName: Full=Gamma-ECS;
DE AltName: Full=Gamma-glutamylcysteine synthetase;
GN Name=GCLC; Synonyms=GLCL, GLCLC;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=1350904; DOI=10.1016/S0006-291X(05)80950-7;
RA Gipp J.J., Chang C., Mulcahy R.T.;
RT "Cloning and nucleotide sequence of a full-length cDNA for human liver
RT gamma-glutamylcysteine synthetase.";
RL Biochem. Biophys. Res. Commun. 185:29-35(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT SER-462.
RG NIEHS SNPs program;
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=14574404; DOI=10.1038/nature02055;
RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E.,
RA Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R.,
RA Almeida J.P., Ambrose K.D., Andrews T.D., Ashwell R.I.S.,
RA Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J.,
RA Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P.,
RA Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y.,
RA Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E.,
RA Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A.,
RA Frankland J., French L., Garner P., Garnett J., Ghori M.J.,
RA Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M.,
RA Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S.,
RA Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R.,
RA Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E.,
RA Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A.,
RA Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M.,
RA Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K.,
RA McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T.,
RA Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R.,
RA Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W.,
RA Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M.,
RA Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L.,
RA Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J.,
RA Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B.,
RA Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L.,
RA Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W.,
RA Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A.,
RA Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S.;
RT "The DNA sequence and analysis of human chromosome 6.";
RL Nature 425:805-811(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Hippocampus, and Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-27.
RC TISSUE=Foreskin fibroblast;
RX PubMed=7726839; DOI=10.1006/bbrc.1995.1493;
RA Mulcahy R.T., Gipp J.J.;
RT "Identification of a putative antioxidant response element in the 5'-
RT flanking region of the human gamma-glutamylcysteine synthetase heavy
RT subunit gene.";
RL Biochem. Biophys. Res. Commun. 209:227-233(1995).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 341-440, AND VARIANT HAGGSD
RP LEU-370.
RX PubMed=10515893;
RA Beutler E., Gelbart T., Kondo T., Matsunaga A.T.;
RT "The molecular basis of a case of gamma-glutamylcysteine synthetase
RT deficiency.";
RL Blood 94:2890-2894(1999).
RN [7]
RP CHARACTERIZATION.
RX PubMed=9675072; DOI=10.1006/prep.1998.0897;
RA Misra I., Griffith O.W.;
RT "Expression and purification of human gamma-glutamylcysteine
RT synthetase.";
RL Protein Expr. Purif. 13:268-276(1998).
RN [8]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, PHOSPHORYLATION [LARGE
RP SCALE ANALYSIS] AT SER-5 AND SER-8, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [10]
RP VARIANT HAGGSD LEU-158.
RX PubMed=10733484;
RA Ristoff E., Augustson C., Geissler J., de Rijk T., Carlsson K.,
RA Luo J.-L., Andersson K., Weening R.S., van Zwieten R., Larsson A.,
RA Roos D.;
RT "A missense mutation in the heavy subunit of gamma-glutamylcysteine
RT synthetase gene causes hemolytic anemia.";
RL Blood 95:2193-2196(2000).
RN [11]
RP VARIANT HAGGSD CYS-127.
RX PubMed=12663448; DOI=10.1182/blood-2002-11-3622;
RA Hamilton D., Wu J.H., Alaoui-Jamali M., Batist G.;
RT "A novel missense mutation in the gamma-glutamylcysteine synthetase
RT catalytic subunit gene causes both decreased enzymatic activity and
RT glutathione production.";
RL Blood 102:725-730(2003).
CC -!- CATALYTIC ACTIVITY: ATP + L-glutamate + L-cysteine = ADP +
CC phosphate + gamma-L-glutamyl-L-cysteine.
CC -!- ENZYME REGULATION: Feedback inhibition by glutathione.
CC -!- PATHWAY: Sulfur metabolism; glutathione biosynthesis; glutathione
CC from L-cysteine and L-glutamate: step 1/2.
CC -!- SUBUNIT: Heterodimer of a catalytic heavy chain and a regulatory
CC light chain.
CC -!- DISEASE: Hemolytic anemia due to gamma-glutamylcysteine synthetase
CC deficiency (HAGGSD) [MIM:230450]: A disease characterized by
CC hemolytic anemia, glutathione deficiency, myopathy, late-onset
CC spinocerebellar degeneration, and peripheral neuropathy. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the glutamate--cysteine ligase type 3
CC family.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/gclc/";
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DR EMBL; M90656; AAA58499.1; -; mRNA.
DR EMBL; AY780794; AAV31778.1; -; Genomic_DNA.
DR EMBL; AL033397; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC022487; AAH22487.1; -; mRNA.
DR EMBL; BC039894; AAH39894.1; -; mRNA.
DR EMBL; L39773; AAC41751.1; -; Genomic_DNA.
DR EMBL; AF118846; AAD18031.1; -; Genomic_DNA.
DR PIR; JH0611; JH0611.
DR RefSeq; NP_001184044.1; NM_001197115.1.
DR RefSeq; NP_001489.1; NM_001498.3.
DR UniGene; Hs.654465; -.
DR ProteinModelPortal; P48506; -.
DR SMR; P48506; 2-610.
DR IntAct; P48506; 2.
DR STRING; 9606.ENSP00000229416; -.
DR BindingDB; P48506; -.
DR ChEMBL; CHEMBL4055; -.
DR DrugBank; DB00151; L-Cysteine.
DR DrugBank; DB00142; L-Glutamic Acid.
DR PhosphoSite; P48506; -.
DR DMDM; 1346190; -.
DR PaxDb; P48506; -.
DR PeptideAtlas; P48506; -.
DR PRIDE; P48506; -.
DR DNASU; 2729; -.
DR Ensembl; ENST00000229416; ENSP00000229416; ENSG00000001084.
DR Ensembl; ENST00000514004; ENSP00000421908; ENSG00000001084.
DR GeneID; 2729; -.
DR KEGG; hsa:2729; -.
DR UCSC; uc003pbv.1; human.
DR CTD; 2729; -.
DR GeneCards; GC06M053409; -.
DR HGNC; HGNC:4311; GCLC.
DR HPA; CAB009569; -.
DR HPA; HPA036359; -.
DR HPA; HPA036360; -.
DR MIM; 230450; phenotype.
DR MIM; 606857; gene+phenotype.
DR neXtProt; NX_P48506; -.
DR Orphanet; 33574; Gamma-glutamylcysteine synthetase deficiency.
DR PharmGKB; PA28612; -.
DR eggNOG; NOG269969; -.
DR HOGENOM; HOG000199354; -.
DR HOVERGEN; HBG005924; -.
DR InParanoid; P48506; -.
DR KO; K11204; -.
DR OMA; RWMREFI; -.
DR OrthoDB; EOG7B8S3B; -.
DR PhylomeDB; P48506; -.
DR BioCyc; MetaCyc:ENSG00000001084-MONOMER; -.
DR BRENDA; 6.3.2.2; 2681.
DR Reactome; REACT_111217; Metabolism.
DR UniPathway; UPA00142; UER00209.
DR ChiTaRS; GCLC; human.
DR GeneWiki; GCLC; -.
DR GenomeRNAi; 2729; -.
DR NextBio; 10756; -.
DR PMAP-CutDB; P48506; -.
DR PRO; PR:P48506; -.
DR ArrayExpress; P48506; -.
DR Bgee; P48506; -.
DR CleanEx; HS_GCLC; -.
DR Genevestigator; P48506; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0017109; C:glutamate-cysteine ligase complex; IEA:Ensembl.
DR GO; GO:0043531; F:ADP binding; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0050662; F:coenzyme binding; IPI:UniProtKB.
DR GO; GO:0016595; F:glutamate binding; IDA:UniProtKB.
DR GO; GO:0004357; F:glutamate-cysteine ligase activity; IDA:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB.
DR GO; GO:0045454; P:cell redox homeostasis; IDA:UniProtKB.
DR GO; GO:0006534; P:cysteine metabolic process; IDA:UniProtKB.
DR GO; GO:0006536; P:glutamate metabolic process; IDA:UniProtKB.
DR GO; GO:0006750; P:glutathione biosynthetic process; IDA:UniProtKB.
DR GO; GO:1901687; P:glutathione derivative biosynthetic process; TAS:Reactome.
DR GO; GO:0019852; P:L-ascorbic acid metabolic process; IEA:Ensembl.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0031397; P:negative regulation of protein ubiquitination; IEA:Ensembl.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-dependent; IDA:UniProtKB.
DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IEA:Ensembl.
DR GO; GO:0050880; P:regulation of blood vessel size; IMP:UniProtKB.
DR GO; GO:0051900; P:regulation of mitochondrial depolarization; IEA:Ensembl.
DR GO; GO:0046685; P:response to arsenic-containing substance; IEA:Ensembl.
DR GO; GO:0009408; P:response to heat; IDA:UniProtKB.
DR GO; GO:0009725; P:response to hormone stimulus; IDA:UniProtKB.
DR GO; GO:0051409; P:response to nitrosative stress; IEA:Ensembl.
DR GO; GO:0006979; P:response to oxidative stress; IDA:UniProtKB.
DR GO; GO:0006805; P:xenobiotic metabolic process; TAS:Reactome.
DR InterPro; IPR004308; GCS.
DR PANTHER; PTHR11164; PTHR11164; 1.
DR Pfam; PF03074; GCS; 1.
PE 1: Evidence at protein level;
KW Acetylation; ATP-binding; Complete proteome; Disease mutation;
KW Glutathione biosynthesis; Hereditary hemolytic anemia; Ligase;
KW Nucleotide-binding; Phosphoprotein; Polymorphism; Reference proteome.
FT CHAIN 1 637 Glutamate--cysteine ligase catalytic
FT subunit.
FT /FTId=PRO_0000192563.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 5 5 Phosphoserine.
FT MOD_RES 8 8 Phosphoserine.
FT VARIANT 55 55 L -> S (in dbSNP:rs2066512).
FT /FTId=VAR_014884.
FT VARIANT 127 127 R -> C (in HAGGSD).
FT /FTId=VAR_021110.
FT VARIANT 158 158 P -> L (in HAGGSD).
FT /FTId=VAR_015403.
FT VARIANT 370 370 H -> L (in HAGGSD).
FT /FTId=VAR_013514.
FT VARIANT 462 462 P -> S (in dbSNP:rs17883718).
FT /FTId=VAR_021100.
SQ SEQUENCE 637 AA; 72766 MW; 511F33F106A15504 CRC64;
MGLLSQGSPL SWEETKRHAD HVRRHGILQF LHIYHAVKDR HKDVLKWGDE VEYMLVSFDH
ENKKVRLVLS GEKVLETLQE KGERTNPNHP TLWRPEYGSY MIEGTPGQPY GGTMSEFNTV
EANMRKRRKE ATSILEENQA LCTITSFPRL GCPGFTLPEV KPNPVEGGAS KSLFFPDEAI
NKHPRFSTLT RNIRHRRGEK VVINVPIFKD KNTPSPFIET FTEDDEASRA SKPDHIYMDA
MGFGMGNCCL QVTFQACSIS EARYLYDQLA TICPIVMALS AASPFYRGYV SDIDCRWGVI
SASVDDRTRE ERGLEPLKNN NYRISKSRYD SIDSYLSKCG EKYNDIDLTI DKEIYEQLLQ
EGIDHLLAQH VAHLFIRDPL TLFEEKIHLD DANESDHFEN IQSTNWQTMR FKPPPPNSDI
GWRVEFRPME VQLTDFENSA YVVFVVLLTR VILSYKLDFL IPLSKVDENM KVAQKRDAVL
QGMFYFRKDI CKGGNAVVDG CGKAQNSTEL AAEEYTLMSI DTIINGKEGV FPGLIPILNS
YLENMEVDVD TRCSILNYLK LIKKRASGEL MTVARWMREF IANHPDYKQD SVITDEMNYS
LILKCNQIAN ELCECPELLG SAFRKVKYSG SKTDSSN
//
ID GSH1_HUMAN Reviewed; 637 AA.
AC P48506; Q14399;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 2.
DT 22-JAN-2014, entry version 128.
DE RecName: Full=Glutamate--cysteine ligase catalytic subunit;
DE EC=6.3.2.2;
DE AltName: Full=GCS heavy chain;
DE AltName: Full=Gamma-ECS;
DE AltName: Full=Gamma-glutamylcysteine synthetase;
GN Name=GCLC; Synonyms=GLCL, GLCLC;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=1350904; DOI=10.1016/S0006-291X(05)80950-7;
RA Gipp J.J., Chang C., Mulcahy R.T.;
RT "Cloning and nucleotide sequence of a full-length cDNA for human liver
RT gamma-glutamylcysteine synthetase.";
RL Biochem. Biophys. Res. Commun. 185:29-35(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT SER-462.
RG NIEHS SNPs program;
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=14574404; DOI=10.1038/nature02055;
RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E.,
RA Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R.,
RA Almeida J.P., Ambrose K.D., Andrews T.D., Ashwell R.I.S.,
RA Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J.,
RA Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P.,
RA Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y.,
RA Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E.,
RA Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A.,
RA Frankland J., French L., Garner P., Garnett J., Ghori M.J.,
RA Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M.,
RA Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S.,
RA Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R.,
RA Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E.,
RA Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A.,
RA Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M.,
RA Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K.,
RA McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T.,
RA Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R.,
RA Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W.,
RA Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M.,
RA Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L.,
RA Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J.,
RA Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B.,
RA Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L.,
RA Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W.,
RA Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A.,
RA Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S.;
RT "The DNA sequence and analysis of human chromosome 6.";
RL Nature 425:805-811(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Hippocampus, and Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-27.
RC TISSUE=Foreskin fibroblast;
RX PubMed=7726839; DOI=10.1006/bbrc.1995.1493;
RA Mulcahy R.T., Gipp J.J.;
RT "Identification of a putative antioxidant response element in the 5'-
RT flanking region of the human gamma-glutamylcysteine synthetase heavy
RT subunit gene.";
RL Biochem. Biophys. Res. Commun. 209:227-233(1995).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 341-440, AND VARIANT HAGGSD
RP LEU-370.
RX PubMed=10515893;
RA Beutler E., Gelbart T., Kondo T., Matsunaga A.T.;
RT "The molecular basis of a case of gamma-glutamylcysteine synthetase
RT deficiency.";
RL Blood 94:2890-2894(1999).
RN [7]
RP CHARACTERIZATION.
RX PubMed=9675072; DOI=10.1006/prep.1998.0897;
RA Misra I., Griffith O.W.;
RT "Expression and purification of human gamma-glutamylcysteine
RT synthetase.";
RL Protein Expr. Purif. 13:268-276(1998).
RN [8]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, PHOSPHORYLATION [LARGE
RP SCALE ANALYSIS] AT SER-5 AND SER-8, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [10]
RP VARIANT HAGGSD LEU-158.
RX PubMed=10733484;
RA Ristoff E., Augustson C., Geissler J., de Rijk T., Carlsson K.,
RA Luo J.-L., Andersson K., Weening R.S., van Zwieten R., Larsson A.,
RA Roos D.;
RT "A missense mutation in the heavy subunit of gamma-glutamylcysteine
RT synthetase gene causes hemolytic anemia.";
RL Blood 95:2193-2196(2000).
RN [11]
RP VARIANT HAGGSD CYS-127.
RX PubMed=12663448; DOI=10.1182/blood-2002-11-3622;
RA Hamilton D., Wu J.H., Alaoui-Jamali M., Batist G.;
RT "A novel missense mutation in the gamma-glutamylcysteine synthetase
RT catalytic subunit gene causes both decreased enzymatic activity and
RT glutathione production.";
RL Blood 102:725-730(2003).
CC -!- CATALYTIC ACTIVITY: ATP + L-glutamate + L-cysteine = ADP +
CC phosphate + gamma-L-glutamyl-L-cysteine.
CC -!- ENZYME REGULATION: Feedback inhibition by glutathione.
CC -!- PATHWAY: Sulfur metabolism; glutathione biosynthesis; glutathione
CC from L-cysteine and L-glutamate: step 1/2.
CC -!- SUBUNIT: Heterodimer of a catalytic heavy chain and a regulatory
CC light chain.
CC -!- DISEASE: Hemolytic anemia due to gamma-glutamylcysteine synthetase
CC deficiency (HAGGSD) [MIM:230450]: A disease characterized by
CC hemolytic anemia, glutathione deficiency, myopathy, late-onset
CC spinocerebellar degeneration, and peripheral neuropathy. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the glutamate--cysteine ligase type 3
CC family.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/gclc/";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; M90656; AAA58499.1; -; mRNA.
DR EMBL; AY780794; AAV31778.1; -; Genomic_DNA.
DR EMBL; AL033397; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC022487; AAH22487.1; -; mRNA.
DR EMBL; BC039894; AAH39894.1; -; mRNA.
DR EMBL; L39773; AAC41751.1; -; Genomic_DNA.
DR EMBL; AF118846; AAD18031.1; -; Genomic_DNA.
DR PIR; JH0611; JH0611.
DR RefSeq; NP_001184044.1; NM_001197115.1.
DR RefSeq; NP_001489.1; NM_001498.3.
DR UniGene; Hs.654465; -.
DR ProteinModelPortal; P48506; -.
DR SMR; P48506; 2-610.
DR IntAct; P48506; 2.
DR STRING; 9606.ENSP00000229416; -.
DR BindingDB; P48506; -.
DR ChEMBL; CHEMBL4055; -.
DR DrugBank; DB00151; L-Cysteine.
DR DrugBank; DB00142; L-Glutamic Acid.
DR PhosphoSite; P48506; -.
DR DMDM; 1346190; -.
DR PaxDb; P48506; -.
DR PeptideAtlas; P48506; -.
DR PRIDE; P48506; -.
DR DNASU; 2729; -.
DR Ensembl; ENST00000229416; ENSP00000229416; ENSG00000001084.
DR Ensembl; ENST00000514004; ENSP00000421908; ENSG00000001084.
DR GeneID; 2729; -.
DR KEGG; hsa:2729; -.
DR UCSC; uc003pbv.1; human.
DR CTD; 2729; -.
DR GeneCards; GC06M053409; -.
DR HGNC; HGNC:4311; GCLC.
DR HPA; CAB009569; -.
DR HPA; HPA036359; -.
DR HPA; HPA036360; -.
DR MIM; 230450; phenotype.
DR MIM; 606857; gene+phenotype.
DR neXtProt; NX_P48506; -.
DR Orphanet; 33574; Gamma-glutamylcysteine synthetase deficiency.
DR PharmGKB; PA28612; -.
DR eggNOG; NOG269969; -.
DR HOGENOM; HOG000199354; -.
DR HOVERGEN; HBG005924; -.
DR InParanoid; P48506; -.
DR KO; K11204; -.
DR OMA; RWMREFI; -.
DR OrthoDB; EOG7B8S3B; -.
DR PhylomeDB; P48506; -.
DR BioCyc; MetaCyc:ENSG00000001084-MONOMER; -.
DR BRENDA; 6.3.2.2; 2681.
DR Reactome; REACT_111217; Metabolism.
DR UniPathway; UPA00142; UER00209.
DR ChiTaRS; GCLC; human.
DR GeneWiki; GCLC; -.
DR GenomeRNAi; 2729; -.
DR NextBio; 10756; -.
DR PMAP-CutDB; P48506; -.
DR PRO; PR:P48506; -.
DR ArrayExpress; P48506; -.
DR Bgee; P48506; -.
DR CleanEx; HS_GCLC; -.
DR Genevestigator; P48506; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0017109; C:glutamate-cysteine ligase complex; IEA:Ensembl.
DR GO; GO:0043531; F:ADP binding; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0050662; F:coenzyme binding; IPI:UniProtKB.
DR GO; GO:0016595; F:glutamate binding; IDA:UniProtKB.
DR GO; GO:0004357; F:glutamate-cysteine ligase activity; IDA:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB.
DR GO; GO:0045454; P:cell redox homeostasis; IDA:UniProtKB.
DR GO; GO:0006534; P:cysteine metabolic process; IDA:UniProtKB.
DR GO; GO:0006536; P:glutamate metabolic process; IDA:UniProtKB.
DR GO; GO:0006750; P:glutathione biosynthetic process; IDA:UniProtKB.
DR GO; GO:1901687; P:glutathione derivative biosynthetic process; TAS:Reactome.
DR GO; GO:0019852; P:L-ascorbic acid metabolic process; IEA:Ensembl.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0031397; P:negative regulation of protein ubiquitination; IEA:Ensembl.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-dependent; IDA:UniProtKB.
DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IEA:Ensembl.
DR GO; GO:0050880; P:regulation of blood vessel size; IMP:UniProtKB.
DR GO; GO:0051900; P:regulation of mitochondrial depolarization; IEA:Ensembl.
DR GO; GO:0046685; P:response to arsenic-containing substance; IEA:Ensembl.
DR GO; GO:0009408; P:response to heat; IDA:UniProtKB.
DR GO; GO:0009725; P:response to hormone stimulus; IDA:UniProtKB.
DR GO; GO:0051409; P:response to nitrosative stress; IEA:Ensembl.
DR GO; GO:0006979; P:response to oxidative stress; IDA:UniProtKB.
DR GO; GO:0006805; P:xenobiotic metabolic process; TAS:Reactome.
DR InterPro; IPR004308; GCS.
DR PANTHER; PTHR11164; PTHR11164; 1.
DR Pfam; PF03074; GCS; 1.
PE 1: Evidence at protein level;
KW Acetylation; ATP-binding; Complete proteome; Disease mutation;
KW Glutathione biosynthesis; Hereditary hemolytic anemia; Ligase;
KW Nucleotide-binding; Phosphoprotein; Polymorphism; Reference proteome.
FT CHAIN 1 637 Glutamate--cysteine ligase catalytic
FT subunit.
FT /FTId=PRO_0000192563.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 5 5 Phosphoserine.
FT MOD_RES 8 8 Phosphoserine.
FT VARIANT 55 55 L -> S (in dbSNP:rs2066512).
FT /FTId=VAR_014884.
FT VARIANT 127 127 R -> C (in HAGGSD).
FT /FTId=VAR_021110.
FT VARIANT 158 158 P -> L (in HAGGSD).
FT /FTId=VAR_015403.
FT VARIANT 370 370 H -> L (in HAGGSD).
FT /FTId=VAR_013514.
FT VARIANT 462 462 P -> S (in dbSNP:rs17883718).
FT /FTId=VAR_021100.
SQ SEQUENCE 637 AA; 72766 MW; 511F33F106A15504 CRC64;
MGLLSQGSPL SWEETKRHAD HVRRHGILQF LHIYHAVKDR HKDVLKWGDE VEYMLVSFDH
ENKKVRLVLS GEKVLETLQE KGERTNPNHP TLWRPEYGSY MIEGTPGQPY GGTMSEFNTV
EANMRKRRKE ATSILEENQA LCTITSFPRL GCPGFTLPEV KPNPVEGGAS KSLFFPDEAI
NKHPRFSTLT RNIRHRRGEK VVINVPIFKD KNTPSPFIET FTEDDEASRA SKPDHIYMDA
MGFGMGNCCL QVTFQACSIS EARYLYDQLA TICPIVMALS AASPFYRGYV SDIDCRWGVI
SASVDDRTRE ERGLEPLKNN NYRISKSRYD SIDSYLSKCG EKYNDIDLTI DKEIYEQLLQ
EGIDHLLAQH VAHLFIRDPL TLFEEKIHLD DANESDHFEN IQSTNWQTMR FKPPPPNSDI
GWRVEFRPME VQLTDFENSA YVVFVVLLTR VILSYKLDFL IPLSKVDENM KVAQKRDAVL
QGMFYFRKDI CKGGNAVVDG CGKAQNSTEL AAEEYTLMSI DTIINGKEGV FPGLIPILNS
YLENMEVDVD TRCSILNYLK LIKKRASGEL MTVARWMREF IANHPDYKQD SVITDEMNYS
LILKCNQIAN ELCECPELLG SAFRKVKYSG SKTDSSN
//
MIM
230450
*RECORD*
*FIELD* NO
230450
*FIELD* TI
#230450 GAMMA-GLUTAMYLCYSTEINE SYNTHETASE DEFICIENCY, HEMOLYTIC ANEMIA DUE
TO
*FIELD* TX
read moreA number sign (#) is used with this entry because the disorder is caused
by mutation in the gene encoding gamma-glutamylcysteine synthetase
(GCLC; 606857), the first rate-limiting enzyme in glutathione
biosynthesis.
DESCRIPTION
Gamma-glutamylcysteine synthetase deficiency is 1 of 4 diseases
involving enzymes in the gamma-glutamyl cycle (Meister, 1974). The other
3 disorders are glutathione synthetase deficiency (231900),
5-oxoprolinuria, which is a severe or generalized form of glutathione
synthetase deficiency (266130), and gamma-glutamyl transpeptidase
deficiency (231950). All except gamma-glutamyl transpeptidase deficiency
are accompanied by hemolytic anemia (Larsson and Anderson, 2001).
CLINICAL FEATURES
Konrad et al. (1972) described a brother and sister of German descent
with hemolytic anemia due to deficiency of the first enzyme of
glutathione synthesis, gamma-glutamylcysteine synthetase. There was no
known consanguinity in the family. Obligatory heterozygotes had an
intermediate level of enzyme. Glutathione levels of red cells were
normal in heterozygotes. Both affected sibs had late-onset
spinocerebellar degeneration. The same sibs were reported by Richards et
al. (1974).
Beutler et al. (1990) reported the second family in which
gamma-glutamylcysteine synthetase deficiency was documented, the first
family being that studied by Konrad et al. (1972) and Richards et al.
(1974). The second family demonstrated that neurologic symptoms are not
necessarily manifestations of this enzyme defect.
Hirono et al. (1996) described the first Japanese patients with chronic
nonspherocytic hemolytic anemia and marked deficiency of red blood cell
glutathione. The 3 patients were unrelated; 1 patient had decreased
glutathione synthetase (601002), and the other 2 had moderate deficiency
of gamma-glutamylcysteine synthetase.
INHERITANCE
Gamma-glutamylcysteine synthetase deficiency is an autosomal recessive
trait. Accordingly, first-degree relatives tend to have partial
reduction of the enzyme (Larsson and Anderson, 2001).
MOLECULAR GENETICS
Beutler et al. (1999) determined the partial genomic structure of the
catalytic subunit of GCLC. They identified a his370-to-leu mutation
(606857.0001) in the GCLC gene in a patient with hemolytic anemia due to
gamma-glutamylcysteine synthetase deficiency.
ANIMAL MODEL
Using gene targeting techniques to disrupt the mouse Gclc gene, Dalton
et al. (2000) observed embryonic lethality prior to embryonic day 13
(E13) in homozygous mutants. Shi et al. (2000) also reported embryonic
lethality by E8.5 in mice lacking functional Gclc. Using Western
immunoblot analysis, Dalton et al. (2000) detected an approximately 50%
reduction in Gclc protein levels in the liver of heterozygous mutant
mice, which had normal viability and fertility. They found a
corresponding decrease of 45% in gamma-glutamylcysteine synthetase (Gcl)
activity in heterozygous animals, but only a 20% decrease in glutathione
levels. A compensatory increase of approximately 30% in hepatic
ascorbate levels occurred in heterozygous animals.
*FIELD* RF
1. Beutler, E.; Gelbart, T.; Kondo, T.; Matsunaga, A. T.: The molecular
basis of a case of gamma-glutamylcysteine synthetase deficiency. Blood 94:
2890-2894, 1999.
2. Beutler, E.; Moroose, R.; Kramer, L.; Gelbart, T.; Forman, L.:
Gamma-glutamylcysteine synthetase deficiency and hemolytic anemia. Blood 75:
271-273, 1990.
3. Dalton, T. P.; Dieter, M. Z.; Yang, Y.; Shertzer, H. G.; Nebert,
D. W.: Knockout of the mouse glutamate cysteine ligase catalytic
subunit (Gclc) gene: embryonic lethal when homozygous, and proposed
model for moderate glutathione deficiency when heterozygous. Biochem.
Biophys. Res. Commun. 279: 324-329, 2000.
4. Hirono, A.; Iyori, H.; Sekine, I.; Ueyama, J.; Chiba, H.; Kanno,
H.; Fujii, H.; Miwa, S.: Three cases of hereditary nonspherocytic
hemolytic anemia associated with red blood cell glutathione deficiency. Blood 87:
2071-2074, 1996.
5. Konrad, P. N.; Richards, F.; Valentine, W. N.; Paglia, D. E.:
Gamma-glutamyl-cysteine synthetase deficiency: a cause of hereditary
hemolytic anemia. New Eng. J. Med. 286: 557-561, 1972.
6. Larsson, A.; Anderson, M. E.: Glutathione synthetase deficiency
and other disorders of the gamma-glutamyl cycle.In: Scriver, C. R.;
Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic and Molecular
Bases of Inherited Disease. Vol. II. New York: McGraw-Hill (8th
ed.): 2001. Pp. 2205-2216.
7. Meister, A.: The gamma-glutamyl cycle: diseases associated with
specific enzyme deficiencies. Ann. Intern. Med. 81: 247-253, 1974.
8. Richards, F., II; Cooper, M. R.; Pearce, L. A.; Cowan, R. J.; Spurr,
C. L.: Familial spinocerebellar degeneration, hemolytic anemia, and
glutathione deficiency. Arch. Intern. Med. 134: 534-537, 1974.
9. Shi, Z.-Z.; Osei-Frimpong, J.; Kala, G.; Kala, S. V.; Barrios,
R. J.; Habib, G. M.; Lukin, D. J.; Danney, C. M.; Matzuk, M. M.; Lieberman,
M. W.: Glutathione synthesis is essential for mouse development but
not for cell growth in culture. Proc. Nat. Acad. Sci. 10: 5101-5106,
2000.
*FIELD* CS
INHERITANCE:
Autosomal recessive
MUSCLE, SOFT TISSUE:
Myopathy
NEUROLOGIC:
[Central nervous system];
Late-onset spinocerebellar degeneration;
[Peripheral nervous system];
Peripheral neuropathy
HEMATOLOGY:
Hemolytic anemia
LABORATORY ABNORMALITIES:
Glutathione deficiency;
Gamma-glutamylcysteine deficiency;
Gamma-glutamylcysteine synthetase (glutamate-cysteine ligase) deficiency
MOLECULAR BASIS:
Caused by mutation in the glutamate-cysteine ligase, catalytic subunit
gene (GCLC, 606857.0001)
*FIELD* CN
Cassandra L. Kniffin - revised: 5/8/2002
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 07/02/2013
joanna: 7/2/2013
joanna: 8/3/2012
ckniffin: 5/9/2002
ckniffin: 5/8/2002
*FIELD* CN
Cassandra L. Kniffin - reorganized: 4/17/2002
Dawn Watkins-Chow - updated: 4/10/2001
Paul J. Converse - updated: 9/22/2000
Victor A. McKusick - updated: 1/19/2000
Victor A. McKusick - updated: 1/25/1999
Alan F. Scott - updated: 3/1/1996
*FIELD* CD
Victor A. McKusick: 6/3/1986
*FIELD* ED
ckniffin: 05/08/2002
carol: 4/17/2002
ckniffin: 4/17/2002
mcapotos: 4/10/2001
carol: 11/13/2000
mgross: 9/22/2000
mcapotos: 1/27/2000
mcapotos: 1/21/2000
terry: 1/19/2000
mgross: 4/7/1999
mgross: 2/5/1999
terry: 1/25/1999
carol: 11/3/1998
carol: 7/30/1998
joanna: 4/25/1997
terry: 1/15/1997
terry: 4/17/1996
mark: 4/4/1996
mark: 3/1/1996
mark: 10/13/1995
mimadm: 2/19/1994
carol: 7/23/1992
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
*RECORD*
*FIELD* NO
230450
*FIELD* TI
#230450 GAMMA-GLUTAMYLCYSTEINE SYNTHETASE DEFICIENCY, HEMOLYTIC ANEMIA DUE
TO
*FIELD* TX
read moreA number sign (#) is used with this entry because the disorder is caused
by mutation in the gene encoding gamma-glutamylcysteine synthetase
(GCLC; 606857), the first rate-limiting enzyme in glutathione
biosynthesis.
DESCRIPTION
Gamma-glutamylcysteine synthetase deficiency is 1 of 4 diseases
involving enzymes in the gamma-glutamyl cycle (Meister, 1974). The other
3 disorders are glutathione synthetase deficiency (231900),
5-oxoprolinuria, which is a severe or generalized form of glutathione
synthetase deficiency (266130), and gamma-glutamyl transpeptidase
deficiency (231950). All except gamma-glutamyl transpeptidase deficiency
are accompanied by hemolytic anemia (Larsson and Anderson, 2001).
CLINICAL FEATURES
Konrad et al. (1972) described a brother and sister of German descent
with hemolytic anemia due to deficiency of the first enzyme of
glutathione synthesis, gamma-glutamylcysteine synthetase. There was no
known consanguinity in the family. Obligatory heterozygotes had an
intermediate level of enzyme. Glutathione levels of red cells were
normal in heterozygotes. Both affected sibs had late-onset
spinocerebellar degeneration. The same sibs were reported by Richards et
al. (1974).
Beutler et al. (1990) reported the second family in which
gamma-glutamylcysteine synthetase deficiency was documented, the first
family being that studied by Konrad et al. (1972) and Richards et al.
(1974). The second family demonstrated that neurologic symptoms are not
necessarily manifestations of this enzyme defect.
Hirono et al. (1996) described the first Japanese patients with chronic
nonspherocytic hemolytic anemia and marked deficiency of red blood cell
glutathione. The 3 patients were unrelated; 1 patient had decreased
glutathione synthetase (601002), and the other 2 had moderate deficiency
of gamma-glutamylcysteine synthetase.
INHERITANCE
Gamma-glutamylcysteine synthetase deficiency is an autosomal recessive
trait. Accordingly, first-degree relatives tend to have partial
reduction of the enzyme (Larsson and Anderson, 2001).
MOLECULAR GENETICS
Beutler et al. (1999) determined the partial genomic structure of the
catalytic subunit of GCLC. They identified a his370-to-leu mutation
(606857.0001) in the GCLC gene in a patient with hemolytic anemia due to
gamma-glutamylcysteine synthetase deficiency.
ANIMAL MODEL
Using gene targeting techniques to disrupt the mouse Gclc gene, Dalton
et al. (2000) observed embryonic lethality prior to embryonic day 13
(E13) in homozygous mutants. Shi et al. (2000) also reported embryonic
lethality by E8.5 in mice lacking functional Gclc. Using Western
immunoblot analysis, Dalton et al. (2000) detected an approximately 50%
reduction in Gclc protein levels in the liver of heterozygous mutant
mice, which had normal viability and fertility. They found a
corresponding decrease of 45% in gamma-glutamylcysteine synthetase (Gcl)
activity in heterozygous animals, but only a 20% decrease in glutathione
levels. A compensatory increase of approximately 30% in hepatic
ascorbate levels occurred in heterozygous animals.
*FIELD* RF
1. Beutler, E.; Gelbart, T.; Kondo, T.; Matsunaga, A. T.: The molecular
basis of a case of gamma-glutamylcysteine synthetase deficiency. Blood 94:
2890-2894, 1999.
2. Beutler, E.; Moroose, R.; Kramer, L.; Gelbart, T.; Forman, L.:
Gamma-glutamylcysteine synthetase deficiency and hemolytic anemia. Blood 75:
271-273, 1990.
3. Dalton, T. P.; Dieter, M. Z.; Yang, Y.; Shertzer, H. G.; Nebert,
D. W.: Knockout of the mouse glutamate cysteine ligase catalytic
subunit (Gclc) gene: embryonic lethal when homozygous, and proposed
model for moderate glutathione deficiency when heterozygous. Biochem.
Biophys. Res. Commun. 279: 324-329, 2000.
4. Hirono, A.; Iyori, H.; Sekine, I.; Ueyama, J.; Chiba, H.; Kanno,
H.; Fujii, H.; Miwa, S.: Three cases of hereditary nonspherocytic
hemolytic anemia associated with red blood cell glutathione deficiency. Blood 87:
2071-2074, 1996.
5. Konrad, P. N.; Richards, F.; Valentine, W. N.; Paglia, D. E.:
Gamma-glutamyl-cysteine synthetase deficiency: a cause of hereditary
hemolytic anemia. New Eng. J. Med. 286: 557-561, 1972.
6. Larsson, A.; Anderson, M. E.: Glutathione synthetase deficiency
and other disorders of the gamma-glutamyl cycle.In: Scriver, C. R.;
Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic and Molecular
Bases of Inherited Disease. Vol. II. New York: McGraw-Hill (8th
ed.): 2001. Pp. 2205-2216.
7. Meister, A.: The gamma-glutamyl cycle: diseases associated with
specific enzyme deficiencies. Ann. Intern. Med. 81: 247-253, 1974.
8. Richards, F., II; Cooper, M. R.; Pearce, L. A.; Cowan, R. J.; Spurr,
C. L.: Familial spinocerebellar degeneration, hemolytic anemia, and
glutathione deficiency. Arch. Intern. Med. 134: 534-537, 1974.
9. Shi, Z.-Z.; Osei-Frimpong, J.; Kala, G.; Kala, S. V.; Barrios,
R. J.; Habib, G. M.; Lukin, D. J.; Danney, C. M.; Matzuk, M. M.; Lieberman,
M. W.: Glutathione synthesis is essential for mouse development but
not for cell growth in culture. Proc. Nat. Acad. Sci. 10: 5101-5106,
2000.
*FIELD* CS
INHERITANCE:
Autosomal recessive
MUSCLE, SOFT TISSUE:
Myopathy
NEUROLOGIC:
[Central nervous system];
Late-onset spinocerebellar degeneration;
[Peripheral nervous system];
Peripheral neuropathy
HEMATOLOGY:
Hemolytic anemia
LABORATORY ABNORMALITIES:
Glutathione deficiency;
Gamma-glutamylcysteine deficiency;
Gamma-glutamylcysteine synthetase (glutamate-cysteine ligase) deficiency
MOLECULAR BASIS:
Caused by mutation in the glutamate-cysteine ligase, catalytic subunit
gene (GCLC, 606857.0001)
*FIELD* CN
Cassandra L. Kniffin - revised: 5/8/2002
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 07/02/2013
joanna: 7/2/2013
joanna: 8/3/2012
ckniffin: 5/9/2002
ckniffin: 5/8/2002
*FIELD* CN
Cassandra L. Kniffin - reorganized: 4/17/2002
Dawn Watkins-Chow - updated: 4/10/2001
Paul J. Converse - updated: 9/22/2000
Victor A. McKusick - updated: 1/19/2000
Victor A. McKusick - updated: 1/25/1999
Alan F. Scott - updated: 3/1/1996
*FIELD* CD
Victor A. McKusick: 6/3/1986
*FIELD* ED
ckniffin: 05/08/2002
carol: 4/17/2002
ckniffin: 4/17/2002
mcapotos: 4/10/2001
carol: 11/13/2000
mgross: 9/22/2000
mcapotos: 1/27/2000
mcapotos: 1/21/2000
terry: 1/19/2000
mgross: 4/7/1999
mgross: 2/5/1999
terry: 1/25/1999
carol: 11/3/1998
carol: 7/30/1998
joanna: 4/25/1997
terry: 1/15/1997
terry: 4/17/1996
mark: 4/4/1996
mark: 3/1/1996
mark: 10/13/1995
mimadm: 2/19/1994
carol: 7/23/1992
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
MIM
606857
*RECORD*
*FIELD* NO
606857
*FIELD* TI
*606857 GLUTAMATE-CYSTEINE LIGASE, CATALYTIC SUBUNIT; GCLC
;;GLCLC;;
GAMMA-GLUTAMYLCYSTEINE SYNTHETASE, CATALYTIC SUBUNIT
read more*FIELD* TX
DESCRIPTION
Gamma-glutamylcysteine synthetase, also known as glutamate-cysteine
ligase (EC 6.3.2.2), is the first rate-limiting enzyme in glutathione
(GSH) biosynthesis.
CLONING
Gipp et al. (1992) cloned and sequenced a full-length GCLC cDNA encoding
a 367-amino acid protein with a calculated molecular mass of
approximately 73 kD.
Sierra-Rivera et al. (1995) noted that gamma-glutamylcysteine synthetase
consists of 2 subunits, a heavy catalytic subunit and a light regulatory
subunit (GCLM; 601176).
GENE STRUCTURE
Beutler et al. (1999) determined the partial genomic structure of the
catalytic subunit of GCLC. By comparing cDNA and genomic DNA sequences
with larger sequences from chromosome 6 in the human genome database,
Gipp and Mulcahy (2000) determined that the GCLC gene is larger than
GCLM, spans approximately 51.4 kb, and contains 16 exons.
MAPPING
Sierra-Rivera et al. (1995) mapped the gene that encodes the heavy or
catalytic subunit of the enzyme to human chromosome 6 by Southern
blotting and PCR amplification of gamma-glutamylcysteine synthetase
specific sequences of genomic DNA from a panel of somatic cell hybrids.
In a note added in proof, they stated that by fluorescence in situ
hybridization (FISH), they had localized the gene to 6p12. Using FISH,
Tsuchiya et al. (1995) confirmed the map position of the human gene at
6p12 and mapped the mouse gene to 9D-E. Walsh et al. (1996) described a
trinucleotide repeat polymorphism located in the 5-prime untranslated
region of the GCLC gene and used it to map the GCLC gene to 6p12 by
linkage analysis (1.6 cM distal to D6S295).
MOLECULAR GENETICS
Beutler et al. (1999) identified a his370-to-leu mutation (606857.0001)
in the GCLC gene in a patient with hemolytic anemia due to
gamma-glutamylcysteine synthetase deficiency (230450).
Koide et al. (2003) identified a -129C-T polymorphism in the GCLC gene
(606857.0002) which was associated with impaired dilation of coronary
arteries and occurred at higher frequency in patients with myocardial
infarction (608446).
In studies of cultured fibroblasts from patients with schizophrenia
(181500), Gysin et al. (2007) found 26% decreased GCL activity, and 29%
GCLC protein expression under stressed conditions compared to control
cells. GSH content was not significantly different between the 2 groups.
Two independent studies of 66 Swiss patients and 322 Danish patients
showed an association between schizophrenia and a trinucleotide GAG
repeat polymorphism, with 7, 8 or 9 repeats, located 10 bp upstream from
the start codon. The most common genotype 7/7 was more frequent in
controls, whereas the rarest genotype 8/8 was up to 3 times more
frequent in patients. Patients with disease-associated genotypes,
including 7/8, 8/8, 8/9, and 9/9, had decreased GCL activity, GCLC
protein, and GSH content compared to individuals with the protective
genotypes 7/7 and 7/9. There was no correlation between genotype and
GCLC gene expression at the mRNA level, suggesting that the
trinucleotide repeat polymorphism may affect mRNA transport or
translation.
*FIELD* AV
.0001
GAMMA-GLUTAMYLCYSTEINE SYNTHETASE DEFICIENCY, HEMOLYTIC ANEMIA DUE
TO
GCLC, HIS370LEU
In a 14-year-old offspring of a presumably incestuous half sib mating,
Beutler et al. (1999) described hemolytic anemia due to deficiency of
gamma-glutamylcysteine synthetase (230450). The proband was homozygous
and her mother was heterozygous for an A-to-T transversion at nucleotide
1109 producing a deduced amino acid change of his370-to-leu. The patient
was noted to become jaundiced 2 or 3 times per month. In the newborn
period, exchange transfusion had been required when total bilirubin
increased to 23 mg/dL. The patient was considered to have a learning
disability with dyslexia.
.0002
MYOCARDIAL INFARCTION, SUSCEPTIBILITY TO
GCLC, -129C-T
Koide et al. (2003) identified a -129C-T polymorphism in the GCLC gene
in which the T allele showed lower promoter activity (50 to 60% of the
activity of the C allele) in response to hydrogen peroxide in human
endothelial cells. Endothelium-dependent dilation of coronary arteries
was impaired in patients with the -129T allele compared to age-matched
controls without it. The T allele was significantly more frequent in
patients with myocardial infarction (MI; 608446) compared to controls (p
less than 0.01), and it was a significant risk factor for MI,
independent of traditional coronary risk factors (OR = 1.81, 95% CI =
1.08-3.03, p = 0.03). Koide et al. (2003) concluded that the -129T
polymorphism may suppress the oxidant-induced response of the GCLC gene,
and that it is implicated in coronary endothelial vasomotor dysfunction
and MI.
*FIELD* RF
1. Beutler, E.; Gelbart, T.; Kondo, T.; Matsunaga, A. T.: The molecular
basis of a case of gamma-glutamylcysteine synthetase deficiency. Blood 94:
2890-2894, 1999.
2. Gipp, J. J.; Chang, C.; Mulcahy, R. T.: Cloning and nucleotide
sequence of a full-length cDNA for human liver gamma-glutamylcysteine
synthetase. Biochem. Biophys. Res. Commun. 185: 29-35, 1992.
3. Gipp, J. J.; Mulcahy, R. T.: Structure of the human glutamate-L-cysteine
ligase catalytic (GLCLC) subunit gene. Cytogenet. Cell Genet. 88:
130-132, 2000.
4. Gysin, R.; Kraftsik, R.; Sandell, J.; Bovet, P.; Chappuis, C.;
Conus, P.; Deppen, P.; Preisig, M.; Ruiz, V.; Steullet, P.; Tosic,
M.; Werge, T.; Cuenod, M.; Do, K. Q.: Impaired glutathione synthesis
in schizophrenia: convergent genetic and functional evidence. Proc.
Nat. Acad. Sci. 104: 16621-16626, 2007.
5. Koide, S.; Kugiyama, K.; Sugiyama, S.; Nakamura, S.; Fukushima,
H.; Honda, O.; Yoshimura, M.; Ogawa, H.: Association of polymorphism
in glutamate-cysteine ligase catalytic subunit gene with coronary
vasomotor dysfunction and myocardial infarction. J. Am. Coll. Cardiol. 41:
539-545, 2003.
6. Sierra-Rivera, E.; Summar, M. L.; Dasouki, M.; Krishnamani, M.
R. S.; Phillips, J. A.; Freeman, M. L.: Assignment of the gene (GLCLC)
that encodes the heavy subunit of gamma-glutamylcysteine synthetase
to human chromosome 6. Cytogenet. Cell Genet. 70: 278-279, 1995.
7. Tsuchiya, K.; Mulcahy, T.; Reid, L. L.; Disteche, C. M.; Kavanagh,
T. J.: Mapping of the glutamate-cysteine ligase catalytic subunit
gene (GLCLC) to human chromosome 6p12 and mouse chromosome 9D-E and
of the regulatory subunit gene (GLCLR) to human chromosome 1p21-p22
and mouse chromosome 3H1-3. Genomics 30: 630-632, 1995.
8. Walsh, A. C.; Li, W.; Rosen, D. R.; Lawrence, D. A.: Genetic mapping
of GLCLC, the human gene encoding the catalytic subunit of gamma-glutamyl-cysteine
synthetase, to chromosome band 6p12 and characterization of a polymorphic
trinucleotide repeat within its 5-prime untranslated region. Cytogenet.
Cell Genet. 75: 14-16, 1996.
*FIELD* CN
Cassandra L. Kniffin - updated: 1/31/2008
*FIELD* CD
Cassandra L. Kniffin: 4/16/2002
*FIELD* ED
carol: 11/02/2011
ckniffin: 4/8/2011
wwang: 2/27/2008
ckniffin: 1/31/2008
tkritzer: 9/9/2004
terry: 6/3/2004
carol: 4/17/2002
ckniffin: 4/17/2002
*RECORD*
*FIELD* NO
606857
*FIELD* TI
*606857 GLUTAMATE-CYSTEINE LIGASE, CATALYTIC SUBUNIT; GCLC
;;GLCLC;;
GAMMA-GLUTAMYLCYSTEINE SYNTHETASE, CATALYTIC SUBUNIT
read more*FIELD* TX
DESCRIPTION
Gamma-glutamylcysteine synthetase, also known as glutamate-cysteine
ligase (EC 6.3.2.2), is the first rate-limiting enzyme in glutathione
(GSH) biosynthesis.
CLONING
Gipp et al. (1992) cloned and sequenced a full-length GCLC cDNA encoding
a 367-amino acid protein with a calculated molecular mass of
approximately 73 kD.
Sierra-Rivera et al. (1995) noted that gamma-glutamylcysteine synthetase
consists of 2 subunits, a heavy catalytic subunit and a light regulatory
subunit (GCLM; 601176).
GENE STRUCTURE
Beutler et al. (1999) determined the partial genomic structure of the
catalytic subunit of GCLC. By comparing cDNA and genomic DNA sequences
with larger sequences from chromosome 6 in the human genome database,
Gipp and Mulcahy (2000) determined that the GCLC gene is larger than
GCLM, spans approximately 51.4 kb, and contains 16 exons.
MAPPING
Sierra-Rivera et al. (1995) mapped the gene that encodes the heavy or
catalytic subunit of the enzyme to human chromosome 6 by Southern
blotting and PCR amplification of gamma-glutamylcysteine synthetase
specific sequences of genomic DNA from a panel of somatic cell hybrids.
In a note added in proof, they stated that by fluorescence in situ
hybridization (FISH), they had localized the gene to 6p12. Using FISH,
Tsuchiya et al. (1995) confirmed the map position of the human gene at
6p12 and mapped the mouse gene to 9D-E. Walsh et al. (1996) described a
trinucleotide repeat polymorphism located in the 5-prime untranslated
region of the GCLC gene and used it to map the GCLC gene to 6p12 by
linkage analysis (1.6 cM distal to D6S295).
MOLECULAR GENETICS
Beutler et al. (1999) identified a his370-to-leu mutation (606857.0001)
in the GCLC gene in a patient with hemolytic anemia due to
gamma-glutamylcysteine synthetase deficiency (230450).
Koide et al. (2003) identified a -129C-T polymorphism in the GCLC gene
(606857.0002) which was associated with impaired dilation of coronary
arteries and occurred at higher frequency in patients with myocardial
infarction (608446).
In studies of cultured fibroblasts from patients with schizophrenia
(181500), Gysin et al. (2007) found 26% decreased GCL activity, and 29%
GCLC protein expression under stressed conditions compared to control
cells. GSH content was not significantly different between the 2 groups.
Two independent studies of 66 Swiss patients and 322 Danish patients
showed an association between schizophrenia and a trinucleotide GAG
repeat polymorphism, with 7, 8 or 9 repeats, located 10 bp upstream from
the start codon. The most common genotype 7/7 was more frequent in
controls, whereas the rarest genotype 8/8 was up to 3 times more
frequent in patients. Patients with disease-associated genotypes,
including 7/8, 8/8, 8/9, and 9/9, had decreased GCL activity, GCLC
protein, and GSH content compared to individuals with the protective
genotypes 7/7 and 7/9. There was no correlation between genotype and
GCLC gene expression at the mRNA level, suggesting that the
trinucleotide repeat polymorphism may affect mRNA transport or
translation.
*FIELD* AV
.0001
GAMMA-GLUTAMYLCYSTEINE SYNTHETASE DEFICIENCY, HEMOLYTIC ANEMIA DUE
TO
GCLC, HIS370LEU
In a 14-year-old offspring of a presumably incestuous half sib mating,
Beutler et al. (1999) described hemolytic anemia due to deficiency of
gamma-glutamylcysteine synthetase (230450). The proband was homozygous
and her mother was heterozygous for an A-to-T transversion at nucleotide
1109 producing a deduced amino acid change of his370-to-leu. The patient
was noted to become jaundiced 2 or 3 times per month. In the newborn
period, exchange transfusion had been required when total bilirubin
increased to 23 mg/dL. The patient was considered to have a learning
disability with dyslexia.
.0002
MYOCARDIAL INFARCTION, SUSCEPTIBILITY TO
GCLC, -129C-T
Koide et al. (2003) identified a -129C-T polymorphism in the GCLC gene
in which the T allele showed lower promoter activity (50 to 60% of the
activity of the C allele) in response to hydrogen peroxide in human
endothelial cells. Endothelium-dependent dilation of coronary arteries
was impaired in patients with the -129T allele compared to age-matched
controls without it. The T allele was significantly more frequent in
patients with myocardial infarction (MI; 608446) compared to controls (p
less than 0.01), and it was a significant risk factor for MI,
independent of traditional coronary risk factors (OR = 1.81, 95% CI =
1.08-3.03, p = 0.03). Koide et al. (2003) concluded that the -129T
polymorphism may suppress the oxidant-induced response of the GCLC gene,
and that it is implicated in coronary endothelial vasomotor dysfunction
and MI.
*FIELD* RF
1. Beutler, E.; Gelbart, T.; Kondo, T.; Matsunaga, A. T.: The molecular
basis of a case of gamma-glutamylcysteine synthetase deficiency. Blood 94:
2890-2894, 1999.
2. Gipp, J. J.; Chang, C.; Mulcahy, R. T.: Cloning and nucleotide
sequence of a full-length cDNA for human liver gamma-glutamylcysteine
synthetase. Biochem. Biophys. Res. Commun. 185: 29-35, 1992.
3. Gipp, J. J.; Mulcahy, R. T.: Structure of the human glutamate-L-cysteine
ligase catalytic (GLCLC) subunit gene. Cytogenet. Cell Genet. 88:
130-132, 2000.
4. Gysin, R.; Kraftsik, R.; Sandell, J.; Bovet, P.; Chappuis, C.;
Conus, P.; Deppen, P.; Preisig, M.; Ruiz, V.; Steullet, P.; Tosic,
M.; Werge, T.; Cuenod, M.; Do, K. Q.: Impaired glutathione synthesis
in schizophrenia: convergent genetic and functional evidence. Proc.
Nat. Acad. Sci. 104: 16621-16626, 2007.
5. Koide, S.; Kugiyama, K.; Sugiyama, S.; Nakamura, S.; Fukushima,
H.; Honda, O.; Yoshimura, M.; Ogawa, H.: Association of polymorphism
in glutamate-cysteine ligase catalytic subunit gene with coronary
vasomotor dysfunction and myocardial infarction. J. Am. Coll. Cardiol. 41:
539-545, 2003.
6. Sierra-Rivera, E.; Summar, M. L.; Dasouki, M.; Krishnamani, M.
R. S.; Phillips, J. A.; Freeman, M. L.: Assignment of the gene (GLCLC)
that encodes the heavy subunit of gamma-glutamylcysteine synthetase
to human chromosome 6. Cytogenet. Cell Genet. 70: 278-279, 1995.
7. Tsuchiya, K.; Mulcahy, T.; Reid, L. L.; Disteche, C. M.; Kavanagh,
T. J.: Mapping of the glutamate-cysteine ligase catalytic subunit
gene (GLCLC) to human chromosome 6p12 and mouse chromosome 9D-E and
of the regulatory subunit gene (GLCLR) to human chromosome 1p21-p22
and mouse chromosome 3H1-3. Genomics 30: 630-632, 1995.
8. Walsh, A. C.; Li, W.; Rosen, D. R.; Lawrence, D. A.: Genetic mapping
of GLCLC, the human gene encoding the catalytic subunit of gamma-glutamyl-cysteine
synthetase, to chromosome band 6p12 and characterization of a polymorphic
trinucleotide repeat within its 5-prime untranslated region. Cytogenet.
Cell Genet. 75: 14-16, 1996.
*FIELD* CN
Cassandra L. Kniffin - updated: 1/31/2008
*FIELD* CD
Cassandra L. Kniffin: 4/16/2002
*FIELD* ED
carol: 11/02/2011
ckniffin: 4/8/2011
wwang: 2/27/2008
ckniffin: 1/31/2008
tkritzer: 9/9/2004
terry: 6/3/2004
carol: 4/17/2002
ckniffin: 4/17/2002