GGT1_MOUSE
ID GGT1_MOUSE Reviewed; 568 AA.
AC Q60928;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 180.
DE RecName: Full=Glutathione hydrolase 1 proenzyme;
DE EC=3.4.19.13 {ECO:0000250|UniProtKB:P19440};
DE AltName: Full=Gamma-glutamyltransferase 1;
DE AltName: Full=Gamma-glutamyltranspeptidase 1;
DE Short=GGT 1;
DE EC=2.3.2.2 {ECO:0000250|UniProtKB:P19440};
DE AltName: Full=Leukotriene-C4 hydrolase;
DE EC=3.4.19.14 {ECO:0000250|UniProtKB:P07314};
DE AltName: CD_antigen=CD224;
DE Contains:
DE RecName: Full=Glutathione hydrolase 1 heavy chain;
DE Contains:
DE RecName: Full=Glutathione hydrolase 1 light chain;
DE Flags: Precursor;
GN Name=Ggt1; Synonyms=Ggt, Ggtp;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=C57BL/6J; TISSUE=Kidney;
RX PubMed=8566783; DOI=10.1016/0378-1119(95)00618-4;
RA Shi Z.Z., Habib G.M., Lebovitz R.M., Lieberman M.W.;
RT "Cloning of cDNA and genomic structure of the mouse gamma-glutamyl
RT transpeptidase-encoding gene.";
RL Gene 167:233-237(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Mammary tumor;
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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP DISRUPTION PHENOTYPE, AND FUNCTION.
RX PubMed=8755578; DOI=10.1073/pnas.93.15.7923;
RA Lieberman M.W., Wiseman A.L., Shi Z.Z., Carter B.Z., Barrios R., Ou C.N.,
RA Chevez-Barrios P., Wang Y., Habib G.M., Goodman J.C., Huang S.L.,
RA Lebovitz R.M., Matzuk M.M.;
RT "Growth retardation and cysteine deficiency in gamma-glutamyl
RT transpeptidase-deficient mice.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:7923-7926(1996).
RN [4]
RP GENE ORGANIZATION, AND ALTERNATIVE PROMOTER USAGE.
RX PubMed=10392451; DOI=10.1016/s0305-0491(99)00013-9;
RA Chikhi N., Holic N., Guellaen G., Laperche Y.;
RT "Gamma-glutamyl transpeptidase gene organization and expression: a
RT comparative analysis in rat, mouse, pig and human species.";
RL Comp. Biochem. Physiol. 122B:367-380(1999).
RN [5]
RP DISEASE.
RX PubMed=9139708; DOI=10.1074/jbc.272.19.12560;
RA Harding C.O., Williams P., Wagner E., Chang D.S., Wild K., Colwell R.E.,
RA Wolff J.A.;
RT "Mice with genetic gamma-glutamyl transpeptidase deficiency exhibit
RT glutathionuria, severe growth failure, reduced life spans, and
RT infertility.";
RL J. Biol. Chem. 272:12560-12567(1997).
RN [6]
RP DISRUPTION PHENOTYPE, AND FUNCTION.
RX PubMed=12810527; DOI=10.1210/en.2002-0071;
RA Levasseur R., Barrios R., Elefteriou F., Glass D.A. II, Lieberman M.W.,
RA Karsenty G.;
RT "Reversible skeletal abnormalities in gamma-glutamyl transpeptidase-
RT deficient mice.";
RL Endocrinology 144:2761-2764(2003).
RN [7]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-114; ASN-229 AND ASN-510.
RX PubMed=19349973; DOI=10.1038/nbt.1532;
RA Wollscheid B., Bausch-Fluck D., Henderson C., O'Brien R., Bibel M.,
RA Schiess R., Aebersold R., Watts J.D.;
RT "Mass-spectrometric identification and relative quantification of N-linked
RT cell surface glycoproteins.";
RL Nat. Biotechnol. 27:378-386(2009).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Kidney, Liver, and Pancreas;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
CC -!- FUNCTION: Cleaves the gamma-glutamyl bond of extracellular glutathione
CC (gamma-Glu-Cys-Gly), glutathione conjugates (such as maresin conjugate
CC (13R)-S-glutathionyl-(14S)-hydroxy-(4Z,7Z,9E,11E,16Z,19Z)-
CC docosahexaenoate, MCTR1) and other gamma-glutamyl compounds (such as
CC leukotriene C4, LTC4). The metabolism of glutathione by GGT1 releases
CC free glutamate and the dipeptide cysteinyl-glycine, which is hydrolyzed
CC to cysteine and glycine by dipeptidases. In the presence of high
CC concentrations of dipeptides and some amino acids, can also catalyze a
CC transpeptidation reaction, transferring the gamma-glutamyl moiety to an
CC acceptor amino acid to form a new gamma-glutamyl compound. Contributes
CC to cysteine homeostasis, glutathione homeostasis and in the conversion
CC of the leukotriene LTC4 to LTD4 (By similarity). Indirectly regulates
CC multiple aspects of skeletal biology (PubMed:12810527).
CC {ECO:0000250|UniProtKB:P19440, ECO:0000269|PubMed:12810527}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an alpha-amino acid + an N-terminal (5-L-glutamyl)-[peptide] =
CC 5-L-glutamyl amino acid + N-terminal L-alpha-aminoacyl-[peptide];
CC Xref=Rhea:RHEA:23904, Rhea:RHEA-COMP:9780, Rhea:RHEA-COMP:9795,
CC ChEBI:CHEBI:77644, ChEBI:CHEBI:78597, ChEBI:CHEBI:78599,
CC ChEBI:CHEBI:78608; EC=2.3.2.2;
CC Evidence={ECO:0000250|UniProtKB:P19440};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:23905;
CC Evidence={ECO:0000250|UniProtKB:P19440};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:23906;
CC Evidence={ECO:0000250|UniProtKB:P07314};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=glutathione + H2O = L-cysteinylglycine + L-glutamate;
CC Xref=Rhea:RHEA:28807, ChEBI:CHEBI:15377, ChEBI:CHEBI:29985,
CC ChEBI:CHEBI:57925, ChEBI:CHEBI:61694; EC=3.4.19.13;
CC Evidence={ECO:0000250|UniProtKB:P19440};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:28808;
CC Evidence={ECO:0000250|UniProtKB:P19440};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an S-substituted glutathione + H2O = an S-substituted L-
CC cysteinylglycine + L-glutamate; Xref=Rhea:RHEA:59468,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:29985, ChEBI:CHEBI:90779,
CC ChEBI:CHEBI:143103; EC=3.4.19.13;
CC Evidence={ECO:0000250|UniProtKB:P19440};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:59469;
CC Evidence={ECO:0000250|UniProtKB:P19440};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + leukotriene C4 = L-glutamate + leukotriene D4;
CC Xref=Rhea:RHEA:31563, ChEBI:CHEBI:15377, ChEBI:CHEBI:29985,
CC ChEBI:CHEBI:57973, ChEBI:CHEBI:63166; EC=3.4.19.14;
CC Evidence={ECO:0000250|UniProtKB:P07314};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:31564;
CC Evidence={ECO:0000250|UniProtKB:P19440};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(13R)-S-glutathionyl-(14S)-hydroxy-(4Z,7Z,9E,11E,16Z,19Z)-
CC docosahexaenoate + H2O = (13R)-S-cysteinylglycyl-(14S)-hydroxy-
CC (4Z,7Z,9E,11E,16Z,19Z)-docosahexaenoate + L-glutamate;
CC Xref=Rhea:RHEA:53512, ChEBI:CHEBI:15377, ChEBI:CHEBI:29985,
CC ChEBI:CHEBI:137407, ChEBI:CHEBI:137408;
CC Evidence={ECO:0000250|UniProtKB:P19440};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53513;
CC Evidence={ECO:0000250|UniProtKB:P19440};
CC -!- ACTIVITY REGULATION: Activated by autocatalytic cleavage.
CC {ECO:0000250|UniProtKB:P19440}.
CC -!- PATHWAY: Sulfur metabolism; glutathione metabolism.
CC {ECO:0000250|UniProtKB:P19440}.
CC -!- PATHWAY: Lipid metabolism; leukotriene D4 biosynthesis.
CC {ECO:0000250|UniProtKB:P19440}.
CC -!- SUBUNIT: Heterodimer composed of the light and heavy chains. The active
CC site is located in the light chain. {ECO:0000250|UniProtKB:P19440}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P19440};
CC Single-pass type II membrane protein {ECO:0000250|UniProtKB:P07314}.
CC -!- PTM: N-glycosylated on both chains. {ECO:0000250|UniProtKB:P19440}.
CC -!- PTM: Cleaved by autocatalysis into a large and a small subunit and the
CC autocatalytic cleavage is essential to the functional activation of the
CC enzyme. {ECO:0000250|UniProtKB:P19440}.
CC -!- DISEASE: Note=Defects in Ggt1 are a cause of glutathionuria, severe
CC growth failure, reduced life spans and infertility. Ggt1-deficient mice
CC have multiple metabolic abnormalities and are dwarf. Some abnormalities
CC can be ameliorated by N-acetylcysteine treatment.
CC {ECO:0000269|PubMed:9139708}.
CC -!- DISRUPTION PHENOTYPE: Deficient mice have growth retardation, skeletal
CC abnormalities. They are sexually immature, develop cataracts, and have
CC coats with a gray cast. Most die between 10 and 18 weeks. They cannot
CC break down GSH into its constituent amino acids as it passes through
CC the proximal tubules of the kidney. They excrete large amounts of GSH
CC in their urine, leading to a fatal cysteine deficiency.
CC {ECO:0000269|PubMed:12810527, ECO:0000269|PubMed:8755578}.
CC -!- SIMILARITY: Belongs to the gamma-glutamyltransferase family.
CC {ECO:0000305}.
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DR EMBL; U30509; AAA97395.1; -; mRNA.
DR EMBL; BC012969; AAH12969.1; -; mRNA.
DR CCDS; CCDS23927.1; -.
DR PIR; JC4570; JC4570.
DR RefSeq; NP_001292921.1; NM_001305992.1.
DR RefSeq; NP_032142.1; NM_008116.3.
DR RefSeq; XP_006513293.1; XM_006513230.3.
DR RefSeq; XP_006513294.1; XM_006513231.3.
DR AlphaFoldDB; Q60928; -.
DR SMR; Q60928; -.
DR STRING; 10090.ENSMUSP00000006508; -.
DR GlyConnect; 2333; 1 N-Linked glycan (1 site).
DR GlyGen; Q60928; 6 sites, 1 N-linked glycan (1 site).
DR iPTMnet; Q60928; -.
DR PhosphoSitePlus; Q60928; -.
DR jPOST; Q60928; -.
DR MaxQB; Q60928; -.
DR PaxDb; Q60928; -.
DR PRIDE; Q60928; -.
DR ProteomicsDB; 266802; -.
DR TopDownProteomics; Q60928; -.
DR DNASU; 14598; -.
DR Ensembl; ENSMUST00000006508; ENSMUSP00000006508; ENSMUSG00000006345.
DR Ensembl; ENSMUST00000134503; ENSMUSP00000121312; ENSMUSG00000006345.
DR GeneID; 14598; -.
DR KEGG; mmu:14598; -.
DR UCSC; uc007fqo.2; mouse.
DR CTD; 2678; -.
DR MGI; MGI:95706; Ggt1.
DR VEuPathDB; HostDB:ENSMUSG00000006345; -.
DR eggNOG; KOG2410; Eukaryota.
DR GeneTree; ENSGT00940000154601; -.
DR HOGENOM; CLU_014813_4_1_1; -.
DR InParanoid; Q60928; -.
DR OMA; KATKNMF; -.
DR OrthoDB; 1419292at2759; -.
DR PhylomeDB; Q60928; -.
DR TreeFam; TF313608; -.
DR Reactome; R-MMU-174403; Glutathione synthesis and recycling.
DR Reactome; R-MMU-2142691; Synthesis of Leukotrienes (LT) and Eoxins (EX).
DR Reactome; R-MMU-5423646; Aflatoxin activation and detoxification.
DR Reactome; R-MMU-9753281; Paracetamol ADME.
DR SABIO-RK; Q60928; -.
DR UniPathway; UPA00204; -.
DR UniPathway; UPA00880; -.
DR BioGRID-ORCS; 14598; 2 hits in 73 CRISPR screens.
DR ChiTaRS; Ggt1; mouse.
DR PRO; PR:Q60928; -.
DR Proteomes; UP000000589; Chromosome 10.
DR RNAct; Q60928; protein.
DR Bgee; ENSMUSG00000006345; Expressed in right kidney and 126 other tissues.
DR ExpressionAtlas; Q60928; baseline and differential.
DR Genevisible; Q60928; MM.
DR GO; GO:0005783; C:endoplasmic reticulum; ISO:MGI.
DR GO; GO:0005615; C:extracellular space; ISO:MGI.
DR GO; GO:0005887; C:integral component of plasma membrane; TAS:MGI.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISO:MGI.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0031982; C:vesicle; IDA:MGI.
DR GO; GO:0016755; F:aminoacyltransferase activity; ISO:MGI.
DR GO; GO:0036374; F:glutathione hydrolase activity; ISS:UniProtKB.
DR GO; GO:0102953; F:hypoglycin A gamma-glutamyl transpeptidase activity; IEA:UniProtKB-EC.
DR GO; GO:0103068; F:leukotriene C4 gamma-glutamyl transferase activity; IEA:UniProtKB-EC.
DR GO; GO:0002951; F:leukotriene-C(4) hydrolase; ISO:MGI.
DR GO; GO:0000048; F:peptidyltransferase activity; ISO:MGI.
DR GO; GO:0007568; P:aging; IEA:Ensembl.
DR GO; GO:0034599; P:cellular response to oxidative stress; IEA:Ensembl.
DR GO; GO:0019344; P:cysteine biosynthetic process; IMP:UniProtKB.
DR GO; GO:0006536; P:glutamate metabolic process; ISS:UniProtKB.
DR GO; GO:0006750; P:glutathione biosynthetic process; IMP:UniProtKB.
DR GO; GO:0006751; P:glutathione catabolic process; ISS:UniProtKB.
DR GO; GO:0006749; P:glutathione metabolic process; TAS:MGI.
DR GO; GO:0061017; P:hepatoblast differentiation; IEA:Ensembl.
DR GO; GO:0070365; P:hepatocyte differentiation; IEA:Ensembl.
DR GO; GO:0097421; P:liver regeneration; IEA:Ensembl.
DR GO; GO:0031179; P:peptide modification; ISO:MGI.
DR GO; GO:0002682; P:regulation of immune system process; IMP:UniProtKB.
DR GO; GO:0050727; P:regulation of inflammatory response; IMP:UniProtKB.
DR GO; GO:0097305; P:response to alcohol; IEA:Ensembl.
DR GO; GO:0032355; P:response to estradiol; IEA:Ensembl.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0034612; P:response to tumor necrosis factor; IEA:Ensembl.
DR GO; GO:0007283; P:spermatogenesis; IMP:MGI.
DR GO; GO:0031638; P:zymogen activation; ISS:UniProtKB.
DR Gene3D; 1.10.246.130; -; 1.
DR Gene3D; 3.60.20.40; -; 1.
DR InterPro; IPR043138; GGT_lsub_C.
DR InterPro; IPR000101; GGT_peptidase.
DR InterPro; IPR043137; GGT_ssub.
DR InterPro; IPR029055; Ntn_hydrolases_N.
DR PANTHER; PTHR11686; PTHR11686; 1.
DR SUPFAM; SSF56235; SSF56235; 1.
DR TIGRFAMs; TIGR00066; g_glut_trans; 1.
DR PROSITE; PS00462; G_GLU_TRANSPEPTIDASE; 1.
PE 1: Evidence at protein level;
KW Acyltransferase; Cell membrane; Disulfide bond; Glutathione biosynthesis;
KW Glycoprotein; Hydrolase; Membrane; Protease; Reference proteome;
KW Signal-anchor; Transferase; Transmembrane; Transmembrane helix; Zymogen.
FT CHAIN 1..379
FT /note="Glutathione hydrolase 1 heavy chain"
FT /id="PRO_0000011060"
FT CHAIN 380..568
FT /note="Glutathione hydrolase 1 light chain"
FT /id="PRO_0000011061"
FT TOPO_DOM 1..4
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P07314"
FT TRANSMEM 5..26
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000250|UniProtKB:P07314"
FT TOPO_DOM 27..568
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:P07314"
FT ACT_SITE 380
FT /note="Nucleophile"
FT /evidence="ECO:0000250|UniProtKB:P19440"
FT BINDING 106
FT /ligand="L-glutamate"
FT /ligand_id="ChEBI:CHEBI:29985"
FT /evidence="ECO:0000250|UniProtKB:P19440"
FT BINDING 398..400
FT /ligand="L-glutamate"
FT /ligand_id="ChEBI:CHEBI:29985"
FT /evidence="ECO:0000250|UniProtKB:P19440"
FT BINDING 419
FT /ligand="L-glutamate"
FT /ligand_id="ChEBI:CHEBI:29985"
FT /evidence="ECO:0000250|UniProtKB:P19440"
FT BINDING 422
FT /ligand="L-glutamate"
FT /ligand_id="ChEBI:CHEBI:29985"
FT /evidence="ECO:0000250|UniProtKB:P19440"
FT BINDING 450..451
FT /ligand="L-glutamate"
FT /ligand_id="ChEBI:CHEBI:29985"
FT /evidence="ECO:0000250|UniProtKB:P19440"
FT BINDING 473
FT /ligand="L-glutamate"
FT /ligand_id="ChEBI:CHEBI:29985"
FT /evidence="ECO:0000250|UniProtKB:P19440"
FT CARBOHYD 94
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 114
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19349973"
FT CARBOHYD 119
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 229
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19349973"
FT CARBOHYD 343
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 510
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19349973"
FT DISULFID 49..73
FT /evidence="ECO:0000250|UniProtKB:P19440"
FT DISULFID 191..195
FT /evidence="ECO:0000250|UniProtKB:P19440"
SQ SEQUENCE 568 AA; 61563 MW; 293C6E224FDC0766 CRC64;
MKNRFLVLGL VAVVLVFVII GLCIWLPYTS GKPDHVYSRA AVATDAKRCS EIGRDILQEG
GSVVDAAIAS LLCMGLMNAH SMGIGGGLFF TIYNSTTGKV EVINAREVAP RLANTTMFNN
SKDSEEGGLS VAVPGEIRGY ELAHQRHGRL PWARLFQPSI QLARHGFPVG KGLAIALDKK
RDVIEKTPAL CEVFCRQGKV LQEGETVTMP KLADTLQILA QEGAKAFYNG SLTAQIVKDI
QEAGGIMTVE DLNNYRAELI EHPMSIGLGD ATLYVPSAPL SGPVLILILN ILKGYNFSPK
SVATPEQKAL TYHRIVEAFR FAYAKRTMLG DPKFVDVSQV IRNMSSEFYA TQLRARITDE
TTHPAAYYEP EFYLQDDGGT AHLSAVSEDG SAVAATSTIN LYFGSKVLSR VSGILFNDEM
DDFSSPNFIN QFRVAPSPAN FIKPGKQPLS SMCPSIILDK DGQVRMVVGA SGGTQITTSV
ALAIINSLWF GYDVKRAVEE PRLHNQLLPN TTTVEKDIDQ VVTAGLKIRH HHTEVTPTFI
AVVQAVVRAS GGWAAASDSR KGGEPAGY
