GGH_MOUSE
ID GGH_MOUSE Reviewed; 317 AA.
AC Q9Z0L8; B1AWC1; Q9Z0L7;
DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 2.
DT 03-AUG-2022, entry version 161.
DE RecName: Full=Gamma-glutamyl hydrolase;
DE EC=3.4.19.9 {ECO:0000250|UniProtKB:Q92820};
DE AltName: Full=Conjugase;
DE AltName: Full=FGPH;
DE AltName: Full=Folylpolyglutamate hydrolase;
DE AltName: Full=GH;
DE AltName: Full=Gamma-Glu-x carboxypeptidase;
DE Flags: Precursor;
GN Name=Ggh;
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], AND ALTERNATIVE SPLICING.
RC STRAIN=129/SvJ, and BALB/cJ; TISSUE=Liver;
RX PubMed=9756990; DOI=10.1016/s0378-1119(98)00384-9;
RA Esaki T., Roy K., Yao R., Galivan J., Sirotnak F.M.;
RT "Cloning of mouse gamma-glutamyl hydrolase in the form of two cDNA variants
RT with different 5' ends and encoding alternate leader peptide sequences.";
RL Gene 219:37-44(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=129/SvJ;
RX PubMed=10393243; DOI=10.1016/s0378-1119(99)00174-2;
RA Esaki T., Masumoto N., Hayes P., Chen J., Sirotnak F.M.;
RT "Organization and structure of the mouse gamma-glutamyl hydrolase gene and
RT the functional identification of its promoter.";
RL Gene 234:93-100(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [4]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-100; ASN-162 AND ASN-188.
RC TISSUE=Epidermis;
RX PubMed=16170054; DOI=10.1074/mcp.m500203-mcp200;
RA Uematsu R., Furukawa J., Nakagawa H., Shinohara Y., Deguchi K., Monde K.,
RA Nishimura S.;
RT "High throughput quantitative glycomics and glycoform-focused proteomics of
RT murine dermis and epidermis.";
RL Mol. Cell. Proteomics 4:1977-1989(2005).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=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: Hydrolyzes the polyglutamate sidechains of
CC pteroylpolyglutamates. Progressively removes gamma-glutamyl residues
CC from pteroylpoly-gamma-glutamate to yield pteroyl-alpha-glutamate
CC (folic acid) and free glutamate. May play an important role in the
CC bioavailability of dietary pteroylpolyglutamates and in the metabolism
CC of pteroylpolyglutamates and antifolates.
CC {ECO:0000250|UniProtKB:Q92820}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(6S)-5,6,7,8-tetrahydrofolyl-(gamma-L-Glu)(n) + (n-1) H2O =
CC (6S)-5,6,7,8-tetrahydrofolate + (n-1) L-glutamate;
CC Xref=Rhea:RHEA:56784, Rhea:RHEA-COMP:14738, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:29985, ChEBI:CHEBI:57453, ChEBI:CHEBI:141005;
CC EC=3.4.19.9; Evidence={ECO:0000250|UniProtKB:Q92820};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:56785;
CC Evidence={ECO:0000250|UniProtKB:Q92820};
CC -!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:Q92820}.
CC -!- SUBCELLULAR LOCATION: Secreted, extracellular space
CC {ECO:0000250|UniProtKB:Q92820}. Lysosome
CC {ECO:0000250|UniProtKB:Q92820}. Melanosome
CC {ECO:0000250|UniProtKB:Q92820}. Note=While its intracellular location
CC is primarily the lysosome, most of the enzyme activity is secreted.
CC Identified by mass spectrometry in melanosome fractions from stage I to
CC stage IV. {ECO:0000250|UniProtKB:Q92820}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=I;
CC IsoId=Q9Z0L8-1; Sequence=Displayed;
CC Name=II;
CC IsoId=Q9Z0L8-2; Sequence=VSP_005447;
CC -!- TISSUE SPECIFICITY: Isoform I (more expressed than isoform II in all
CC tissues) is highly expressed in salivary gland, followed by kidney,
CC liver, lung, stomach and uterus, and weakly expressed in small
CC intestine, brain and fetal liver. Also expressed at a lower level in
CC thymus, spleen and skeletal muscle. Also expressed in tumors.
CC -!- SIMILARITY: Belongs to the peptidase C26 family. {ECO:0000305}.
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DR EMBL; AF051102; AAC70002.1; -; mRNA.
DR EMBL; AF051103; AAC70003.1; -; mRNA.
DR EMBL; AF090732; AAD47388.1; -; Genomic_DNA.
DR EMBL; AF090725; AAD47388.1; JOINED; Genomic_DNA.
DR EMBL; AF090726; AAD47388.1; JOINED; Genomic_DNA.
DR EMBL; AF090727; AAD47388.1; JOINED; Genomic_DNA.
DR EMBL; AF090728; AAD47388.1; JOINED; Genomic_DNA.
DR EMBL; AF090729; AAD47388.1; JOINED; Genomic_DNA.
DR EMBL; AF090730; AAD47388.1; JOINED; Genomic_DNA.
DR EMBL; AF090731; AAD47388.1; JOINED; Genomic_DNA.
DR EMBL; AL732527; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CR931798; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS51126.1; -. [Q9Z0L8-1]
DR RefSeq; NP_034411.2; NM_010281.2. [Q9Z0L8-1]
DR AlphaFoldDB; Q9Z0L8; -.
DR SMR; Q9Z0L8; -.
DR BioGRID; 199908; 3.
DR STRING; 10090.ENSMUSP00000095843; -.
DR MEROPS; C26.001; -.
DR GlyConnect; 2330; 4 N-Linked glycans (2 sites).
DR GlyGen; Q9Z0L8; 5 sites, 4 N-linked glycans (2 sites).
DR iPTMnet; Q9Z0L8; -.
DR PhosphoSitePlus; Q9Z0L8; -.
DR CPTAC; non-CPTAC-3352; -.
DR CPTAC; non-CPTAC-3353; -.
DR MaxQB; Q9Z0L8; -.
DR PaxDb; Q9Z0L8; -.
DR PRIDE; Q9Z0L8; -.
DR ProteomicsDB; 266800; -. [Q9Z0L8-1]
DR ProteomicsDB; 266801; -. [Q9Z0L8-2]
DR Antibodypedia; 4517; 323 antibodies from 30 providers.
DR DNASU; 14590; -.
DR Ensembl; ENSMUST00000098242; ENSMUSP00000095843; ENSMUSG00000073987. [Q9Z0L8-1]
DR GeneID; 14590; -.
DR KEGG; mmu:14590; -.
DR UCSC; uc008sck.1; mouse. [Q9Z0L8-1]
DR CTD; 8836; -.
DR MGI; MGI:1329035; Ggh.
DR VEuPathDB; HostDB:ENSMUSG00000073987; -.
DR eggNOG; KOG1559; Eukaryota.
DR GeneTree; ENSGT00490000043388; -.
DR HOGENOM; CLU_058704_1_1_1; -.
DR InParanoid; Q9Z0L8; -.
DR OMA; APYEWGK; -.
DR OrthoDB; 877490at2759; -.
DR PhylomeDB; Q9Z0L8; -.
DR TreeFam; TF323437; -.
DR Reactome; R-MMU-6798695; Neutrophil degranulation.
DR BioGRID-ORCS; 14590; 1 hit in 74 CRISPR screens.
DR ChiTaRS; Ggh; mouse.
DR PRO; PR:Q9Z0L8; -.
DR Proteomes; UP000000589; Chromosome 4.
DR RNAct; Q9Z0L8; protein.
DR Bgee; ENSMUSG00000073987; Expressed in parotid gland and 248 other tissues.
DR Genevisible; Q9Z0L8; MM.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005615; C:extracellular space; HDA:BHF-UCL.
DR GO; GO:0005764; C:lysosome; TAS:MGI.
DR GO; GO:0042470; C:melanosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005773; C:vacuole; IBA:GO_Central.
DR GO; GO:0034722; F:gamma-glutamyl-peptidase activity; ISS:UniProtKB.
DR GO; GO:0070500; P:poly-gamma-glutamate metabolic process; ISO:MGI.
DR GO; GO:0045471; P:response to ethanol; ISO:MGI.
DR GO; GO:0032868; P:response to insulin; ISO:MGI.
DR GO; GO:0009410; P:response to xenobiotic stimulus; ISO:MGI.
DR GO; GO:0010043; P:response to zinc ion; ISO:MGI.
DR GO; GO:0046900; P:tetrahydrofolylpolyglutamate metabolic process; IBA:GO_Central.
DR Gene3D; 3.40.50.880; -; 1.
DR InterPro; IPR029062; Class_I_gatase-like.
DR InterPro; IPR015527; Pept_C26_g-glut_hydrolase.
DR InterPro; IPR011697; Peptidase_C26.
DR PANTHER; PTHR11315; PTHR11315; 1.
DR Pfam; PF07722; Peptidase_C26; 1.
DR SUPFAM; SSF52317; SSF52317; 1.
DR PROSITE; PS51275; PEPTIDASE_C26_GGH; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Glycoprotein; Hydrolase; Lysosome;
KW Reference proteome; Secreted; Signal.
FT SIGNAL 1..24
FT /evidence="ECO:0000250|UniProtKB:Q62867"
FT CHAIN 25..317
FT /note="Gamma-glutamyl hydrolase"
FT /id="PRO_0000026540"
FT DOMAIN 25..317
FT /note="Gamma-glutamyl hydrolase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00607"
FT ACT_SITE 133
FT /note="Nucleophile"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00607"
FT ACT_SITE 243
FT /note="Proton donor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00607"
FT CARBOHYD 100
FT /note="N-linked (GlcNAc...) (high mannose) asparagine"
FT /evidence="ECO:0000269|PubMed:16170054"
FT CARBOHYD 162
FT /note="N-linked (GlcNAc...) (high mannose) asparagine"
FT /evidence="ECO:0000269|PubMed:16170054"
FT CARBOHYD 188
FT /note="N-linked (GlcNAc...) (high mannose) asparagine"
FT /evidence="ECO:0000269|PubMed:16170054"
FT CARBOHYD 202
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 306
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 1..16
FT /note="MANLGYLLCLLGLLLC -> MVRGWRLLGVLMLS (in isoform II)"
FT /evidence="ECO:0000305"
FT /id="VSP_005447"
FT CONFLICT 125
FT /note="D -> G (in Ref. 1; AAC70002/AAC70003 and 2;
FT AAD47388)"
FT /evidence="ECO:0000305"
FT CONFLICT 170..171
FT /note="SR -> NK (in Ref. 1; AAC70002/AAC70003 and 2;
FT AAD47388)"
FT /evidence="ECO:0000305"
FT CONFLICT 248
FT /note="A -> P (in Ref. 1; AAC70002/AAC70003 and 2;
FT AAD47388)"
FT /evidence="ECO:0000305"
FT CONFLICT 299..300
FT /note="FN -> VY (in Ref. 1; AAC70002/AAC70003 and 2;
FT AAD47388)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 317 AA; 35470 MW; 139F56E1EFE6F801 CRC64;
MANLGYLLCL LGLLLCGLSS PGMSRPYNHG SERPIIGVVM QECFGKMAKL GNYYIAASYV
KYIESAGARV VPIRPDLSDA EYEELFRSIN GVLLPGGGAN LTDSGYSRVA KIFFSKALES
FDNGDHFPVW GTCLGFEELS VLVSGENLLT STDTKSKKLP LNFTEGARKS RMFKHFPTEL
LDSLALENLT ANFHKWSLSV KNFTENEKLK KFFNILTTNT DGKTEFISSM EGFKYPVYAV
QWHPEKAAFE WKNLGGISHA PNAVKTSFYL AEFLVSEARK NSHHFENVVK ETASLIYKFN
PIYTGNISSF QQAYMFD
