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   27-MAR-2024, entry version 170.
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}.
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
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   GlyCosmos; Q9Z0L8; 5 sites, 4 glycans.
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; 10090-ENSMUSP00000095843; -.
DR   ProteomicsDB; 266800; -. [Q9Z0L8-1]
DR   ProteomicsDB; 266801; -. [Q9Z0L8-2]
DR   Pumba; Q9Z0L8; -.
DR   Antibodypedia; 4517; 353 antibodies from 31 providers.
DR   DNASU; 14590; -.
DR   Ensembl; ENSMUST00000098242.4; ENSMUSP00000095843.4; ENSMUSG00000073987.5. [Q9Z0L8-1]
DR   GeneID; 14590; -.
DR   KEGG; mmu:14590; -.
DR   UCSC; uc008sck.1; mouse. [Q9Z0L8-1]
DR   AGR; MGI:1329035; -.
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; QNYTRNA; -.
DR   OrthoDB; 102889at2759; -.
DR   PhylomeDB; Q9Z0L8; -.
DR   TreeFam; TF323437; -.
DR   Reactome; R-MMU-6798695; Neutrophil degranulation.
DR   BioGRID-ORCS; 14590; 1 hit in 79 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 250 other cell types or tissues.
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: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:SF0; GAMMA-GLUTAMYL HYDROLASE; 1.
DR   PANTHER; PTHR11315; PROTEASE FAMILY C26 GAMMA-GLUTAMYL HYDROLASE; 1.
DR   Pfam; PF07722; Peptidase_C26; 1.
DR   SUPFAM; SSF52317; Class I glutamine amidotransferase-like; 1.
DR   PROSITE; PS51275; PEPTIDASE_C26_GGH; 1.
DR   Genevisible; Q9Z0L8; MM.
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
//