ID   GGH_HUMAN               Reviewed;         318 AA.
AC   Q92820;
DT   15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT   01-AUG-1998, sequence version 2.
DT   27-MAR-2024, entry version 193.
DE   RecName: Full=Gamma-glutamyl hydrolase {ECO:0000305};
DE            EC=3.4.19.9 {ECO:0000269|PubMed:11005824, ECO:0000269|PubMed:8816764};
DE   AltName: Full=Conjugase;
DE   AltName: Full=GH;
DE   AltName: Full=Gamma-Glu-X carboxypeptidase;
DE   Flags: Precursor;
GN   Name=GGH {ECO:0000312|HGNC:HGNC:4248};
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND CATALYTIC ACTIVITY.
RX   PubMed=8816764; DOI=10.1073/pnas.93.19.10134;
RA   Yao R., Schneider E., Ryan T.J., Galivan J.;
RT   "Human gamma-glutamyl hydrolase: cloning and characterization of the enzyme
RT   expressed in vitro.";
RL   Proc. Natl. Acad. Sci. U.S.A. 93:10134-10138(1996).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=10570974; DOI=10.1016/s0378-1119(99)00362-5;
RA   Yin D., Chave K.J., Macaluso C.R., Galivan J., Yao R.;
RT   "Structural organization of the human gamma-glutamyl hydrolase gene.";
RL   Gene 238:463-470(1999).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Skin;
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   [4]
RP   MUTAGENESIS OF CYS-134.
RX   PubMed=10527932; DOI=10.1042/bj3430551;
RA   Chave K.J., Galivan J., Ryan T.J.;
RT   "Site-directed mutagenesis establishes cysteine-110 as essential for enzyme
RT   activity in human gamma-glutamyl hydrolase.";
RL   Biochem. J. 343:551-555(1999).
RN   [5]
RP   FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, MUTAGENESIS OF
RP   CYS-134; HIS-244 AND GLU-246, AND 3D-STRUCTURE MODELING.
RX   PubMed=11005824; DOI=10.1074/jbc.m007908200;
RA   Chave K.J., Auger I.E., Galivan J., Ryan T.J.;
RT   "Molecular modeling and site-directed mutagenesis define the catalytic
RT   motif in human gamma -glutamyl hydrolase.";
RL   J. Biol. Chem. 275:40365-40370(2000).
RN   [6]
RP   SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS].
RC   TISSUE=Melanoma;
RX   PubMed=12643545; DOI=10.1021/pr025562r;
RA   Basrur V., Yang F., Kushimoto T., Higashimoto Y., Yasumoto K., Valencia J.,
RA   Muller J., Vieira W.D., Watabe H., Shabanowitz J., Hearing V.J., Hunt D.F.,
RA   Appella E.;
RT   "Proteomic analysis of early melanosomes: identification of novel
RT   melanosomal proteins.";
RL   J. Proteome Res. 2:69-79(2003).
RN   [7]
RP   SUBUNIT.
RX   PubMed=16945597; DOI=10.1016/j.bbapap.2006.06.008;
RA   Eisele L.E., Chave K.J., Lehning A.C., Ryan T.J.;
RT   "Characterization of human gamma-glutamyl hydrolase in solution
RT   demonstrates that the enzyme is a non-dissociating homodimer.";
RL   Biochim. Biophys. Acta 1764:1479-1486(2006).
RN   [8]
RP   SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS].
RC   TISSUE=Melanoma;
RX   PubMed=17081065; DOI=10.1021/pr060363j;
RA   Chi A., Valencia J.C., Hu Z.-Z., Watabe H., Yamaguchi H., Mangini N.J.,
RA   Huang H., Canfield V.A., Cheng K.C., Yang F., Abe R., Yamagishi S.,
RA   Shabanowitz J., Hearing V.J., Wu C., Appella E., Hunt D.F.;
RT   "Proteomic and bioinformatic characterization of the biogenesis and
RT   function of melanosomes.";
RL   J. Proteome Res. 5:3135-3144(2006).
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., Buerckstuemmer T.,
RA   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   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA   Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA   Ye M., Zou H.;
RT   "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT   phosphoproteome.";
RL   J. Proteomics 96:253-262(2014).
RN   [11]
RP   X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) OF 25-318, IDENTIFICATION BY MASS
RP   SPECTROMETRY, GLYCOSYLATION AT ASN-163; ASN-203 AND ASN-307, AND SUBUNIT.
RX   PubMed=11953431; DOI=10.1074/jbc.m202020200;
RA   Li H., Ryan T.J., Chave K.J., Van Roey P.;
RT   "Three-dimensional structure of human gamma -glutamyl hydrolase. A class I
RT   glutamine amidotransferase adapted for a complex substate.";
RL   J. Biol. Chem. 277:24522-24529(2002).
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 (PubMed:11005824, PubMed:8816764). May
CC       play an important role in the bioavailability of dietary
CC       pteroylpolyglutamates and in the metabolism of pteroylpolyglutamates
CC       and antifolates. {ECO:0000269|PubMed:11005824,
CC       ECO:0000269|PubMed:8816764}.
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:0000269|PubMed:11005824};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:56785;
CC         Evidence={ECO:0000305|PubMed:11005824};
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=29.45 uM for of tetrahydrofolate-Glu2
CC         {ECO:0000269|PubMed:11005824};
CC   -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:11953431,
CC       ECO:0000269|PubMed:16945597}.
CC   -!- INTERACTION:
CC       Q92820; Q96EQ0: SGTB; NbExp=3; IntAct=EBI-3045534, EBI-744081;
CC   -!- SUBCELLULAR LOCATION: Secreted, extracellular space {ECO:0000305}.
CC       Lysosome {ECO:0000269|PubMed:12643545}. Melanosome
CC       {ECO:0000269|PubMed:12643545}. Note=While its intracellular location is
CC       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:0000269|PubMed:12643545}.
CC   -!- SIMILARITY: Belongs to the peptidase C26 family. {ECO:0000305}.
CC   -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC       Haematology;
CC       URL="https://atlasgeneticsoncology.org/gene/44358/GGH";
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DR   EMBL; U55206; AAC05579.1; -; mRNA.
DR   EMBL; AF147083; AAF03360.1; -; Genomic_DNA.
DR   EMBL; AF147081; AAF03360.1; JOINED; Genomic_DNA.
DR   EMBL; AF147082; AAF03360.1; JOINED; Genomic_DNA.
DR   EMBL; BC025025; AAH25025.1; -; mRNA.
DR   CCDS; CCDS6177.1; -.
DR   PIR; JC6115; JC6115.
DR   RefSeq; NP_003869.1; NM_003878.2.
DR   PDB; 1L9X; X-ray; 1.60 A; A/B/C/D=25-318.
DR   PDBsum; 1L9X; -.
DR   AlphaFoldDB; Q92820; -.
DR   SMR; Q92820; -.
DR   BioGRID; 114363; 266.
DR   IntAct; Q92820; 34.
DR   MINT; Q92820; -.
DR   STRING; 9606.ENSP00000260118; -.
DR   BindingDB; Q92820; -.
DR   ChEMBL; CHEMBL2223; -.
DR   DrugBank; DB00158; Folic acid.
DR   DrugBank; DB00563; Methotrexate.
DR   MEROPS; C26.001; -.
DR   GlyConnect; 1257; 26 N-Linked glycans (4 sites).
DR   GlyCosmos; Q92820; 4 sites, 27 glycans.
DR   GlyGen; Q92820; 5 sites, 34 N-linked glycans (4 sites), 1 O-linked glycan (1 site).
DR   iPTMnet; Q92820; -.
DR   PhosphoSitePlus; Q92820; -.
DR   SwissPalm; Q92820; -.
DR   BioMuta; GGH; -.
DR   DMDM; 6016127; -.
DR   EPD; Q92820; -.
DR   jPOST; Q92820; -.
DR   MassIVE; Q92820; -.
DR   MaxQB; Q92820; -.
DR   PaxDb; 9606-ENSP00000260118; -.
DR   PeptideAtlas; Q92820; -.
DR   PRIDE; Q92820; -.
DR   ProteomicsDB; 75496; -.
DR   Pumba; Q92820; -.
DR   Antibodypedia; 4517; 353 antibodies from 31 providers.
DR   DNASU; 8836; -.
DR   Ensembl; ENST00000260118.7; ENSP00000260118.6; ENSG00000137563.13.
DR   GeneID; 8836; -.
DR   KEGG; hsa:8836; -.
DR   MANE-Select; ENST00000260118.7; ENSP00000260118.6; NM_003878.3; NP_003869.1.
DR   UCSC; uc003xuw.4; human.
DR   AGR; HGNC:4248; -.
DR   CTD; 8836; -.
DR   DisGeNET; 8836; -.
DR   GeneCards; GGH; -.
DR   HGNC; HGNC:4248; GGH.
DR   HPA; ENSG00000137563; Tissue enhanced (kidney, liver).
DR   MIM; 601509; gene.
DR   neXtProt; NX_Q92820; -.
DR   OpenTargets; ENSG00000137563; -.
DR   PharmGKB; PA432; -.
DR   VEuPathDB; HostDB:ENSG00000137563; -.
DR   eggNOG; KOG1559; Eukaryota.
DR   GeneTree; ENSGT00490000043388; -.
DR   HOGENOM; CLU_058704_1_1_1; -.
DR   InParanoid; Q92820; -.
DR   OMA; PVTANFH; -.
DR   OrthoDB; 102889at2759; -.
DR   PhylomeDB; Q92820; -.
DR   TreeFam; TF323437; -.
DR   BRENDA; 3.4.19.9; 2681.
DR   PathwayCommons; Q92820; -.
DR   Reactome; R-HSA-6798695; Neutrophil degranulation.
DR   SignaLink; Q92820; -.
DR   SIGNOR; Q92820; -.
DR   BioGRID-ORCS; 8836; 16 hits in 1163 CRISPR screens.
DR   ChiTaRS; GGH; human.
DR   EvolutionaryTrace; Q92820; -.
DR   GeneWiki; GGH_(gene); -.
DR   GenomeRNAi; 8836; -.
DR   Pharos; Q92820; Tchem.
DR   PRO; PR:Q92820; -.
DR   Proteomes; UP000005640; Chromosome 8.
DR   RNAct; Q92820; Protein.
DR   Bgee; ENSG00000137563; Expressed in rectum and 188 other cell types or tissues.
DR   GO; GO:0035578; C:azurophil granule lumen; TAS:Reactome.
DR   GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR   GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR   GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR   GO; GO:0042470; C:melanosome; IEA:UniProtKB-SubCell.
DR   GO; GO:0005634; C:nucleus; HDA:UniProtKB.
DR   GO; GO:0035580; C:specific granule lumen; TAS:Reactome.
DR   GO; GO:1904724; C:tertiary granule lumen; TAS:Reactome.
DR   GO; GO:0005773; C:vacuole; IBA:GO_Central.
DR   GO; GO:0008238; F:exopeptidase activity; TAS:ProtInc.
DR   GO; GO:0034722; F:gamma-glutamyl-peptidase activity; IDA:UniProtKB.
DR   GO; GO:0008242; F:omega peptidase activity; TAS:ProtInc.
DR   GO; GO:0046900; P:tetrahydrofolylpolyglutamate metabolic process; IBA:GO_Central.
DR   CDD; cd01747; GATase1_Glutamyl_Hydrolase; 1.
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; Q92820; HS.
PE   1: Evidence at protein level;
KW   3D-structure; Glycoprotein; Hydrolase; Lysosome; Reference proteome;
KW   Secreted; Signal.
FT   SIGNAL          1..24
FT                   /evidence="ECO:0000250|UniProtKB:Q62867"
FT   CHAIN           25..318
FT                   /note="Gamma-glutamyl hydrolase"
FT                   /id="PRO_0000026539"
FT   DOMAIN          25..318
FT                   /note="Gamma-glutamyl hydrolase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00607"
FT   ACT_SITE        134
FT                   /note="Nucleophile"
FT   ACT_SITE        244
FT                   /note="Proton donor"
FT   CARBOHYD        116
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        163
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000269|PubMed:11953431"
FT   CARBOHYD        203
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000269|PubMed:11953431"
FT   CARBOHYD        307
FT                   /note="N-linked (GlcNAc...) asparagine; partial"
FT                   /evidence="ECO:0000269|PubMed:11953431"
FT   VARIANT         6
FT                   /note="C -> R (in dbSNP:rs1800909)"
FT                   /id="VAR_014697"
FT   VARIANT         31
FT                   /note="A -> T (in dbSNP:rs11545077)"
FT                   /id="VAR_029230"
FT   VARIANT         151
FT                   /note="T -> I (in dbSNP:rs11545078)"
FT                   /id="VAR_029231"
FT   MUTAGEN         134
FT                   /note="C->A: Loss of activity."
FT                   /evidence="ECO:0000269|PubMed:10527932,
FT                   ECO:0000269|PubMed:11005824"
FT   MUTAGEN         195
FT                   /note="H->N: Reduces activity 250-fold."
FT   MUTAGEN         244
FT                   /note="H->A: Loss of activity."
FT                   /evidence="ECO:0000269|PubMed:11005824"
FT   MUTAGEN         246
FT                   /note="E->A: Slightly reduced catalytic activity."
FT                   /evidence="ECO:0000269|PubMed:11005824"
FT   STRAND          35..39
FT                   /evidence="ECO:0007829|PDB:1L9X"
FT   HELIX           46..49
FT                   /evidence="ECO:0007829|PDB:1L9X"
FT   STRAND          53..57
FT                   /evidence="ECO:0007829|PDB:1L9X"
FT   HELIX           58..66
FT                   /evidence="ECO:0007829|PDB:1L9X"
FT   STRAND          70..74
FT                   /evidence="ECO:0007829|PDB:1L9X"
FT   HELIX           80..89
FT                   /evidence="ECO:0007829|PDB:1L9X"
FT   STRAND          90..95
FT                   /evidence="ECO:0007829|PDB:1L9X"
FT   TURN            102..104
FT                   /evidence="ECO:0007829|PDB:1L9X"
FT   HELIX           106..123
FT                   /evidence="ECO:0007829|PDB:1L9X"
FT   STRAND          130..133
FT                   /evidence="ECO:0007829|PDB:1L9X"
FT   HELIX           135..145
FT                   /evidence="ECO:0007829|PDB:1L9X"
FT   STRAND          151..160
FT                   /evidence="ECO:0007829|PDB:1L9X"
FT   TURN            167..170
FT                   /evidence="ECO:0007829|PDB:1L9X"
FT   TURN            173..176
FT                   /evidence="ECO:0007829|PDB:1L9X"
FT   HELIX           179..187
FT                   /evidence="ECO:0007829|PDB:1L9X"
FT   STRAND          191..198
FT                   /evidence="ECO:0007829|PDB:1L9X"
FT   HELIX           201..205
FT                   /evidence="ECO:0007829|PDB:1L9X"
FT   HELIX           208..213
FT                   /evidence="ECO:0007829|PDB:1L9X"
FT   STRAND          214..224
FT                   /evidence="ECO:0007829|PDB:1L9X"
FT   STRAND          226..236
FT                   /evidence="ECO:0007829|PDB:1L9X"
FT   STRAND          238..243
FT                   /evidence="ECO:0007829|PDB:1L9X"
FT   HELIX           247..250
FT                   /evidence="ECO:0007829|PDB:1L9X"
FT   HELIX           262..279
FT                   /evidence="ECO:0007829|PDB:1L9X"
FT   HELIX           289..295
FT                   /evidence="ECO:0007829|PDB:1L9X"
FT   HELIX           297..299
FT                   /evidence="ECO:0007829|PDB:1L9X"
FT   TURN            306..308
FT                   /evidence="ECO:0007829|PDB:1L9X"
FT   STRAND          312..317
FT                   /evidence="ECO:0007829|PDB:1L9X"
SQ   SEQUENCE   318 AA;  35964 MW;  C4069953573B9B24 CRC64;
     MASPGCLLCV LGLLLCGAAS LELSRPHGDT AKKPIIGILM QKCRNKVMKN YGRYYIAASY
     VKYLESAGAR VVPVRLDLTE KDYEILFKSI NGILFPGGSV DLRRSDYAKV AKIFYNLSIQ
     SFDDGDYFPV WGTCLGFEEL SLLISGECLL TATDTVDVAM PLNFTGGQLH SRMFQNFPTE
     LLLSLAVEPL TANFHKWSLS VKNFTMNEKL KKFFNVLTTN TDGKIEFIST MEGYKYPVYG
     VQWHPEKAPY EWKNLDGISH APNAVKTAFY LAEFFVNEAR KNNHHFKSES EEEKALIYQF
     SPIYTGNISS FQQCYIFD
//