GGH_HUMAN
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 03-AUG-2022, entry version 184.
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="http://atlasgeneticsoncology.org/Genes/GGHID44358ch8q12.html";
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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; 248.
DR IntAct; Q92820; 28.
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 GlyGen; Q92820; 4 sites, 31 N-linked glycans (4 sites).
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; Q92820; -.
DR PeptideAtlas; Q92820; -.
DR PRIDE; Q92820; -.
DR ProteomicsDB; 75496; -.
DR Antibodypedia; 4517; 323 antibodies from 30 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 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 Orphanet; 565785; Methotrexate dose selection.
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; APYEWGK; -.
DR OrthoDB; 877490at2759; -.
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; 15 hits in 1083 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 186 other tissues.
DR Genevisible; Q92820; HS.
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 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 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
