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GGH (gamma-glutamyl hydrolase (conjugase, folylpolygammaglutamyl hydrolase)

Identity

Other namesConjugase
GH
FPGH
HGNC (Hugo) GGH
LocusID (NCBI) 8836
Location 8q12.3
Location_base_pair Starts at 63927639 and ends at 63951610 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

 
  Genomic structure of GGH and CpG islands in the GGH promoter region. Two CpG islands in the GGH 5' promoter region extend into intron 1. The CpG1 and CpG2 regions (shaded areas) are indicated relative to the A of the translation start codon defined as nucleotide +1.
Description The GGH gene is 23,749 bp in length, consisting of 9 exons.
Transcription The sequence upstream of exon 1 consists of a promoter-like GC-rich region and a number of putative cis active elements; there is no TATA sequence. There are 2 CpG islands in the region extending from the GGH promoter through the first exon and into intron 1. Methylation of both CpG is associated with significantly reduced GGH mRNA expression.
Pseudogene None identified.

Protein

Description The cDNA encodes a 318-amino acid protein. Catalytically essential residues, Cys-110 and His-220, are located in the center of a large l-shaped cleft that is closed at one end and open at the other. The N-terminal 24 residues are likely a leader sequence that mediates translocation of GGH into the endoplasmic reticulum for secretion.
Expression Wide. Expressions are high in tissues such as liver, kidney, and placenta, and are relatively low in spleen, lung, small intestine, and peripheral blood leukocytes, as determined by Northern blot and RT-PCR analyses.
Localisation Lysosome (primarily intracellular location), secreted, extracellular space, melanosome.
Function GGH catalyzes the removal of gamma-linked polyglutamates, including folylpoly-gamma-glutamates and antifolylpoly-gamma-glutamates, including MTX polyglutamates.
Homology Human GGH encodes a deduced amino acid sequence 67% identical to that of the rat enzyme. While human GGH primarily functioned as an exopeptidase, rat Ggh showed exclusively endopeptidase activity, cleaving the innermost gamma-glutamyl linkage.

Mutations

 
  Structure modeling of wild-type and T127I variant GGH. (A) Comparison of local structure of wild-type GGH (green) versus the T127I variant (orange). The structure of T127I GGH model is superimposed onto that of wild-type GGH. The local backbone structures of open tail end, loop 123-128, 74-79 and beta 9 168-173, are depicted as green (GGH) or orange (T127I) ribbons. The side chain overlapping four residues from Cys124 to Thr127 is also represented in green (GGH) and orange (T127I). (B) The crystal structure of carbamoyl-phosphate synthetase (eCPS) variant H353N (magenta) and glutamine thioester (orange) complex was used to superimpose onto the complex of GGH (green) and MTXPG5 substrate by least-squares fitting of a-carbons of 20 residues around the active site. Docking models: (C) wild-type GGH with MTXPG5; (D) T127I variant with MTXPPG5; (E) wild-type GGH with MTXPG2; (F) T127I variant with MTXPG2. Docking models are shown at the end of the cleft-tail. The arrows indicate protrusions of the region at the surface of residues Cys124 and Leu125.
Germinal GGH SNP 452C -->T (rs11545078) alters the molecular surface conformation at the catalytic cleft-tail, and reduces binding affinity with long-chain MTXPG, but not short-chain MTXPG, in acute lymphoblastic leukemia (ALL) cells. However, the side effects of MTX in inflammatory bowel disease were not associated with GGH SNP 452C -->T, indicating a different genetic regulation between cancer and normal cells in response to MTX treatment. Caucasians (10%) were found to have a significantly higher frequency of 452C -->T variant allele than African-Americans (4.4%) and Japanese (5.6%).
Rheumatoid arthritis patients with homozygous variant allele of GGH -401C -->T had stronger GGH activity.
GGH promoter SNP -124T G (rs11545076) is associated with a stepwise increase in DNA uracil content, might modulate the risk of carcinogenesis.
Somatic GGH promoter SNP -401C -->T (rs3758149) is associated with higher GGH expression and better response to platinum-based neoadjuvant chemotherapy in patients with cervical cancer.

Implicated in

Entity Childhood acute lymphoblastic leukemia (ALL)
Note GGH activity is directly related to GGH mRNA expression in acute lymphoblastic leukemia (ALL) cells in patients with a wildtype germline GGH genotype, and methylation of entire GGH promoter region (seen in leukemia cells from approximately 15% of patients with nonhyperdiploid B-lineage ALL) is associated with significantly reduced GGH mRNA expression and catalytic activity and with significantly higher accumulation of MTX polyglutamates in ALL cells.
Cytogenetics Chromosomal gain can alter the concordance of germline genotype and cancer cell phenotypes. GGH activities in somatic cells were concordant with germline genotypes, whereas activities in leukemia cells were determined by chromosomal number and whether the acquired chromosomes contained a wildtype or variant allele. Leukemia cells that had acquired an additional chromosome containing a wildtype GGH allele had significantly lower accumulation of methotrexate polyglutamates.
 
GGH activity in human leukemia cells is regulated by epigenetic modification, genetic polymorphisms and karyotypic abnormalities, which collectively determine interindividual differences in GGH activity and influence MTXPG accumulation in leukemia cells.
  
Entity Colorectal cancer
Note Low expression of gamma-glutamyl hydrolase (GGH) is strongly associated with CpG island methylator phenotype (CIMP+) in colorectal cancer (CRC), and CIMP+-related clinicopathological and molecular features. Trends for inverse association between GGH expression and the concentration of folate intermediates were also observed. CIMP+ CRC is associated with low expression of GGH, suggesting involvement of the folate pathway in the development and/or progression of this phenotype.
5-fluorouracil (5-FU) plus leucovorin (LV) is a standard chemotherapy regimen for colorectal cancer. Downregulation of GGH by siRNA increased cellular sensitivity to 5-fluoro-2'-deoxyuridine (FdUrd)-combined with leucovorin (LV). These results suggest that FPGS and GGH expression levels in tumors are determinants of the efficacy of LV in enhancing the antitumor activity of 5-fluorouracil (5-FU).
  
Entity Pulmonary neuroendocrine tumors
Note Undetectable GGH protein expression is correlated with good prognosis in patients with pulmonary neuroendocrine tumors.
  

External links

Nomenclature
HGNC (Hugo)GGH   4248
Cards
AtlasGGHID44358ch8q12
Entrez_Gene (NCBI)GGH  8836  gamma-glutamyl hydrolase (conjugase, folylpolygammaglutamyl hydrolase)
GeneCards (Weizmann)GGH
Ensembl (Hinxton)ENSG00000137563 [Gene_View]  chr8:63927639-63951610 [Contig_View]  GGH [Vega]
ICGC DataPortalENSG00000137563
cBioPortalGGH
AceView (NCBI)GGH
Genatlas (Paris)GGH
WikiGenes8836
SOURCE (Princeton)NM_003878
Genomic and cartography
GoldenPath (UCSC)GGH  -  8q12.3   chr8:63927639-63951610 -  8q12.3   [Description]    (hg19-Feb_2009)
EnsemblGGH - 8q12.3 [CytoView]
Mapping of homologs : NCBIGGH [Mapview]
OMIM601509   
Gene and transcription
Genbank (Entrez)AK290450 AK301094 BC025025 JF432643 U55206
RefSeq transcript (Entrez)NM_003878
RefSeq genomic (Entrez)AC_000140 NC_000008 NC_018919 NG_028126 NT_008183 NW_001839132 NW_004929339
Consensus coding sequences : CCDS (NCBI)GGH
Cluster EST : UnigeneHs.78619 [ NCBI ]
CGAP (NCI)Hs.78619
Alternative Splicing : Fast-db (Paris)GSHG0029607
Alternative Splicing GalleryENSG00000137563
Gene ExpressionGGH [ NCBI-GEO ]     GGH [ SEEK ]   GGH [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ92820 (Uniprot)
NextProtQ92820  [Medical]
With graphics : InterProQ92820
Splice isoforms : SwissVarQ92820 (Swissvar)
Catalytic activity : Enzyme3.4.19.9 [ Enzyme-Expasy ]   3.4.19.93.4.19.9 [ IntEnz-EBI ]   3.4.19.9 [ BRENDA ]   3.4.19.9 [ KEGG ]   
Domaine pattern : Prosite (Expaxy)PEPTIDASE_C26_GGH (PS51275)   
Domains : Interpro (EBI)Class_I_gatase-like [organisation]   Pept_C26_g-glut_hydrolase [organisation]   Peptidase_C26 [organisation]  
Related proteins : CluSTrQ92820
Domain families : Pfam (Sanger)Peptidase_C26 (PF07722)   
Domain families : Pfam (NCBI)pfam07722   
DMDM Disease mutations8836
Blocks (Seattle)Q92820
PDB (SRS)1L9X   
PDB (PDBSum)1L9X   
PDB (IMB)1L9X   
PDB (RSDB)1L9X   
Human Protein AtlasENSG00000137563 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasQ92820
HPRD03299
IPIIPI00023728   IPI00984031   
Protein Interaction databases
DIP (DOE-UCLA)Q92820
IntAct (EBI)Q92820
FunCoupENSG00000137563
BioGRIDGGH
InParanoidQ92820
Interologous Interaction database Q92820
IntegromeDBGGH
STRING (EMBL)GGH
Ontologies - Pathways
Ontology : AmiGOextracellular space  nucleus  lysosome  cytosol  proteolysis  proteolysis  proteolysis  glutamine metabolic process  exopeptidase activity  omega peptidase activity  response to zinc ion  response to insulin  gamma-glutamyl-peptidase activity  melanosome  response to drug  response to ethanol  extracellular vesicular exosome  
Ontology : EGO-EBIextracellular space  nucleus  lysosome  cytosol  proteolysis  proteolysis  proteolysis  glutamine metabolic process  exopeptidase activity  omega peptidase activity  response to zinc ion  response to insulin  gamma-glutamyl-peptidase activity  melanosome  response to drug  response to ethanol  extracellular vesicular exosome  
Pathways : KEGGFolate biosynthesis   
Protein Interaction DatabaseGGH
Wikipedia pathwaysGGH
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)GGH
snp3D : Map Gene to Disease8836
SNP (GeneSNP Utah)GGH
SNP : HGBaseGGH
Genetic variants : HAPMAPGGH
Exome VariantGGH
1000_GenomesGGH 
ICGC programENSG00000137563 
Somatic Mutations in Cancer : COSMICGGH 
CONAN: Copy Number AnalysisGGH 
Mutations and Diseases : HGMDGGH
Mutations and Diseases : intOGenGGH
Genomic VariantsGGH  GGH [DGVbeta]
dbVarGGH
ClinVarGGH
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM601509   
MedgenGGH
GENETestsGGH
Disease Genetic AssociationGGH
Huge Navigator GGH [HugePedia]  GGH [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneGGH
Homology/Alignments : Family Browser (UCSC)GGH
Phylogenetic Trees/Animal Genes : TreeFamGGH
Chemical/Protein Interactions : CTD8836
Chemical/Pharm GKB GenePA432
Clinical trialGGH
Cancer Resource (Charite)ENSG00000137563
Other databases
Probes
Litterature
PubMed63 Pubmed reference(s) in Entrez
CoreMineGGH
iHOPGGH
OncoSearchGGH

Bibliography

Human gamma-glutamyl hydrolase: cloning and characterization of the enzyme expressed in vitro.
Yao R, Schneider E, Ryan TJ, Galivan J.
Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10134-8.
PMID 8816764
 
Structural organization of the human gamma-glutamyl hydrolase gene.
Yin D, Chave KJ, Macaluso CR, Galivan J, Yao R.
Gene. 1999 Oct 1;238(2):463-70.
PMID 10570974
 
Three-dimensional structure of human gamma -glutamyl hydrolase. A class I glatamine amidotransferase adapted for a complex substate.
Li H, Ryan TJ, Chave KJ, Van Roey P.
J Biol Chem. 2002 Jul 5;277(27):24522-9. Epub 2002 Apr 12.
PMID 11953431
 
Identification of single nucleotide polymorphisms in the human gamma-glutamyl hydrolase gene and characterization of promoter polymorphisms.
Chave KJ, Ryan TJ, Chmura SE, Galivan J.
Gene. 2003 Nov 13;319:167-75.
PMID 14597182
 
Characterization of the human gamma-glutamyl hydrolase promoter and its gene expression in human tissues and cancer cell lines.
Yin D, Galivan J, Ao W, Yao R.
Gene. 2003 Jul 17;312:281-8.
PMID 12909365
 
A substrate specific functional polymorphism of human gamma-glutamyl hydrolase alters catalytic activity and methotrexate polyglutamate accumulation in acute lymphoblastic leukaemia cells.
Cheng Q, Wu B, Kager L, Panetta JC, Zheng J, Pui CH, Relling MV, Evans WE.
Pharmacogenetics. 2004 Aug;14(8):557-67.
PMID 15284538
 
Contribution of common polymorphisms in reduced folate carrier and gamma-glutamylhydrolase to methotrexate polyglutamate levels in patients with rheumatoid arthritis.
Dervieux T, Kremer J, Lein DO, Capps R, Barham R, Meyer G, Smith K, Caldwell J, Furst DE.
Pharmacogenetics. 2004 Nov;14(11):733-9.
PMID 15564880
 
Identification of carboxypeptidase E and gamma-glutamyl hydrolase as biomarkers for pulmonary neuroendocrine tumors by cDNA microarray.
He P, Varticovski L, Bowman ED, Fukuoka J, Welsh JA, Miura K, Jen J, Gabrielson E, Brambilla E, Travis WD, Harris CC.
Hum Pathol. 2004 Oct;35(10):1196-209.
PMID 15492986
 
Karyotypic abnormalities create discordance of germline genotype and cancer cell phenotypes.
Cheng Q, Yang W, Raimondi SC, Pui CH, Relling MV, Evans WE.
Nat Genet. 2005 Aug;37(8):878-82. Epub 2005 Jul 24.
PMID 16041371
 
Epigenetic regulation of human gamma-glutamyl hydrolase activity in acute lymphoblastic leukemia cells.
Cheng Q, Cheng C, Crews KR, Ribeiro RC, Pui CH, Relling MV, Evans WE.
Am J Hum Genet. 2006 Aug;79(2):264-74. Epub 2006 Jun 6.
PMID 16826517
 
Genetic polymorphism of C452T (T127I) in human gamma-glutamyl hydrolase in a Japanese population.
Hayashi H, Fujimaki C, Inoue K, Suzuki T, Itoh K.
Biol Pharm Bull. 2007 Apr;30(4):839-41.
PMID 17409534
 
Associations between single nucleotide polymorphisms in folate uptake and metabolizing genes with blood folate, homocysteine, and DNA uracil concentrations.
DeVos L, Chanson A, Liu Z, Ciappio ED, Parnell LD, Mason JB, Tucker KL, Crott JW.
Am J Clin Nutr. 2008 Oct;88(4):1149-58.
PMID 18842806
 
Low expression of gamma-glutamyl hydrolase mRNA in primary colorectal cancer with the CpG island methylator phenotype.
Kawakami K, Ooyama A, Ruszkiewicz A, Jin M, Watanabe G, Moore J, Oka T, Iacopetta B, Minamoto T.
Br J Cancer. 2008 May 6;98(9):1555-61. Epub 2008 Apr 15.
PMID 18414409
 
XRCC1 Arginine194Tryptophan and GGH-401Cytosine/Thymine polymorphisms are associated with response to platinum-based neoadjuvant chemotherapy in cervical cancer.
Kim K, Kang SB, Chung HH, Kim JW, Park NH, Song YS.
Gynecol Oncol. 2008 Dec;111(3):509-15. Epub 2008 Oct 12.
PMID 18851872
 
Folylpolyglutamate synthase and gamma-glutamyl hydrolase regulate leucovorin-enhanced 5-fluorouracil anticancer activity.
Sakamoto E, Tsukioka S, Oie S, Kobunai T, Tsujimoto H, Sakamoto K, Okayama Y, Sugimoto Y, Oka T, Fukushima M, Oka T.
Biochem Biophys Res Commun. 2008 Jan 25;365(4):801-7. Epub 2007 Nov 21.
PMID 18035049
 
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Contributor(s)

Written12-2008Qing Cheng, William E Evans
Duke Institute for Genome Sciences & Policy, Duke University Medical Center, Durham, North Carolina 27710, USA (QC); St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105,USA (WEE)

Citation

This paper should be referenced as such :
Cheng, Q ; Evans, WE
GGH (gamma-glutamyl hydrolase (conjugase, folylpolygammaglutamyl hydrolase)
Atlas Genet Cytogenet Oncol Haematol. 2009;13(11):841-844.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/GGHID44358ch8q12.html

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indexed on : Tue Aug 26 15:27:13 CEST 2014

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