Q92820 (GGH_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Gamma-glutamyl hydrolase
EC=3.4.19.9

Alternative name(s):
Conjugase
GH
Gamma-Glu-X carboxypeptidase

Gene names

Name:

GGH

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	318 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Hydrolyzes the polyglutamate sidechains of pteroylpolyglutamates. Progressively removes gamma-glutamyl residues from pteroylpoly-gamma-glutamate to yield pteroyl-alpha-glutamate (folic acid) and free glutamate. May play an important role in the bioavailability of dietary pteroylpolyglutamates and in the metabolism of pteroylpolyglutamates and antifolates.
Catalytic activity	Hydrolysis of a gamma-glutamyl bond.
Subunit structure	Homodimer. Ref.7 Ref.10
Subcellular location	Secreted › extracellular space. Lysosome. Melanosome. Note: While its intracellular location is primarily the lysosome, most of the enzyme activity is secreted. Identified by mass spectrometry in melanosome fractions from stage I to stage IV. Ref.6 Ref.8
Sequence similarities	Belongs to the peptidase C26 family. Contains 1 gamma-glutamyl hydrolase domain.

Ontologies

Keywords
Cellular component	Lysosome Secreted
Coding sequence diversity	Polymorphism
Domain	Signal
Molecular function	Hydrolase
PTM	Glycoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	glutamine metabolic process Inferred from electronic annotation. Source: InterPro response to drug Inferred from electronic annotation. Source: Compara response to ethanol Inferred from electronic annotation. Source: Compara response to insulin stimulus Inferred from electronic annotation. Source: Compara response to zinc ion Inferred from electronic annotation. Source: Compara
Cellular_component	cytosol Inferred from electronic annotation. Source: Compara extracellular space Inferred from electronic annotation. Source: UniProtKB-SubCell lysosome Inferred from electronic annotation. Source: UniProtKB-SubCell melanosome Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	gamma-glutamyl-peptidase activity Inferred from direct assay Ref.5. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 24

24

By similarity

Chain

25 – 318

294

Gamma-glutamyl hydrolase

PRO_0000026539

Regions

Domain

25 – 318

294

Gamma-glutamyl hydrolase

Sites

Active site

134

1

Nucleophile

Active site

244

1

Proton donor

Amino acid modifications

Glycosylation

116

1

N-linked (GlcNAc...) Potential

Glycosylation

163

1

N-linked (GlcNAc...) Ref.10

Glycosylation

203

1

N-linked (GlcNAc...) Ref.10

Glycosylation

307

1

N-linked (GlcNAc...); partial Ref.10

Natural variations

Natural variant

6

1

C → R.
Corresponds to variant rs1800909 [ dbSNP | Ensembl ].

VAR_014697

Natural variant

31

1

A → T.
Corresponds to variant rs11545077 [ dbSNP | Ensembl ].

VAR_029230

Natural variant

151

1

T → I.
Corresponds to variant rs11545078 [ dbSNP | Ensembl ].

VAR_029231

Experimental info

Mutagenesis

134

1

C → A: Loss of activity. Ref.4 Ref.5

Mutagenesis

195

1

H → N: Reduces activity 250-fold.

Mutagenesis

244

1

H → A: Loss of activity. Ref.5

Mutagenesis

246

1

E → A: Slightly reduced catalytic activity. Ref.5

Secondary structure

1

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318

Helix Strand Turn

Details...

Beta strand

35 – 39

5

Helix

46 – 49

4

Beta strand

53 – 57

5

Helix

58 – 66

9

Beta strand

70 – 74

5

Helix

80 – 89

10

Beta strand

90 – 95

6

Turn

102 – 104

3

Helix

106 – 123

18

Beta strand

130 – 133

4

Helix

135 – 145

11

Beta strand

151 – 160

10

Turn

167 – 170

4

Turn

173 – 176

4

Helix

179 – 187

9

Beta strand

191 – 198

8

Helix

201 – 205

5

Helix

208 – 213

6

Beta strand

214 – 224

11

Beta strand

226 – 236

11

Beta strand

238 – 243

6

Helix

247 – 250

4

Helix

262 – 279

18

Helix

289 – 295

7

Helix

297 – 299

3

Turn

306 – 308

3

Beta strand

312 – 317

6

Sequences

	Sequence		Length	Mass (Da)
	Q92820 [UniParc]. Last modified August 1, 1998. Version 2. Checksum: C4069953573B9B24	FASTA	318	35,964
	10 20 30 40 50 60 MASPGCLLCV LGLLLCGAAS LELSRPHGDT AKKPIIGILM QKCRNKVMKN YGRYYIAASY 70 80 90 100 110 120 VKYLESAGAR VVPVRLDLTE KDYEILFKSI NGILFPGGSV DLRRSDYAKV AKIFYNLSIQ 130 140 150 160 170 180 SFDDGDYFPV WGTCLGFEEL SLLISGECLL TATDTVDVAM PLNFTGGQLH SRMFQNFPTE 190 200 210 220 230 240 LLLSLAVEPL TANFHKWSLS VKNFTMNEKL KKFFNVLTTN TDGKIEFIST MEGYKYPVYG 250 260 270 280 290 300 VQWHPEKAPY EWKNLDGISH APNAVKTAFY LAEFFVNEAR KNNHHFKSES EEEKALIYQF 310 SPIYTGNISS FQQCYIFD

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Human gamma-glutamyl hydrolase: cloning and characterization of the enzyme expressed in vitro." Yao R., Schneider E., Ryan T.J., Galivan J. Proc. Natl. Acad. Sci. U.S.A. 93:10134-10138(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Structural organization of the human gamma-glutamyl hydrolase gene." Yin D., Chave K.J., Macaluso C.R., Galivan J., Yao R. Gene 238:463-470(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Skin.
[4]	"Site-directed mutagenesis establishes cysteine-110 as essential for enzyme activity in human gamma-glutamyl hydrolase." Chave K.J., Galivan J., Ryan T.J. Biochem. J. 343:551-555(1999) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF CYS-134.
[5]	"Molecular modeling and site-directed mutagenesis define the catalytic motif in human gamma -glutamyl hydrolase." Chave K.J., Auger I.E., Galivan J., Ryan T.J. J. Biol. Chem. 275:40365-40370(2000) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF CYS-134; HIS-244 AND GLU-246, 3D-STRUCTURE MODELING.
[6]	"Proteomic analysis of early melanosomes: identification of novel melanosomal proteins." Basrur V., Yang F., Kushimoto T., Higashimoto Y., Yasumoto K., Valencia J., Muller J., Vieira W.D., Watabe H., Shabanowitz J., Hearing V.J., Hunt D.F., Appella E. J. Proteome Res. 2:69-79(2003) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY. Tissue: Melanoma.
[7]	"Characterization of human gamma-glutamyl hydrolase in solution demonstrates that the enzyme is a non-dissociating homodimer." Eisele L.E., Chave K.J., Lehning A.C., Ryan T.J. Biochim. Biophys. Acta 1764:1479-1486(2006) [PubMed] [Europe PMC] [Abstract] Cited for: SUBUNIT.
[8]	"Proteomic and bioinformatic characterization of the biogenesis and function of melanosomes." Chi A., Valencia J.C., Hu Z.-Z., Watabe H., Yamaguchi H., Mangini N.J., Huang H., Canfield V.A., Cheng K.C., Yang F., Abe R., Yamagishi S., Shabanowitz J., Hearing V.J., Wu C., Appella E., Hunt D.F. J. Proteome Res. 5:3135-3144(2006) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY. Tissue: Melanoma.
[9]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[10]	"Three-dimensional structure of human gamma -glutamyl hydrolase. A class I glutamine amidotransferase adapted for a complex substate." Li H., Ryan T.J., Chave K.J., Van Roey P. J. Biol. Chem. 277:24522-24529(2002) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) OF 25-318, MASS SPECTROMETRY, GLYCOSYLATION AT ASN-163; ASN-203 AND ASN-307, SUBUNIT.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U55206 mRNA. Translation: AAC05579.1.
AF147083, AF147081, AF147082 Genomic DNA. Translation: AAF03360.1.
BC025025 mRNA. Translation: AAH25025.1.

IPI

IPI00023728.

PIR

JC6115.

RefSeq

NP_003869.1. NM_003878.2.

UniGene

Hs.78619.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1L9X	X-ray	1.60	A/B/C/D	25-318	[»]

ProteinModelPortal

Q92820.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q92820. 2 interactions.

STRING

9606.ENSP00000260118.

Protein family/group databases

MEROPS

C26.001.

PTM databases

PhosphoSite

Q92820.

Polymorphism databases

DMDM

6016127.

Proteomic databases

PaxDb

Q92820.

PeptideAtlas

Q92820.

PRIDE

Q92820.

Protocols and materials databases

DNASU

8836.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000260118; ENSP00000260118; ENSG00000137563.

GeneID

8836.

KEGG

hsa:8836.

UCSC

uc003xuw.3. human.

Organism-specific databases

CTD

8836.

GeneCards

GC08M063977.

HGNC

HGNC:4248. GGH.

HPA

CAB019296.
HPA025226.

MIM

601509. gene.

neXtProt

NX_Q92820.

PharmGKB

PA432.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG251450.

HOGENOM

HOG000006721.

HOVERGEN

HBG005833.

InParanoid

Q92820.

KO

K01307.

OMA

ISTMEGY.

OrthoDB

EOG4ZS93Z.

PhylomeDB

Q92820.

Enzyme and pathway databases

BRENDA

3.4.19.9. 2681.

Gene expression databases

ArrayExpress

Q92820.

Bgee

Q92820.

CleanEx

HS_GGH.

Genevestigator

Q92820.

GermOnline

ENSG00000137563. Homo sapiens.

Family and domain databases

InterPro

IPR015527. Pept_C26_g-glut_hydrolase.
IPR011697. Peptidase_C26.
[Graphical view]

PANTHER

PTHR11315. PTHR11315. 1 hit.

Pfam

PF07722. Peptidase_C26. 1 hit.
[Graphical view]

PROSITE

PS51275. PEPTIDASE_C26_GGH. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

Q92820.

ChEMBL

CHEMBL2223.

DrugBank

DB00158. Folic Acid.
DB00142. L-Glutamic Acid.

EvolutionaryTrace

Q92820.

GenomeRNAi

8836.

NextBio

33164.

SOURCE

Search...

Entry information

Entry name

GGH_HUMAN

Accession

Primary (citable) accession number: Q92820

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1999
Last sequence update:	August 1, 1998
Last modified:	May 1, 2013
This is version 119 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.