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Enzyme Nomenclature
Information on EC 3.4.19.13 - glutathione gamma-glutamate hydrolase and Organism(s) Homo sapiens and UniProt Accession P36269
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EC Tree
3.4.19.13 glutathione gamma-glutamate hydrolaseSpecify your search results
Word Map
- 3.4.19.13
- medicine
-
hydroxyacyl
- halide
-
alpha-globin
-
formyl
-
dihalomethanes
- methanes
- phosphoglycolate
-
monoxide
-
decomposes
-
diverted
-
halogenated
- formaldehyde
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Reaction Schemes
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
reduced glutathione + H2O
L-cysteinylglycine + L-glutamate
-
-
-
?
S-(4-nitro-benzyl)glutathione + H2O
S-(4-nitro-benzyl)-L-cysteinylglycine + L-glutamate
-
-
-
?
S-methylglutathione + H2O
S-methyl-L-cysteinylglycine + L-glutamate
-
-
-
?
7-(gamma-L-glutamylamino)-4-methylcoumarin + H2O
7-amino-4-methylcoumarin + L-glutamate
-
-
-
-
?
reduced glutathione + H2O
L-cysteinylglycine + L-glutamate
-
-
-
?
S-(4-nitro-benzyl)glutathione + H2O
S-(4-nitro-benzyl)-L-cysteinylglycine + L-glutamate
-
-
-
?
S-(5-hydroxy-2-pentyltetrahydrofuran-3-yl)glutathione + H2O
S-(5-hydroxy-2-pentyltetrahydrofuran-3-yl)-L-cysteinylglycine + L-glutamate
-
-
the GGT-dependent metabolism of S-(5-hydroxy-2-pentyltetrahydrofuran-3-yl)glutathione in the V79 GGT cell line is associated with a considerable increase of cytotoxicity. The cytotoxic effect is dose- and time-dependent, with 100% cellular death at 200 mM S-(5-hydroxy-2-pentyltetrahydrofuran-3-yl)glutathione after 24 h incubation in V79 GGT cells
-
?
S-linked bis-GSH conjugate of 1,6-hexamethylene diisocyanate + H2O
bis(Cys-Gly)-1,6-hexamethylene diisocyanate + 2 L-glutamate
-
-
-
?
S-linked bis-GSH conjugate of 4,4'-methylene diphenyl diisocyanate + H2O
bis(Cys-Gly)-4,4'-methylene diphenyl diisocyanate + 2 L-glutamate
-
-
-
?
S-linked mono-GSH conjugate of 1,6-hexamethylene diisocyanate + H2O
(Cys-Gly)-1,6-hexamethylene diisocyanate + L-glutamate
-
-
-
?
S-linked mono-GSH conjugate of 4,4'-methylene diphenyl diisocyanate + H2O
(Cys-Gly)-4,4'-methylene diphenyl diisocyanate + L-glutamate
-
-
-
?
S-methylglutathione + H2O
S-methyl-L-cysteinylglycine + L-glutamate
-
-
-
?
additional information
?
-
protein additionally has EC 2.3.2.2, gamma-glutamyltransferase activity
-
-
?
additional information
?
-
protein additionally has EC 2.3.2.2, gamma-glutamyltransferase activity
-
-
?
additional information
?
-
protein additionally has EC 2.3.2.2, gamma-glutamyltransferase activity
-
-
?
additional information
?
-
protein additionally has EC 2.3.2.2, gamma-glutamyltransferase activity
-
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
serine borate
competitive, 8fold less effective as an inhibitor of isoform GGT5 than of GGT1
(2RS)-2-amino-4-((S)-1-[N-(carboxymethyl)carbamoyl]propyl(phenyl)-phosphono)butanoic acid
-
potent and irreversible inhibitor of human enzyme, second-order rate constant value 145 per M and s, and good mimic of the putative transition state
2-amino-4-[[3-(carboxymethyl)phenoxy](methoxy)phosphoryl] butanoic acid
the mechanism-based inhibitor is a stable compound. It inactivates the human enzyme significantly faster than the other phosphonates, and does not inhibit a glutamine amidotransferase. The inhibitor shows no cytotoxicity toward human fibroblasts and hepatic stellate cells up to 1 mM. It serves as a non-toxic, selective and highly potent irreversible inhibitor that can be used for various in vivo as well as in vitro biochemical studies. Critical electrostatic interaction between the terminal carboxylate of the inhibitor and the active-site residue Lys562 of human enzyme for potent inhibition
serine borate
competitive, 8fold less effective as an inhibitor of isoform GGT5 than of GGT1
additional information
neutral phosphonate diesters are more potent inhibitors than monoanionic phosphonates
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
phylogenetic analysis of gamma-glutamyltranspeptidase proteins from different organisms divides the gamma-glutamyltranspeptidases into various clades and offers several interesting insights into the evolution and relatedness of these gamma-glutamyltranspeptidases. The present study focuses on the residues that are highly specific to each gamma-glutamyltranspeptidase subfamily and underlines their importance in imparting unique functional properties to the gamma-glutamyltranspeptidase proteins of each clade. The present study highlights the clade specific variation in the GXXGG motif, where SP (XX) of bacterial gamma-glutamyltranspeptidases is substituted by VM, CA, AS in extremophilic bacteria, archaea, and eukaryotes respectively, which could explain the differences in rates of enzyme reaction in gamma-glutamyltranspeptidases of these clades as this motif is known to be involved in gamma-glutamyltranspeptidase-substrate complex intermediate formation and the rate of final product release. Many sites predicted to be contributing to type 2 functional divergence are quite often found lining the substrate binding cavity and are close to the highly conserved known functional residues. This implies that they may be affecting the biochemical environment of the binding cavity and influencing the catalytic residues, thereby contributing to the functional differences among gamma-glutamyltranspeptidase-like proteins of various clades
metabolism
physiological function
metabolism
capacity of the enzyme to cleave GSH conjugates of both aromatic and aliphatic diisocyanates, suggesting a potential role in their metabolism
metabolism
the enzyme plays a role in asthma, reperfusion injury, and cancer
physiological function
-
construction of stably transfected NIH/3T3 mouse fibroblasts that express the enzyme in its proper orientation on the outer surface of the cell. NIH/3T3 fibroblasts require cysteine for growth and are unable to use extracellular glutathione as a source of cysteine. NIH/3T3 fibroblasts expressing the enzyme are able to grow in cysteine-free medium supplemented with glutathione. Cysteine derived from the cleavage of extracellular glutathione can be used to maintain intracellular levels of glutathione, and cells are able to replenish intracellular glutathione when incubated in cysteine-free medium containing glutathione
physiological function
-
extracellular cleavage of glutathione by the enzyme leads to reactive oxygen species production, depending on the generation and enhanced reactivity of cysteinylglycine. This production of reactive oxygen species induces the NF-kappaB-binding and transactivation activities. The induction mimicks the one observed by H2O2 and is inhibited by catalase
physiological function
-
the relatively small increase of glutathione amount in the presence of oxidative and electrophilic agents such as hydrogen peroxide or N-ethylmaleimide compared to other thiol reactive agents is not due to increased gamma-glutamyltranspeptidase-mediated degradation of glutathione
physiological function
gamma-glutamyl transpeptidase 1 is essential in cysteine homeostasis
physiological function
gamma-glutamyl transpeptidase plays a key role in the balance of glutathione by breaking down extracellular glutathione
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). GGT5_HUMAN
586
1
62261
Swiss-Prot
Secretory Pathway (Reliability: 1)
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
crystals of are grown at room temperature by vapor diffusion with the hanging drop method. For crystallization studies, the natural variant V272A of the human enzyme is expressed in Pichia pastoris strain X-33, purified, and deglycosylated. Crystal structures of human enzyme, including the free enzyme, inhibitor-bound transition states, and glutamate-bound enzyme. Crystal structures of human gamma-glutamyl transpeptidase show conformational changes within the active site as the enzyme progresses from the free enzyme to inhibitor bound tetrahedral transition states and finally to the glutamate bound structure prior to the release of this final product of the reaction. The structure of the apoenzyme shows flexibility within the active site. The serine-borate-bound enzyme crystal structure demonstrates that serine-borate occupies the active site of the enzyme, resulting in an enzyme-inhibitor complex that replicates the enzyme's tetrahedral intermediate/transition state. The structure of 2-amino-4-[[3-(carboxymethyl)phenyl](methyl)phosphono]-butanoic acid-bound enzyme reveals its interactions with the enzyme and why neutral phosphonate diesters are more potent inhibitors than monoanionic phosphonates
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
70.5
melting temperature of the enzyme inactivated with 2-amino-4-[[3-(carboxymethyl)phenyl](methyl)phosphono]-butanoic acid in BisTris buffer, pH 5.0
71
melting temperature of the enzyme inactivated with 2-amino-4-[[3-(carboxymethyl)phenyl](methyl)phosphono]-butanoic acid in bicine buffer, pH 10.0
75
melting temperature of the enzyme inactivated with 2-amino-4-[[3-(carboxymethyl)phenyl](methyl)phosphono]-butanoic acid in sodium citrate buffer, pH 6.7
additional information
inactivating the enzyme with 2-amino-4-[[3-(carboxymethyl)phenyl](methyl)phosphono]-butanoic acid stabilizes the structure of the enzyme. It increases the melting temperature of the enzyme by about 20°C at all pH levels tested independent of the buffer
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
for crystallization studies, the natural variant V272A of the human enzyme is expressed in Pichia pastoris strain X-33, purified, and deglycosylated
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
the natural variant V272A of the human enzyme is expressed in Pichia pastoris strain X-33
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
diagnostics
ultrasensitive detection of glutathione according to its hydrolysis by gamma-glutamyl transpeptidase and the as-prepared simple and robust LC-based sensing platform has potentials in the diagnosis of glutathione-related diseases, e.g. cancer, liver damage, and malignant neoplasms
medicine
pharmacology
the enzyme is involved in a number of physiological and pathological processes through glutathione metabolism and is an attractive pharmaceutical target
medicine
-
the metabolism of S-(5-hydroxy-2-pentyltetrahydrofuran-3-yl)glutathione in the V79 GGT cell line is associated with a considerable increase of cytotoxicity. The cytotoxic effect is dose- and time-dependent, with 100% cellular death at 200 mM S-(5-hydroxy-2-pentyltetrahydrofuran-3-yl)glutathione after 24 h incubation in V79 GGT cells
medicine
-
the relatively small increase of glutathione amount in the presence of oxidative and electrophilic agents such as hydrogen peroxide or N-ethylmaleimide compared to other thiol reactive agents is not due to increased gamma-glutamyltranspeptidase-mediated degradation of glutathione
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Wickham, S.; West, M.; Cook, P.; Hanigan, M.
Gamma-glutamyl compounds: Substrate specificity of gamma-glutamyl transpeptidase enzymes
Anal. Biochem.
414
208-214
2011
Homo sapiens (P19440), Homo sapiens (P36269)
Enoiu, M.; Herber, R.; Wennig, R.; Marson, C.; Bodaud, H.; Leroy, P.; Mitrea, N.; Siest, G.; Wellman, M.
gamma-Glutamyltranspeptidase-dependent metabolism of 4-hydroxynonenal-glutathione conjugate
Arch. Biochem. Biophys.
397
18-27
2002
Homo sapiens
Accaoui, M.; Enoiu, M.; Mergny, M.; Masson, C.; Dominici, S.; Wellman, M.; Visvikis, A.
Gamma-glutamyltranspeptidase-dependent glutathione catabolism results in activation of NF-kB
Biochem. Biophys. Res. Commun.
276
1062-1067
2000
Homo sapiens
Hanigan, M.; Ricketts, W.
Extracellular glutathione is a source of cysteine for cells that express gamma-glutamyl transpeptidase
Biochemistry
32
6302-6306
1993
Homo sapiens
Hultberg, M.; Hultberg, B.
Glutathione turnover in human cell lines in the presence of agents with glutathione influencing potential with and without acivicin inhibition of gamma-glutamyltranspeptidase
Biochim. Biophys. Acta
1726
42-47
2005
Homo sapiens
Nakajima, M.; Watanabe, B.; Han, L.; Shimizu, B.; Wada, K.; Fukuyama, K.; Suzuki, H.; Hiratake, J.
Glutathione-analogous peptidyl phosphorus esters as mechanism-based inhibitors of gamma-glutamyl transpeptidase for probing cysteinyl-glycine binding site
Bioorg. Med. Chem.
22
1176-1194
2014
Escherichia coli, Homo sapiens
Zhou, L.; Kang, Q.; Hu, O.; Yu, L.
Ultrasensitive detection of glutathione based on liquid crystals in the presence of gamma-glutamyl transpeptidase
Anal. Chim. Acta
1040
187-195
2018
Homo sapiens (P19440)
Verma, V.V.; Gupta, R.; Goel, M.
Phylogenetic and evolutionary analysis of functional divergence among Gamma glutamyl transpeptidase (GGT) subfamilies
Biol. Direct
10
49
2015
Bacillus anthracis (Q51693), Bacillus subtilis, Bacillus subtilis BEST7613, Escherichia coli (P18956), Escherichia coli K12 (P18956), Halalkalibacterium halodurans, Helicobacter pylori (Q9F5N9), Homo sapiens (P19440), Saccharomyces cerevisiae (Q05902), Saccharomyces cerevisiae ATCC 204508 (Q05902), Thermoplasma acidophilum (Q9HJH4), Thermoplasma acidophilum ATCC 25905 (Q9HJH4)
Kamiyama, A.; Nakajima, M.; Han, L.; Wada, K.; Mizutani, M.; Tabuchi, Y.; Kojima-Yuasa, A.; Matsui-Yuasa, I.; Suzuki, H.; Fukuyama, K.; Watanabe, B.; Hiratake, J.
Phosphonate-based irreversible inhibitors of human gamma-glutamyl transpeptidase (GGT). GGsTop is a non-toxic and highly selective inhibitor with critical electrostatic interaction with an active-site residue Lys562 for enhanced inhibitory activity
Bioorg. Med. Chem.
24
5340-5352
2016
Escherichia coli (P18956), Escherichia coli K12 (P18956), Homo sapiens (P19440)
Terzyan, S.S.; Burgett, A.W.; Heroux, A.; Smith, C.A.; Mooers, B.H.; Hanigan, M.H.
Human gamma-glutamyl transpeptidase 1 structures of the free enzyme, inhibitor-bound tetrahedral transition states, and glutamate-bound enzyme reveal novel movement within the active site during catalysis
J. Biol. Chem.
290
17576-17586
2015
Homo sapiens (P19440)
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