Information on EC 3.4.19.13 - glutathione hydrolase

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The expected taxonomic range for this enzyme is: Eukaryota, Bacteria

EC NUMBER
COMMENTARY hide
3.4.19.13
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RECOMMENDED NAME
GeneOntology No.
glutathione hydrolase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
glutathione + H2O = L-cysteinylglycine + L-glutamate
show the reaction diagram
PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
Glutathione metabolism
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Metabolic pathways
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-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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-
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Manually annotated by BRENDA team
enzyme catalyses both gamma-glutamyl transfer, reaction of EC 2.3.2.2, and hydrolysis reactions at the same time
UniProt
Manually annotated by BRENDA team
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UniProt
Manually annotated by BRENDA team
enzyme displays both glutathione hydrolase and gamma-glutamyl transpeptidase activity, EC 2.3.2.2
UniProt
Manually annotated by BRENDA team
enzyme displays both glutathione hydrolase and gamma-glutamyl transpeptidase activity, EC 2.3.2.2
UniProt
Manually annotated by BRENDA team
enzyme displays both glutathione hydrolase and gamma-glutamyl transpeptidase activity, EC 2.3.2.2
UniProt
Manually annotated by BRENDA team
enzyme displays both glutathione hydrolase and gamma-glutamyl transpeptidase activity, EC 2.3.2.2
UniProt
Manually annotated by BRENDA team
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-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
metabolism
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in the presence of 1alpha,25-dihydroxyvitamin D3, gamma-glutamyl transpeptidase activity is significantly increased in LLC-PK1 cells, with an increase in enzymic activity also found in the cell medium. While the stimulatory effect of 1-hydroxyvitamin D3 is similar to that of 1alpha,25-dihydroxyvitamin D3, vitamin D3 and 25-hydroxyvitamin D3 have no effect on activity. The increase in activity is due to prolonged turnover
physiological function
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
7-(gamma-L-glutamylamino)-4-methylcoumarin + H2O
7-amino-4-methylcoumarin + L-glutamate
show the reaction diagram
diclofenac-S-acyl-glutathione + H2O
diclofenac-S-acyl-L-cysteinylglycine + L-glutamate
show the reaction diagram
gamma-glutamyl L-leucine + H2O
L-leucine + L-glutamate
show the reaction diagram
-
-
-
?
glutathione + H2O
L-cysteinylglycine + L-glutamate
show the reaction diagram
glutathione S-bimane + H2O
L-cysteinylglycyl S-bimane + L-glutamate
show the reaction diagram
-
-
-
?
glutathione sulfonic acid + H2O
? + L-glutamate
show the reaction diagram
-
-
-
?
glutathione-S-monobromobimane conjugate + H2O
L-cysteinylglycine-S-monobrombimane conjugate + L-glutamate
show the reaction diagram
-
-
-
-
?
L-glutamic acid 4-nitroanilide + H2O
4-nitroaniline + L-glutamate
show the reaction diagram
L-glutamic acid-(4-nitroanilide) + H2O
4-nitroaniline + L-glutamate
show the reaction diagram
L-glutamine + H2O
L-glutamate + NH3
show the reaction diagram
leukotriene C4 + H2O
?
show the reaction diagram
-
-
-
?
oxidized glutathione + H2O
? + L-glutamate
show the reaction diagram
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-
-
?
reduced glutathione + H2O
L-cysteinylglycine + L-glutamate
show the reaction diagram
-
-
-
?
S-(2-(4-chlorophenoxy)-2-methylpropanoyl)glutathione + H2O
S-(2-(4-chlorophenoxy)-2-methylpropanoyl)-L-cysteinylglycine + L-glutamate
show the reaction diagram
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i.e. clofibril-S-acylglutathione
the first step in the degradation of clofibril S-acylglutathione. complete degradation with formation of clofibryl-S-acyl-N-acetylcysteine and its disulfide, with no detection of clofibryl-S-acyl-cysteinylglycine thioester
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?
S-(4-nitro-benzyl)glutathione + H2O
S-(4-nitro-benzyl)-L-cysteinylglycine + L-glutamate
show the reaction diagram
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-
-
?
S-(5-hydroxy-2-pentyltetrahydrofuran-3-yl)glutathione + H2O
S-(5-hydroxy-2-pentyltetrahydrofuran-3-yl)-L-cysteinylglycine + L-glutamate
show the reaction diagram
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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
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?
S-methylglutathione + H2O
S-methyl-L-cysteinylglycine + L-glutamate
show the reaction diagram
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-
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?
additional information
?
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Ca2+
50 mM, 320% of initial activity
Co2+
1 mM, 217% of initial activity
Mg2+
50 mM, 313% of initial activity
Mn2+
50 mM, 301% of initial activity
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(2RS)-2-amino-4-((R)-1-[N-(carboxymethyl)carbamoyl]-2-chloroethyl(phenyl)-phosphono)butanoic acid
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potent and irreversible inhibitor of enzyme, second-order rate constant value 188 per M and s, and good mimic of the putative transition state
(2RS)-2-amino-4-((S)-1-[N-(carboxymethyl)carbamoyl]-2-phenylethyl(phenyl)-phosphono)butanoic acid
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potent and irreversible inhibitor of enzyme, second-order rate constant value 389 per M and s, and good mimic of the putative transition state
(2RS)-2-amino-4-((S)-1-[N-(carboxymethyl)carbamoyl]propyl(phenyl)-phosphono)butanoic acid
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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
6-diazo-5-oxo-L-norleucine
pretreatment of cells completely abolishes the extracellular hydrolysis of lgutathione and glutamine
acivicin
diclofenac-S-acyl-glutathione
Na+
0.2 M, 80% residual activity
serine borate
competitive, 8fold less effective as an inhibitor of isoform GGT5 than of GGT1; competitive, 8fold less effective as an inhibitor of isoform GGT5 than of GGT1
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0457
diclofenac-S-acyl-glutathione
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pH 7.4, 37°C
0.0334
gamma-glutamyl L-leucine
pH 7.4, 37°C
0.918
glutathione
pH 6.0, 37°C
0.0346 - 0.0751
glutathione sulfonic acid
0.0125 - 1.06
L-glutamic acid-(4-nitroanilide)
0.00133 - 0.52
L-glutamine
0.0102 - 0.0108
leukotriene C4
0.0088 - 0.0426
oxidized glutathione
0.0105 - 0.0106
reduced glutathione
0.0131 - 0.0148
S-(4-nitro-benzyl)glutathione
0.0182 - 0.099
S-Methylglutathione
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2.09 - 55.11
L-glutamic acid-(4-nitroanilide)
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
1.97 - 67.92
L-glutamic acid-(4-nitroanilide)
42479
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
4.2
serine borate
pH 7.4, 37°C
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7 - 9.3
hydrolysis activity is optimal and almost constant within
9
wild-type as well as deletion mutants
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
4 - 12
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
30 - 60
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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nontumorigenic cell line, low level of gamma-glutamyltranspeptidase
Manually annotated by BRENDA team
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tumorigenic cell line, high level of gamma-glutamyl transpeptidase
Manually annotated by BRENDA team
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isoform GGT3 is a major contributor to total enzymic activity in roots, but a relatively minor contributor in other tissues
Manually annotated by BRENDA team
additional information
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isoform GGT3 is transcribed at relatively high levels in all parts of the plant. It is a major contributor to total enzymic activity in roots, but a relatively minor contributor in other tissues
Manually annotated by BRENDA team
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
23000
and 40000, SDS-PAGE, small and large subunit
57330
unprocessed protein, calculated
60000
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x * 60000, proenzyme, x * 40000, large subunit, plus x * 20000, small subunit, SDS-PAGE
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
?
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x * 60000, proenzyme, x * 40000, large subunit, plus x * 20000, small subunit, SDS-PAGE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
proteolytic modification
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
in complex with acivicin, to 1.8 A resolution. Acivicin is bound covalently through its C3 atom with sp2 hybridization to Thr403 Ogamma, the catalytic nucleophile of the enzyme
mutant T391A, unable to undergo autocatalytic processing, at 2.55 A resolution. Structural comparison of the precursor and mature protein demonstrates that the structures of the core regions in the two proteins are unchanged, with marked differences near the active site. In the precursor, the segment corresponding to the C-terminal region of the L-subunit occupies the site where the loop, residues 438-449, forms the lid of the gamma-glutamyl group-binding pocket in the mature enzyme. Upon cleavage of the N-terminal peptide bond of Thr391, the newly produced C-terminus, residues 375–390, flips out, allowing the 438-449 segment to form the gamma-glutamyl group-binding pocket. A water molecule is located near the carbonyl carbon atom of Gln-390. The spatial arrangement around the water and Thr391 relative to the scissile peptide bond appears suitable for the initiation of autocatalytic processing
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to 1.95 A resolution. The enzyme has a stacked alphabetabetaalpha fold comprising the large and small subunits, similar to the folds seen in members of the N-terminal nucleophile hydrolase superfamily. The active site residue Thr391, the N-terminal residue of the small subunit, is located in the groove, from which the pocket for gamma-glutamyl moiety binding follows. The gamma-glutamyl-enzyme intermediate and the structure of the complex with L-glutamate reveal how the gamma-glutamyl moiety and L-glutamate are recognized by the enzyme. A water molecule is seen on the carbonyl carbon of the gamma-glutamyl-Thr391 O bond in the intermediate that is to be hydrolyzed. The residues essential for enzymic activity, i.e. Arg114, Asp433, Ser462, and Ser463, are all involved in the binding of the gamma-glutamyl moiety
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to 1.9 A resolution. The refined model contains two 40-kDa/20-kDa heterodimers in the asymmetric unit and has structural features comparable with other N-terminal nucleophile hydrolases. Autoprocessing of the enzyme leads to a large conformational change, with the loop preceding the catalytic residue Thr380 moving more than 35 A, thus relieving steric constraints that likely limit substrate binding. Cleavage of the proenzyme results in the formation of a threonine-threonine dyad comprised of Thr380 and Thr398. The hydroxyl group of Thr398 is located equidistant from the alpha-amino group and hydroxyl side chain of Thr380
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
45.3 - 47.9
melting temoeratures of deletion mutants
50
24 h, 50% residual activity
60
or above, melting temerature of wild-type
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
recombinant protein
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expression in Escherichia coli
expression in NIH/3T3 cell
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expression in V79 fibroblast cell
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
transcripts encoding Sclerotinia sclerotiorum gamma-glutamyl transpeptidase accumulate specifically during sclerotium, apothecium, and compound appressorium development
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
DELTAY385-E398
no autocatalytic processing, no catalytic activity
DELTAY385-I387
mutant is able to autoprocess itself, leading to the formation of a small and a large subunit with masses of about 41 kDa and 22 kDa, respectively. Mutant shows increase in catalytic efficiency
DELTAY385-I396
mutant is able to autoprocess itself, albeit slowly, leading to the formation of a small and a large subunit with masses of about 41 kDa and 22 kDa, respectively. Mutant shows decrease in catalytic efficiency
DELTAY385-K394
mutant is able to autoprocess itself, albeit slowly, leading to the formation of a small and a large subunit with masses of about 41 kDa and 22 kDa, respectively. Mutant shows decrease in catalytic efficiency
DELTAY385-P391
mutant is able to autoprocess itself, albeit slowly, leading to the formation of a small and a large subunit with masses of about 41 kDa and 22 kDa, respectively. Mutant shows decrease in catalytic efficiency
DELTAY385-V388
mutant is able to autoprocess itself, leading to the formation of a small and a large subunit with masses of about 41 kDa and 22 kDa, respectively. Mutant shows increase in catalytic efficiency
T398A
mutation results in an enzyme that is fully capable of autoprocessing but is devoid of enzymatic activity
T398S
retains considerable enzymatic activity, but hydrolysis rates are reduced about 5fold relative to wild-type enzyme and overall catalyticefficiency is diminished by nearly an order of magnitude
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
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