Information on EC 3.6.1.56 - 2-hydroxy-dATP diphosphatase

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The enzyme appears in viruses and cellular organisms

EC NUMBER
COMMENTARY hide
3.6.1.56
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RECOMMENDED NAME
GeneOntology No.
2-hydroxy-dATP diphosphatase
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REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
2-hydroxy-dATP + H2O = 2-hydroxy-dAMP + diphosphate
show the reaction diagram
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SYSTEMATIC NAME
IUBMB Comments
2-hydroxy-dATP diphosphohydrolase
The enzyme hydrolyses oxidized purine nucleoside triphosphates such as 2-hydroxy-dATP, thereby preventing their misincorporation into DNA. It can also recognize 8-oxo-dGTP and 8-oxo-dATP, but with lower efficiency (cf. EC 3.6.1.55, 8-oxo-dGTP diphosphatase) [3].
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
-
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Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
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
2-hydroxy-ATP + H2O
2-hydroxy-AMP + diphosphate
show the reaction diagram
2-hydroxy-dATP + 2 H2O
2-hydroxy-dAMP + 2 phosphate
show the reaction diagram
2-hydroxy-dATP + H2O
2-hydroxy-dAMP + diphosphate
show the reaction diagram
8-oxo-ATP + H2O
8-oxo-AMP + diphosphate
show the reaction diagram
8-oxo-dATP + H2O
8-oxo-dAMP + diphosphate
show the reaction diagram
8-oxo-dGTP + H2O
8-oxo-dGMP + diphosphate
show the reaction diagram
8-oxo-GDP + H2O
8-oxo-GMP + phosphate
show the reaction diagram
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Vmax/Km is 4% of the value for 8-oxo-GTP
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-
?
8-oxo-GTP + H2O
8-oxo-GMP + diphosphate
show the reaction diagram
dGTP + H2O
dGMP + diphosphate
show the reaction diagram
GTP + H2O
GDP + diphosphate
show the reaction diagram
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Vmax/Km is 31% of the value for 8-oxo-GTP
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-
?
additional information
?
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
2-hydroxy-ATP + H2O
2-hydroxy-AMP + diphosphate
show the reaction diagram
P36639
8-oxo-dGTP i.e. 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate. MTH1 hydrolyzes oxidized purine nucleoside triphosphates such as 8-oxo-dGTP, 8-oxo-dATP, 2-hydroxy-dATP, and 2-hydroxy-ATP to monophosphates, and thus avoids errors caused by their misincorporation during DNA replication or transcription, which may result in carcinogenesis or neurodegeneration
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-
?
2-hydroxy-dATP + 2 H2O
2-hydroxy-dAMP + 2 phosphate
show the reaction diagram
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8-oxo-dGTP i.e. 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate. MTH1 protein is an antimutagenic (2'-deoxy) ribonucleoside 5'-triphosphate pyrophosphohydrolase that prevents the incorporation of oxidatively modified nucleotides into nucleic acids. It decomposes most specifically the miscoding products of oxidative damage to purine nucleic acid precursors (e.g. 8-oxo-dGTP, 2-hydroxy-dATP, 2-hydroxy-ATP, 8-oxo-GTP) that may cause point mutations or transcription errors when incorporated into DNA and RNA, respectively
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-
?
2-hydroxy-dATP + H2O
2-hydroxy-dAMP + diphosphate
show the reaction diagram
8-oxo-dATP + H2O
8-oxo-dAMP + diphosphate
show the reaction diagram
P36639
8-oxo-dGTP i.e. 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate. MTH1 hydrolyzes oxidized purine nucleoside triphosphates such as 8-oxo-dGTP, 8-oxo-dATP, 2-hydroxy-dATP, and 2-hydroxy-ATP to monophosphates, and thus avoids errors caused by their misincorporation during DNA replication or transcription, which may result in carcinogenesis or neurodegeneration
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-
?
8-oxo-dGTP + H2O
8-oxo-dGMP + diphosphate
show the reaction diagram
8-oxo-GTP + H2O
8-oxo-GMP + diphosphate
show the reaction diagram
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this enzyme is a 2-hydroxy-dATP diphosphatase that also exhibits activity with 8-oxo-dGTP
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?
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2'-deoxy-8-hydroxyguanosine 5'-triphosphate
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2-hydroxy-dADP
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competitively inhibits both the 2-hydroxy-dATP hydrolase and 8-hydroxy-dGTP hydrolase activities of hMTH1
2-hydroxy-dATP
the hydrolysis of 8-oxo-dGTP (0.01 mM) by wild type and F27A decreases to 42% and 44% of the control in the presence of 0.01 mM 2-hydroxy-dATP. 8-oxo-dGTPase activities of D119A and D119N mutants are not altered in the presence of 2-hydroxy-dATP up to 0.1 mM
8-oxo-dADP
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8-oxo-dGDP
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competitively inhibits both the 2-hydroxy-dATP hydrolase and 8-hydroxy-dGTP hydrolase activities of hMTH1
8-oxo-dGTP
dATP
the 8-oxo-dGTPase activity of wild type hMTH1 decreases to 79.6% of the control in the presence of 0.1 mM dATP
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0043
2-hydroxy-ATP
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pH 8.0, 30°C
0.0043 - 5.7
2-hydroxy-dATP
0.051
8-oxo-ATP
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pH 8.0, 30°C
0.0139
8-oxo-dATP
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pH 8.0, 30°C
0.0151 - 12.8
8-oxo-dGTP
0.044
8-oxo-GDP
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pH 8.0, 30°C
0.055 - 0.29
8-oxo-GTP
0.258 - 258
dGTP
0.79
GTP
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pH 8.0, 30°C
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
4.7
2-hydroxy-ATP
Homo sapiens
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pH 8.0, 30°C
4.7 - 31
2-hydroxy-dATP
1.1
8-oxo-ATP
Homo sapiens
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pH 8.0, 30°C
10.8
8-oxo-dATP
Homo sapiens
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pH 8.0, 30°C
2.1 - 25.9
8-oxo-dGTP
2.6
8-oxo-GTP
Homo sapiens
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pH 8.0, 30°C
15.7
dGTP
Homo sapiens
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pH 8.0, 30°C
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
1093
2-hydroxy-ATP
Homo sapiens
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pH 8.0, 30°C
12142
0.00168 - 3300
2-hydroxy-dATP
2804
22
8-oxo-ATP
Homo sapiens
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pH 8.0, 30°C
41709
78 - 780
8-oxo-dATP
12157
16 - 1710
8-oxo-dGTP
2299
47
8-oxo-GTP
Homo sapiens
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pH 8.0, 30°C
8390
6 - 60
dGTP
219
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0097
2'-deoxy-8-hydroxyguanosine 5'-triphosphate
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pH 8.0, 30°C, inhibition of 2-hydroxy-dATPase activity
0.0002 - 0.00022
8-oxo-dADP
0.00051 - 0.00072
8-oxo-dGDP
0.0129
8-oxo-dGTP
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pH 8.0, 30°C, inhibition of 2-hydroxy-dATPase activity
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.7 - 8.2
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hydrolysis of 8-oxo-dGTP
7.7 - 8.8
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hydrolysis of 2-hydroxy-dATP
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.2 - 8.8
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pH 7.2: about 60% of maximal activity, pH 8.8: about 95% of maximal activity, hydrolysis of 2-hydroxy-dATP
7.7 - 8.8
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pH 7.2: about 15% of maximal activity, pH 7.7: about 95% of maximal activity, pH 8.8: about 50% of maximal activity, hydrolysis of 8-oxo-dGTP
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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MTH1 expression is not associated with proliferation rate
Manually annotated by BRENDA team
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MTH1 expression is not associated with proliferation rate
Manually annotated by BRENDA team
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high level of activity
Manually annotated by BRENDA team
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a statistically significant induction of 8-oxo-dGTPase by 137Cs gamma radiation (given as a single whole-body dose (1 Gy/min)) is found in brains, testes and kidneys but not in lungs, hearts or livers
Manually annotated by BRENDA team
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high level of activity
Manually annotated by BRENDA team
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MTH1 expression is not associated with proliferation rate
Manually annotated by BRENDA team
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MTH1 expression is not associated with proliferation rate
Manually annotated by BRENDA team
-
MTH1 expression is not associated with proliferation rate
Manually annotated by BRENDA team
-
MTH1 expression is not associated with proliferation rate
Manually annotated by BRENDA team
-
MTH1 expression is not associated with proliferation rate
Manually annotated by BRENDA team
-
a statistically significant induction of 8-oxo-dGTPase by 137Cs gamma radiation (given as a single whole-body dose (1 Gy/min)) is found in brains, testes and kidneys but not in lungs, hearts or livers
Manually annotated by BRENDA team
-
high level of activity
Manually annotated by BRENDA team
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
17896
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x * 17896, calculated from sequence
17900
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x * 17900, SDS-PAGE
18000
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x * 18000, SDS-PAGE
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
50
Tm-value for mutant enzyme L150A
60
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5 min, Met83-MTH1 loses 31-46% of its activity, Val83-MTH1 retains full activity
61
Tm-value for mutant enzyme V156A
65
Tm-value for wild-type enzyme. 10 min, wild type hMTH1 retains 49% of the activity in the untreated extracts, mutant enzyme L150A retains 14% of the activity in the untreated extracts
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
both types of MTH1 protein (Met83-MTH1 and Val83-MTH1) are expressed in Escherichia coli mutT- cells
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expressed in Escherichia coli mutT2 mutant cells devoid of their own 8-oxo-dGTPase activity
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expression in Escherichia coli. Expression of cDNA for mMTH2 reduces significantly the elevated level of spontaneous mutation frequency of Escherichia coli mutT(-) cells
the increase in the production of erroneous proteins by oxidative damage is 28fold over the wild-type cells in Escherichia coli mutT deficient cells. By the expression of MTH1 in the cells, it is reduced to 1.2fold
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when the human cDNA is expressed in Escherichia coli mutT- mutant cells, there is a significant amount of 8-oxo-dGTPase activity
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
a statistically significant induction of 8-oxo-dGTPase by 137Cs gamma radiation (given as a single whole-body dose (1 Gy/min)) is found in brains, testes and kidneys but not in lungs, hearts or livers
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age-related accumulation of 8-oxoguanine in RNA is correlated with decreased expression of MTH1
increased amounts of 8-oxoguanine in the RNA, and decreased expression of MTH1 are observed in the hippocampi of patients suffering from Alzheimer's disease
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oxidative stress in brain induces expression of MTH1 especially in microglia, thus avoiding cellular dysfunction
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
L150A
mutant enzyme with decrased thermostability. Tm-value is 50°C compared to 65°C for the wild-type enzyme
N33A
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mutation decreases catalytic activity toward 2-hydroxy-dATP to 5% of the wild-type activity. The mutant shows 14% of the wild-type 8-oxo-dGTP activity
N33E
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mutation decreases catalytic activity toward 2-hydroxy-dATP to 53% of the wild-type activity. Activity towards 8-oxo-dGTP is totally abolished
V156A
mutant enzyme with decrased thermostability. Tm-value is 61°C compared to 65°C for the wild-type enzyme
V83M
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Met83-MTH1 is more thermolabile than that of Val83-MTH1. Substitution of valine for methionine at the residue 83 of MTH1 protein appears to lead to alteration in the secondary structure which renders the protein more labile than the normal type protein
additional information
sequence comparison with the Escherichia coli homolog, MutT, which hydrolyzes only 8-oxo-dGTP and 8-oxo-GTP but not oxidized forms of dATP or ATP. Neither a replacement of the phosphohydrolase module of MTH1 with that of MutT nor deletions of the C-terminal region of MTH1, which is unique for MTH1, alter the substrate specificity of MTH1. In contrast, the substitution of residues at position Trp117 and Asp119 of MTH1, which show apparent chemical shift perturbations with 8-oxo-dGDP in NMR analyses but are not conserved in MutT, affected the substrate specificity. Trp117 is essential for MTH1 to recognize both 8-oxo-dGTP and 2-hydroxy-dATP, whereas Asp119 is only essential for recognizing 2-hydroxy-dATP, thus suggesting that origins of the substrate-binding pockets for MTH1 and MutT are different
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine