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Information on EC 3.6.1.56 - 2-hydroxy-dATP diphosphatase and Organism(s) Mus musculus and UniProt Accession P53368

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EC Tree
     3 Hydrolases
         3.6 Acting on acid anhydrides
             3.6.1 In phosphorus-containing anhydrides
                3.6.1.56 2-hydroxy-dATP diphosphatase
IUBMB Comments
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) .
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This record set is specific for:
Mus musculus
UNIPROT: P53368
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The taxonomic range for the selected organisms is: Mus musculus
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
Synonyms
hmth1, nudix hydrolase 2, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
MutT homologue 1
-
(2'-deoxy) ribonucleoside 5'-triphosphate pyrophosphohydrolase
-
-
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].
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 + H2O
2-hydroxy-dAMP + 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
dGTP + H2O
dGMP + diphosphate
show the reaction diagram
-
-
-
?
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-GTP + H2O
8-oxo-GMP + diphosphate
show the reaction diagram
-
8-oxo-dGTP i.e. 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
8-oxo-dGTP + H2O
8-oxo-dGMP + diphosphate
show the reaction diagram
8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP) is formed in the nucleotide pool of a cell during normal cellular metabolism, and when it is incorporated into DNA causes mutation. Organisms possess 8-oxo-dGTPase, an enzyme that specifically degrades 8-oxo-dGTP to 8-oxo-dGMP. This enzyme is a 2-hydroxy-dATP diphosphatase that also exhibits activity with 8-oxo-dGTP
-
-
?
2-hydroxy-dATP + 2 H2O
2-hydroxy-dAMP + 2 phosphate
show the reaction diagram
-
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
-
-
?
8-oxo-dGTP + H2O
8-oxo-dGMP + diphosphate
show the reaction diagram
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
N4-cyclopropyl-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine
i.e. TH588
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.032
8-oxo-dGTP
pH and temperature not specified in the publication
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.000032 - 0.000138
N4-cyclopropyl-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine
0.000132
TH1579
Mus musculus
wild type enzyme, at pH 8.0 and 22°C
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
SwissProt
Manually annotated by BRENDA team
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
high level of activity
Manually annotated by BRENDA team
high level of activity
Manually annotated by BRENDA team
high level of activity
Manually annotated by BRENDA team
high level of activity
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
-
normal mouse livers and hepatectomized regenerating livers. 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
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
physiological function
MTH1 protects the dopamine neurons from oxidative damage in the nucleic acids, especially in the mitochondrial DNA of striatal nerve terminals of dopamine neurons
malfunction
-
MTH1-null mouse embryo fibroblasts are highly susceptible to cell dysfunction and death caused by exposure to H2O2, with condensed nuclei and degenerated mitochondria in which electron dense deposits are seen in place of intact cristae. The cell death observed is not dependent on either poly(ADP-ribose) polymerase or caspases. A continuous accumulation of 8-oxoG, both in the nuclear and mitochondrial DNA, is observed after exposure to H2O2. All of the H2O2-induced alterations observed in MTH1-null MEFs are effectively suppressed by the expression of wild-type human MTH1
physiological function
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
8ODP_MOUSE
156
0
17908
Swiss-Prot
Mitochondrion (Reliability: 5)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
17896
x * 17896, calculated from sequence
18000
x * 18000, SDS-PAGE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
in complex with inhibitor TH588, sitting drop vapor diffusion method, using 200 mM potassium thiocyanate and 20% (w/v) PEG 3350. In complex with substrate 8-oxo-dGTP, sitting drop vapor diffusion method, using 200 mM ammonium nitrate, 34% (w/v) PEG 3350, and 10 mM copper(II) chloride dihydrate
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
L116M
the mutation causes a considerable drop in activity with dGTP compared to the wild type enzyme
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
HisTrap column chromatography and Superdex 75 gel filtration
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli BL21(DE3) cells
expressed in Escherichia coli mutT2 mutant cells devoid of their own 8-oxo-dGTPase activity
expression in Escherichia coli. Expression of cDNA for mMTH2 reduces significantly the elevated level of spontaneous mutation frequency of Escherichia coli mutT(-) cells
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
-
age-related accumulation of 8-oxoguanine in RNA is correlated with decreased expression of MTH1
-
oxidative stress in brain induces expression of MTH1 especially in microglia, thus avoiding cellular dysfunction
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
-
measurements of 8-oxo-dGTPase activity in brains, testes and kidneys may serve as a rough indicator rather than a quantifiable marker of radiation-induced oxidative stress
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Yamaguchi, H.; Kajitani, K.; Dan, Y.; Furuichi, M.; Ohno, M.; Sakumi, K.; Kang, D.; Nakabeppu, Y.
MTH1, an oxidized purine nucleoside triphosphatase, protects the dopamine neurons from oxidative damage in nucleic acids caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Cell Death Differ.
13
551-563
2006
Homo sapiens (P36639), Mus musculus (P53368)
Manually annotated by BRENDA team
Kajitani, K.; Yamaguchi, H.; Dan, Y.; Furuichi, M.; Kang, D.; Nakabeppu, Y.
MTH1, an oxidized purine nucleoside triphosphatase, suppresses the accumulation of oxidative damage of nucleic acids in the hippocampal microglia during kainate-induced excitotoxicity
J. Neurosci.
26
1688-1698
2006
Mus musculus
Manually annotated by BRENDA team
Cai, J.P.; Ishibashi, T.; Takagi, Y.; Hayakawa, H.; Sekiguchi, M.
Mouse MTH2 protein which prevents mutations caused by 8-oxoguanine nucleotides
Biochem. Biophys. Res. Commun.
305
1073-1077
2003
Mus musculus (Q8BG93)
Manually annotated by BRENDA team
Bialkowski, K.; Kasprzak, K.S.
Cellular 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate pyrophosphohydrolase activity of human and mouse MTH1 proteins does not depend on the proliferation rate
Free Radic. Biol. Med.
37
1534-1541
2004
Homo sapiens, Mus musculus
Manually annotated by BRENDA team
Kakuma, T.; Nishida, J.; Tsuzuki, T.;, Sekiguchi, M.
Mouse MTH1 protein with 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphatase activity that prevents transversion mutation. cDNA cloning and tissue distribution
J. Biol. Chem.
270
25942-25948
1995
Mus musculus (P53368)
Manually annotated by BRENDA team
Nakabeppu, Y.; Oka, S.; Sheng, Z.; Tsuchimoto, D.; Sakumi, K.
Programmed cell death triggered by nucleotide pool damage and its prevention by MutT homolog-1 (MTH1) with oxidized purine nucleoside triphosphatase
Mutat. Res.
703
51-58
2010
Homo sapiens, Mus musculus
Manually annotated by BRENDA team
Song, X.N.; Zhang, L.Q.; Liu, D.G.; Lin, J.; Zheng, J.D.; Dai, D.P.; Hei, A.L.; Hayakawa, H.; Sekiguchi, M.; Cai, J.P.
Oxidative damage to RNA and expression patterns of MTH1 in the hippocampi of senescence-accelerated SAMP8 mice and Alzheimer's disease patients
Neurochem. Res.
36
1558-1565
2011
Homo sapiens, Mus musculus, Mus musculus SAMP8
Manually annotated by BRENDA team
Bialkowski, K.; Szpila, A.; Kasprzak, K.S.
Up-regulation of 8-oxo-dGTPase activity of MTH1 protein in the brain, testes and kidneys of mice exposed to (137)Cs gamma radiation
Radiat. Res.
172
187-197
2009
Mus musculus
Manually annotated by BRENDA team
Narwal, M.; Jemth, A.S.; Gustafsson, R.; Almloef, I.; Warpman Berglund, U.; Helleday, T.; Stenmark, P.
Crystal structures and inhibitor interactions of mouse and dog MTH1 reveal species-specific differences in affinity
Biochemistry
57
593-603
2018
Canis lupus familiaris (F1P963), Homo sapiens (P36639), Mus musculus (P53368)
Manually annotated by BRENDA team