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NUDT1  -  nudix (nucleoside diphosphate linked...

Homo sapiens

Synonyms: 2-hydroxy-dATP diphosphatase, 7,8-dihydro-8-oxoguanine triphosphatase, 8-oxo-dGTPase, MTH1, Nucleoside diphosphate-linked moiety X motif 1, ...
 
 
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Disease relevance of NUDT1

 

High impact information on NUDT1

  • ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology [6].
  • The MTH1 gene encodes an enzyme that hydrolyzes 8-oxo-dGTP to monophosphate in the nucleotide pool, thereby preventing occurrence of transversion mutations [7].
  • The MTH1-deficient mouse will provide a useful model for investigating the role of the MTH1 protein in normal conditions and under oxidative stress [7].
  • By means of gene targeting, we have established MTH1 gene-knockout cell lines and mice [7].
  • When examined 18 months after birth, a greater number of tumors were formed in the lungs, livers, and stomachs of MTH1-deficient mice, as compared with wild-type mice [7].
 

Chemical compound and disease context of NUDT1

 

Biological context of NUDT1

 

Anatomical context of NUDT1

 

Associations of NUDT1 with chemical compounds

  • Human MTH1 (hMTH1) protein hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-dGTP, 8-oxo-dATP, and 2-hydroxy (OH)-dATP, thus suggesting that these oxidized nucleotides are deleterious for cells [14].
  • MTH1 hydrolyzes oxidized purine nucleoside triphosphates such as 8-oxo-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP) and 2-hydroxy-2'-deoxyadenosine 5'-triphosphate (2-OH-dATP) and thus protects cells from damage caused by their misincorporation into DNA [16].
  • Role of tryptophan residues in the recognition of mutagenic oxidized nucleotides by human antimutator MTH1 protein [19].
  • One of these, MTH1, hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-2'-deoxyguanosine triphosphate and 2-hydroxy-2'-deoxyadenosine triphosphate, to their monophosphate forms [20].
  • We have shown a significant increase in 8-oxoG in mitochondrial DNA as well as an elevated expression of MTH1, OGG1, and MUTYH in nigrostriatal dopaminergic neurons of PD patients, suggesting that the buildup of these lesions may cause dopamine neuron loss [20].
 

Other interactions of NUDT1

  • There were no clearly pathogenic mutations in MTH1 or OGG1 in any tumor [2].
  • In mammalian cells, MTH1 and NUDT5 proteins degrade 8-oxoGTP and 8-oxoGDP to 8-oxoGMP, which is an unusable form for RNA synthesis [21].
  • In this paper, we describe the hMTH1 activity for 8-chloro-dGTP, which could be formed in inflamed tissue by the reaction of dGTP with hypochlorous acid, a product of myeloperoxidase from activated human neutrophils [22].
  • Investigation of the physical and enzymatic properties of NUDT9 indicates that it is functional as a monomer, optimally active at near neutral pH, and that it requires divalent metal ions and an intact Nudix motif for enzymatic activity [23].
  • The high spontaneous hprt mutation rate of MMR-defective msh2(-/-) mouse embryonic fibroblasts was attenuated by expression of the hMTH1 protein, which degrades oxidized purine dNTPs [24].
 

Analytical, diagnostic and therapeutic context of NUDT1

  • Electron microscopic immunocytochemistry, using a specific antibody against MTH1 protein, showed localization of MTH1 protein in the mitochondrial matrix [17].
  • The hMTH1 protein was mixed with 1-20 microM of 8-chloro-dGTP and 8-hydroxy-dGTP, and the reaction products were quantified by anion-exchange HPLC to measure the pyrophosphatase reaction rate [22].
  • METHODS: We measured the level of 8-oxoG in DNA of 47 patients by high-performance liquid chromatography/electrochemical detection (HPLC/ECD), hOGG1 activity in tissue extracts of 56 patients by the nicking assay using an oligodeoxynucleotide containing a single 8-oxoG, and hMTH1 activity in tissue extracts of 33 patients by HPLC/UV detection [25].
  • Site-directed mutagenesis of diphosphoinositol polyphosphate phosphohydrolase, a dual specificity NUDT enzyme that attacks diadenosine polyphosphates and diphosphoinositol polyphosphates [26].
  • Quantitative real-time RT-PCR analysis showed that Mth1 mRNA expression was slightly, but significantly, increased in the primary carcinomas (P = 0.001 using GAPDH for normalization, and P = 0.002 using histone H4, t-test), contrary to our expectation, and was decreased to 1 / 2 in the cell lines [27].

References

  1. Structure of human MTH1, a Nudix family hydrolase that selectively degrades oxidized purine nucleoside triphosphates. Mishima, M., Sakai, Y., Itoh, N., Kamiya, H., Furuichi, M., Takahashi, M., Yamagata, Y., Iwai, S., Nakabeppu, Y., Shirakawa, M. J. Biol. Chem. (2004) [Pubmed]
  2. Germline mutations but not somatic changes at the MYH locus contribute to the pathogenesis of unselected colorectal cancers. Halford, S.E., Rowan, A.J., Lipton, L., Sieber, O.M., Pack, K., Thomas, H.J., Hodgson, S.V., Bodmer, W.F., Tomlinson, I.P. Am. J. Pathol. (2003) [Pubmed]
  3. Enhanced expression of the 8-oxo-7,8-dihydrodeoxyguanosine triphosphatase gene in human breast tumor cells. Wani, G., Milo, G.E., D'Ambrosio, S.M. Cancer Lett. (1998) [Pubmed]
  4. Biological significance of the defense mechanisms against oxidative damage in nucleic acids caused by reactive oxygen species: from mitochondria to nuclei. Nakabeppu, Y., Tsuchimoto, D., Ichinoe, A., Ohno, M., Ide, Y., Hirano, S., Yoshimura, D., Tominaga, Y., Furuichi, M., Sakumi, K. Ann. N. Y. Acad. Sci. (2004) [Pubmed]
  5. Defense mechanism to oxidative DNA damage in glial cells. Iida, T., Furuta, A., Nakabeppu, Y., Iwaki, T. Neuropathology : official journal of the Japanese Society of Neuropathology. (2004) [Pubmed]
  6. ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology. Perraud, A.L., Fleig, A., Dunn, C.A., Bagley, L.A., Launay, P., Schmitz, C., Stokes, A.J., Zhu, Q., Bessman, M.J., Penner, R., Kinet, J.P., Scharenberg, A.M. Nature (2001) [Pubmed]
  7. Spontaneous tumorigenesis in mice defective in the MTH1 gene encoding 8-oxo-dGTPase. Tsuzuki, T., Egashira, A., Igarashi, H., Iwakuma, T., Nakatsuru, Y., Tominaga, Y., Kawate, H., Nakao, K., Nakamura, K., Ide, F., Kura, S., Nakabeppu, Y., Katsuki, M., Ishikawa, T., Sekiguchi, M. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  8. A novel mechanism for preventing mutations caused by oxidation of guanine nucleotides. Ishibashi, T., Hayakawa, H., Sekiguchi, M. EMBO Rep. (2003) [Pubmed]
  9. Inhibition of 8-oxo-2'-deoxyguanosine 5'-triphosphate pyrophosphohydrolase (8-oxo-dGTPase) activity of the antimutagenic human MTH1 protein by nucleoside 5'-diphosphates. Bialkowski, K., Kasprzak, K.S. Free Radic. Biol. Med. (2003) [Pubmed]
  10. Functional significance of the conserved residues for the 23-residue module among MTH1 and MutT family proteins. Fujii, Y., Shimokawa, H., Sekiguchi, M., Nakabeppu, Y. J. Biol. Chem. (1999) [Pubmed]
  11. Sensitivity of Escherichia coli (MutT) and human (MTH1) 8-oxo-dGTPases to in vitro inhibition by the carcinogenic metals, nickel(II), copper(II), cobalt(II) and cadmium(II). Porter, D.W., Yakushiji, H., Nakabeppu, Y., Sekiguchi, M., Fivash, M.J., Kasprzak, K.S. Carcinogenesis (1997) [Pubmed]
  12. A valine to methionine polymorphism at codon 83 in the 8-oxo-dGTPase gene MTH1 is not associated with sporadic Parkinson's disease. Satoh, J., Kuroda, Y. Eur. J. Neurol. (2000) [Pubmed]
  13. Identification and characterization of FTSJ2, a novel human nucleolar protein homologous to bacterial ribosomal RNA methyltransferase. Ching, Y.P., Zhou, H.J., Yuan, J.G., Qiang, B.Q., Kung Hf, H.F., Jin, D.Y. Genomics (2002) [Pubmed]
  14. Regulation of intracellular localization of human MTH1, OGG1, and MYH proteins for repair of oxidative DNA damage. Nakabeppu, Y. Prog. Nucleic Acid Res. Mol. Biol. (2001) [Pubmed]
  15. Oxidative damage is increased in human liver tissue adjacent to hepatocellular carcinoma. Jüngst, C., Cheng, B., Gehrke, R., Schmitz, V., Nischalke, H.D., Ramakers, J., Schramel, P., Schirmacher, P., Sauerbruch, T., Caselmann, W.H. Hepatology (2004) [Pubmed]
  16. An oxidized purine nucleoside triphosphatase, MTH1, suppresses cell death caused by oxidative stress. Yoshimura, D., Sakumi, K., Ohno, M., Sakai, Y., Furuichi, M., Iwai, S., Nakabeppu, Y. J. Biol. Chem. (2003) [Pubmed]
  17. Intracellular localization of 8-oxo-dGTPase in human cells, with special reference to the role of the enzyme in mitochondria. Kang, D., Nishida, J., Iyama, A., Nakabeppu, Y., Furuichi, M., Fujiwara, T., Sekiguchi, M., Takeshige, K. J. Biol. Chem. (1995) [Pubmed]
  18. Regulation of expression of the human MTH1 gene encoding 8-oxo-dGTPase. Alternative splicing of transcription products. Oda, H., Nakabeppu, Y., Furuichi, M., Sekiguchi, M. J. Biol. Chem. (1997) [Pubmed]
  19. Role of tryptophan residues in the recognition of mutagenic oxidized nucleotides by human antimutator MTH1 protein. Takahashi, M., Maraboeuf, F., Sakai, Y., Yakushiji, H., Mishima, M., Shirakawa, M., Iwai, S., Hayakawa, H., Sekiguchi, M., Nakabeppu, Y. J. Mol. Biol. (2002) [Pubmed]
  20. Oxidative damage in nucleic acids and Parkinson's disease. Nakabeppu, Y., Tsuchimoto, D., Yamaguchi, H., Sakumi, K. J. Neurosci. Res. (2007) [Pubmed]
  21. Human polynucleotide phosphorylase protein in response to oxidative stress. Hayakawa, H., Sekiguchi, M. Biochemistry (2006) [Pubmed]
  22. 8-Chloro-dGTP, a hypochlorous acid-modified nucleotide, is hydrolyzed by hMTH1, the human MutT homolog. Fujikawa, K., Yakushiji, H., Nakabeppu, Y., Suzuki, T., Masuda, M., Ohshima, H., Kasai, H. FEBS Lett. (2002) [Pubmed]
  23. NUDT9, a member of the Nudix hydrolase family, is an evolutionarily conserved mitochondrial ADP-ribose pyrophosphatase. Perraud, A.L., Shen, B., Dunn, C.A., Rippe, K., Smith, M.K., Bessman, M.J., Stoddard, B.L., Scharenberg, A.M. J. Biol. Chem. (2003) [Pubmed]
  24. The oxidized deoxynucleoside triphosphate pool is a significant contributor to genetic instability in mismatch repair-deficient cells. Russo, M.T., Blasi, M.F., Chiera, F., Fortini, P., Degan, P., Macpherson, P., Furuichi, M., Nakabeppu, Y., Karran, P., Aquilina, G., Bignami, M. Mol. Cell. Biol. (2004) [Pubmed]
  25. Contribution of hMTH1 to the maintenance of 8-oxoguanine levels in lung DNA of non-small-cell lung cancer patients. Speina, E., Arczewska, K.D., Gackowski, D., Zielińska, M., Siomek, A., Kowalewski, J., Oliński, R., Tudek, B., Kuśmierek, J.T. J. Natl. Cancer Inst. (2005) [Pubmed]
  26. Site-directed mutagenesis of diphosphoinositol polyphosphate phosphohydrolase, a dual specificity NUDT enzyme that attacks diadenosine polyphosphates and diphosphoinositol polyphosphates. Yang, X., Safrany, S.T., Shears, S.B. J. Biol. Chem. (1999) [Pubmed]
  27. The absence of Mth1 inactivation and DNA polymerase kappa overexpression in rat mammary carcinomas with frequent A:T to C:G transversions. Okochi, E., Ichimura, S., Sugimura, T., Ushijima, T. Jpn. J. Cancer Res. (2002) [Pubmed]
 
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