NUDT1 hydrolyses 8-oxo-dGTP to 8-oxo-dGMP

Stable Identifier
R-HSA-2395849
Type
Reaction [transition]
Species
Homo sapiens
Compartment
Synonyms
8-oxo-dGTP + H2O => 8-oxo-dGMP + PPi (NUDT1)
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NUDT1 (MTH1) catalyzes the reaction of 8-oxo-dGTP and water to form 8-oxo-dGMP and PPi (pyrophosphate). Four NUDT1 proteins have been identified, encoded by a single gene with alternative start codons (Oda et al. 1999). The shortest of these, NUDT1 p18, has been biochemically (Sakumi et al. 1993; Takagi et al. 2012) and structurally (Mishima et al. 2004) characterized and shown to catalyze hydrolysis of 8-oxo-dGTP. The active enzyme is a monomer associated with a magnesium ion (Mishima et al. 2004). The longer isoforms all consist of the p18 polypeptide with aminoterminal extensions and are presumed to be active as well but have not been experimentally characterized. The p18 isoform is predominantly cytosolic (Kang et al. 1995). Its expression prevents the accumulation of oxo-guanine bases in DNA in mutant mouse cells lacking endogenous NUDT1 activity (Yoshimura et al. 2003).

Together, these data support the hypothesis that by cleaving 8-oxo-dGTP and thus preventing its incorporation into DNA NUDT1 provides a physiologically important defense against mutagenesis due to oxidative stress. This hypothesis is further supported by the demonstration that mice lacking NUDT1 show an increased lifetime incidence of liver and other tumors compared to normal controls, and that rapidly metabolizing tumor cells in culture are killed under conditions where synthesis of NUDT1 protein is suppressed or its catalytic activity is inhibited (Gad et al. 2014; Huber et al. 2014).

Literature References
PubMed ID Title Journal Year
24695224 MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool

Gad, H, Koolmeister, T, Jemth, AS, Eshtad, S, Jacques, SA, Ström, CE, Svensson, LM, Schultz, N, Lundbäck, T, Einarsdottir, BO, Saleh, A, Göktürk, C, Baranczewski, P, Svensson, R, Berntsson, RP, Gustafsson, R, Strömberg, K, Sanjiv, K, Jacques-Cordonnier, MC, Desroses, M, Gustavsson, AL, Olofsson, R, Johansson, F, Homan, EJ, Loseva, O, Bräutigam, L, Johansson, L, Höglund, A, Hagenkort, A, Pham, T, Altun, M, Gaugaz, FZ, Vikingsson, S, Evers, B, Henriksson, M, Vallin, KS, Wallner, OA, Hammarström, LG, Wiita, E, Almlöf, I, Kalderén, C, Axelsson, H, Djureinovic, T, Puigvert, JC, Häggblad, M, Jeppsson, F, Martens, U, Lundin, C, Lundgren, B, Granelli, I, Jensen, AJ, Artursson, P, Nilsson, JA, Stenmark, P, Scobie, M, Berglund, UW, Helleday, T

Nature 2014
15133035 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
12857738 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
22556419 Human MTH3 (NUDT18) Protein Hydrolyzes Oxidized Forms of Guanosine and Deoxyguanosine Diphosphates: COMPARISON WITH MTH1 AND MTH2

Takagi, Y, Setoyama, D, Ito, R, Kamiya, H, Yamagata, Y, Sekiguchi, M

J. Biol. Chem. 2012
10536140 Multi-forms of human MTH1 polypeptides produced by alternative translation initiation and single nucleotide polymorphism

Oda, H, Taketomi, A, Maruyama, R, Itoh, R, Nishioka, K, Yakushiji, H, Suzuki, T, Sekiguchi, M, Nakabeppu, Y

Nucleic Acids Res. 1999
7782328 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
8226881 Cloning and expression of cDNA for a human enzyme that hydrolyzes 8-oxo-dGTP, a mutagenic substrate for DNA synthesis

Sakumi, K, Furuichi, M, Tsuzuki, T, Kakuma, T, Kawabata, S, Maki, H, Sekiguchi, M

J. Biol. Chem. 1993
24695225 Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy

Huber, KV, Salah, E, Radic, B, Gridling, M, Elkins, JM, Stukalov, A, Jemth, AS, Göktürk, C, Sanjiv, K, Strömberg, K, Pham, T, Berglund, UW, Colinge, J, Bennett, KL, Loizou, JI, Helleday, T, Knapp, S, Superti-Furga, G

Nature 2014
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Title
8-oxo-7,8-dihydrodeoxyguanosine triphosphate pyrophosphatase activity of NUDT1 [cytosol]
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