NUDT1 hydrolyses 2-OH-dATP to 2-OH-dAMP

Stable Identifier
R-HSA-2395818
Type
Reaction [transition]
Species
Homo sapiens
Compartment
Synonyms
2-hydroxy-dATP + H2O => 2-hydroxy-dAMP + PPi
Locations in the PathwayBrowser
General
SVG |   | PPTX  | SBGN
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout

NUDT1 (MTH1) catalyzes the reaction of 2-hydroxy-dATP and water to form 2-hydroxy-dAMP 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 shown to catalyze hydrolysis of 2-hydroxy-dATP (Fujikawa et al. 1993; Sakai et al. 2002). 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 modified adenosine bases in DNA in mutant mouse cells lacking endogenous NUDT1 activity (Yoshimura et al. 2003).

Together, these data support the hypothesis that by cleaving 2-hydroxy-dATP 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
11756418 A molecular basis for the selective recognition of 2-hydroxy-dATP and 8-oxo-dGTP by human MTH1

Sakai, Y, Furuichi, M, Takahashi, M, Mishima, M, Iwai, S, Shirakawa, M, Nakabeppu, Y

J. Biol. Chem. 2002
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
10373420 The oxidized forms of dATP are substrates for the human MutT homologue, the hMTH1 protein

Fujikawa, K, Kamiya, H, Yakushiji, H, Fujii, Y, Nakabeppu, Y, Kasai, H

J. Biol. Chem. 1999
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
Participants
Participant Of
Catalyst Activity
Catalyst Activity
Title
2-hydroxy-(deoxy)adenosine-triphosphate pyrophosphatase activity of NUDT1 [cytosol]
Physical Entity
Activity
Orthologous Events
Cross References
Rhea
Authored
Reviewed
Created