Phosphate bond hydrolysis by NUDT proteins

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R-HSA-2393930
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Pathway
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Homo sapiens
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Enzymes that belong to the NUDT (Nudix) superfamily catalyze the hydrolysis of phosphodiester bonds in molecules including nucleoside triphosphates and diphosphates and nucleotide sugars. Family members are defined by the presence of an amino acid sequence motif shared with the E. coli MutT gene product, and are involved in diverse physiological processes (Mildvan et al. 2005; McLennan 2006).

The hydrolysis of nucleoside di and triphosphates whose purine bases have been oxidized or deaminated may protect the cell from the mutational damage that would occur if modified deoxyribonucleotides were incorporated into DNA and from the aberrant protein synthesis that would occur if modified ribonucleotides were incorporated into mRNA (Iyama et al. 2010; Takagi et al. 2012). The hydrolysis of ADP ribose may prevent the aberrant spontaneous ADP ribosylation of cellular proteins that could occur were this molecule to accumulate to high levels in the cell (Perraud et al. 2003; Shen et al. 2003). 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
16378245 The Nudix hydrolase superfamily

McLennan, AG

Cell. Mol. Life Sci. 2006
12427752 NUDT9, a member of the Nudix hydrolase family, is an evolutionarily conserved mitochondrial ADP-ribose pyrophosphatase

Perraud, AL, Shen, BW, Dunn, CA, Rippe, K, Smith, MK, Bessman, MJ, Stoddard, BL, Scharenberg, AM

J. Biol. Chem. 2003
12948489 The crystal structure and mutational analysis of human NUDT9

Shen, BW, Perraud, AL, Scharenberg, AM, Stoddard, BL

J. Mol. Biol. 2003
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
15581572 Structures and mechanisms of Nudix hydrolases

Mildvan, AS, Xia, Z, Azurmendi, HF, Saraswat, V, Legler, PM, Massiah, MA, Gabelli, SB, Bianchet, MA, Kang, LW, Amzel, LM

Arch. Biochem. Biophys. 2005
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
20385596 NUDT16 is a (deoxy)inosine diphosphatase, and its deficiency induces accumulation of single-strand breaks in nuclear DNA and growth arrest

Iyama, T, Abolhassani, N, Tsuchimoto, D, Nonaka, M, Nakabeppu, Y

Nucleic Acids Res. 2010
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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