Abstract
Many members of the nudix hydrolase family exhibit considerable substrate multispecificity and ambiguity, which raises significant issues when assessing their functions in vivo and gives rise to errors in database annotation. Several display low antimutator activity when expressed in bacterial tester strains as well as some degree of activity in vitro towards mutagenic, oxidized nucleotides such as 8-oxo-dGTP. However, many of these show greater activity towards other nucleotides such as ADP-ribose or diadenosine tetraphosphate (Ap4A). The antimutator activities have tended to gain prominence in the literature, whereas they may in fact represent the residual activity of an ancestral antimutator enzyme that has become secondary to the more recently evolved major activity after gene duplication. Whether any meaningful antimutagenic function has also been retained in vivo requires very careful assessment. Then again, other examples of substrate ambiguity may indicate as yet unexplored regulatory systems. For example, bacterial Ap4A hydrolases also efficiently remove pyrophosphate from the 5′ termini of mRNAs, suggesting a potential role for Ap4A in the control of bacterial mRNA turnover, while the ability of some eukaryotic mRNA decapping enzymes to degrade IDP and dIDP or diphosphoinositol polyphosphates (DIPs) may also be indicative of new regulatory networks in RNA metabolism. DIP phosphohydrolases also degrade diadenosine polyphosphates and inorganic polyphosphates, suggesting further avenues for investigation. This article uses these and other examples to highlight the need for a greater awareness of the possible significance of substrate ambiguity among the nudix hydrolases as well as the need to exert caution when interpreting incomplete analyses.
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Hult K, Berglund P (2007) Enzyme promiscuity: mechanism and applications. Trends Biotechnol 25:231–238
Khersonsky O, Roodveldt C, Tawfik DS (2006) Enzyme promiscuity: evolutionary and mechanistic aspects. Curr Opin Chem Biol 10:498–508
Khersonsky O, Tawfik DS (2010) Enzyme promiscuity: a mechanistic and evolutionary perspective. Annu Rev Biochem 79:471–505
O’Brien PJ, Herschlag D (1999) Catalytic promiscuity and the evolution of new enzymatic activities. Chem Biol 6:R91–R105
Gould SM, Tawfik DS (2005) Directed evolution of the promiscuous esterase activity of carbonic anhydrase II. Biochemistry 44:5444–5452
Copley SD (2003) Enzymes with extra talents: moonlighting functions and catalytic promiscuity. Curr Opin Chem Biol 7:265–272
O’Brien PJ, Herschlag D (2001) Functional interrelationships in the alkaline phosphatase superfamily: phosphodiesterase activity of Escherichia coli alkaline phosphatase. Biochemistry 40:5691–5699
Jensen RA (1976) Enzyme recruitment in evolution of new function. Annu Rev Microbiol 30:409–425
Schmidt DMZ, Mundorff EC, Dojka M et al (2003) Evolutionary potential of (β/α)8-barrels: functional promiscuity produced by single substitutions in the enolase superfamily. Biochemistry 42:8387–8393
Varadarajan N, Gam J, Olsen MJ et al (2005) Engineering of protease variants exhibiting high catalytic activity and exquisite substrate selectivity. Proc Natl Acad Sci USA 102:6855–6860
James LC, Tawfik DS (2003) Conformational diversity and protein evolution – a 60-year-old hypothesis revisited. Trends Biochem Sci 28:361–368
McLennan AG (2006) The Nudix hydrolase superfamily. Cell Mol Life Sci 63:123–143
Mildvan AS, Xia Z, Azurmendi HF et al (2005) Structures and mechanisms of Nudix hydrolases. Arch Biochem Biophys 433:129–143
Kraszewska E (2008) The plant Nudix hydrolase family. Acta Biochim Pol 55:663–671
Bessman MJ, Frick DN, O’Handley SF (1996) The MutT proteins or “nudix” hydrolases, a family of versatile, widely distributed, “housecleaning” enzymes. J Biol Chem 271:25059–25062
Fisher DI, Cartwright JL, Harashima H et al (2004) Characterization of a Nudix hydrolase from Deinococcus radiodurans with a marked specificity for (deoxy)ribonucleoside 5′-diphosphates. BMC Biochem 5:7
Hori M, Fujikawa K, Kasai H et al (2005) Dual hydrolysis of diphosphate and triphosphate derivatives of oxidized deoxyadenosine by Orf17 (NtpA), a MutT-type enzyme. DNA Repair 4:33–39
Ito R, Hayakawa H, Sekiguchi M et al (2005) Multiple enzyme activities of Escherichia coli MutT protein for sanitization of DNA and RNA precursor pools. Biochemistry 44:6670–6674
Xu WL, Jones CR, Dunn CA et al (2004) Gene ytkD of Bacillus subtilis encodes an atypical nucleoside triphosphatase member of the Nudix hydrolase superfamily. J Bacteriol 186:8380–8384
Safrany ST, Caffrey JJ, Yang XN et al (1998) A novel context for the ‘MutT’ module, a guardian of cell integrity, in a diphosphoinositol polyphosphate phosphohydrolase. EMBO J 17:6599–6607
Safrany ST, Ingram SW, Cartwright JL et al (1999) The diadenosine hexaphosphate hydrolases from Schizosaccharomyces pombe and Saccharomyces cerevisiae are homologues of the human diphosphoinositol polyphosphate phosphohydrolase – overlapping substrate specificities in a MutT-type protein. J Biol Chem 274:21735–21740
Fisher DI, Safrany ST, Strike P et al (2002) Nudix hydrolases that degrade dinucleoside and diphosphoinositol polyphosphates also have 5-phosphoribosyl 1-pyrophosphate (PRPP) pyrophosphatase activity that generates the glycolytic activator ribose 1,5-bisphosphate. J Biol Chem 277:47313–47317
Lawhorn BG, Gerdes SY, Begley TP (2004) A genetic screen for the identification of thiamin metabolic genes. J Biol Chem 279:43555–43559
Klaus SMJ, Wegkamp A, Sybesma W et al (2005) A nudix enzyme removes pyrophosphate from dihydroneopterin triphosphate in the folate synthesis pathway of bacteria and plants. J Biol Chem 280:5274–5280
Gabelli SB, Bianchet MA, Xu WL et al (2007) Structure and function of the E. coli dihydroneopterin triphosphate pyrophosphatase: a nudix enzyme involved in folate biosynthesis. Structure 15:1014–1022
Coseno M, Martin G, Berger C et al (2008) Crystal structure of the 25 kDa subunit of human cleavage factor Im. Nucleic Acids Res 36:3474–3483
Tresaugues L, Stenmark P, Schuler H et al (2008) The crystal structure of human cleavage and polyadenylation specific factor-5 reveals a dimeric Nudix protein with a conserved catalytic site. Proteins 73:1047–1052
Koonin EV (1993) A highly conserved sequence motif defining the family of MutT-related proteins from eubacteria, eukaryotes and viruses. Nucleic Acids Res 21:4847
Ooga T, Yoshiba S, Nakagawa N et al (2005) Molecular mechanism of the Thermus thermophilus ADP-ribose pyrophosphatase from mutational and kinetic studies. Biochemistry 44:9320–9329
Fowler RG, Schaaper RM (1997) The role of the mutT gene of Escherichia coli in maintaining replication fidelity. FEMS Microbiol Rev 21:43–54
Batra VK, Beard WA, Hou EW et al (2010) Mutagenic conformation of 8-oxo-7,8-dihydro-2′-dGTP in the confines of a DNA polymerase active site. Nat Struct Mol Biol 17:889–890
Nakamura T, Meshitsuka S, Kitagawa S et al (2010) Structural and dynamic features of the MutT protein in the recognition of nucleotides with the mutagenic 8-oxoguanine base. J Biol Chem 285:444–452
Saraswat V, Azurmendi HF, Mildvan AS (2004) Mutational, NMR, and NH exchange studies of the tight and selective binding of 8-oxo-dGMP by the MutT pyrophosphohydrolase. Biochemistry 43:3404–3414
Setoyama D, Ito R, Takagi Y et al (2011) Molecular actions of Escherichia coli MutT for control of spontaneous mutagenesis. Mutat Res 707:9–14
Kamiya H, Suzuki A, Kawai K et al (2007) Effects of 8-hydroxy-GTP and 2-hydroxy-ATP on in vitro transcription. Free Radic Biol Med 43:837–843
Taddei F, Hayakawa H, Bouton M-F et al (1997) Counteraction by MutT protein of transcriptional errors caused by oxidative damage. Science 278:128–130
Kamiya H, Ishiguro C, Harashima H (2004) Increased A:T → C:G mutations in the mutT strain upon 8-hydroxy-dGTP treatment: direct evidence for MutT involvement in the prevention of mutations by oxidized dGTP. J Biochem 136:359–362
Kamiya H (2010) Mutagenicity of oxidized DNA precursors in living cells: roles of nucleotide pool sanitization and DNA repair enzymes, and translesion synthesis DNA polymerases. Mutat Res 703:32–36
Tassotto ML, Mathews CK (2002) Assessing the metabolic function of the MutT 8-oxodeoxyguanosine triphosphatase in Escherichia coli by nucleotide pool analysis. J Biol Chem 277:15807–15812
Rotman E, Kuzminov A (2007) The mutT defect does not elevate chromosomal fragmentation in Escherichia coli because of the surprisingly low levels of MutM/MutY-recognized DNA modifications. J Bacteriol 189:6976–6988
Hori M, Asanuma T, Inanami O et al (2006) Effects of overexpression and antisense RNA expression of Orf17, a MutT-type enzyme. Biol Pharm Bull 29:1087–1091
Gerdes SY, Scholle MD, Campbell JW et al (2003) Experimental determination and system level analysis of essential genes in Escherichia coli MG1655. J Bacteriol 185:5673–5684
McLennan AG (2007) Folate synthesis: an old enzyme identified. Structure 15:891–892
Fujikawa K, Kasai H (2002) The oxidized pyrimidine ribonucleotide, 5-hydroxy-CTP, is hydrolyzed efficiently by the Escherichia coli recombinant Orf135 protein. DNA Repair 1:571–576
Iida E, Satou K, Mishima M et al (2005) Amino acid residues involved in substrate recognition of the Escherichia coli Orf 135 protein. Biochemistry 44:5683–5689
O’Handley SF, Dunn CA, Bessman MJ (2001) Orf135 from Escherichia coli is a nudix hydrolase specific for CTP, dCTP, and 5-methyl-dCTP. J Biol Chem 276:5421–5426
Fujikawa K, Kamiya H, Kasa H (1998) The mutations induced by oxidatively damaged nucleotides, 5-formyl-dUTP and 5-hydroxy-dCTP in Escherichia coli. Nucleic Acids Res 26:4582–4587
Kamiya H, Iida E, Murata-Kamiya N et al (2003) Suppression of spontaneous and hydrogen peroxide-induced mutations by a MutT-type nucleotide pool sanitization enzyme, the Escherichia coli Orf135 protein. Genes Cells 8:941–950
Kellinger MW, Song CX, Chong J et al (2012) 5-Formylcytosine and 5-carboxylcytosine reduce the rate and substrate specificity of RNA polymerase II transcription. Nat Struct Mol Biol 19:831–833
Ramirez MI, Castellanos-Juarez FX, Yasbin RE et al (2004) The ytkD (mutTA) gene of Bacillus subtilis encodes a functional antimutator 8-oxo-(dGTP/GTP)ase and is under dual control of sigma A and sigma F RNA polymerases. J Bacteriol 186:1050–1059
Richards J, Liu Q, Pellegrini O et al (2011) An RNA pyrophosphohydrolase triggers 5′-exonucleolytic degradation of mRNA in Bacillus subtilis. Mol Cell 43:940–949
Fujikawa K, Kamiya H, Yakushiji H et al (1999) The oxidized forms of dATP are substrates for the human MutT homologue, the hMTH1 protein. J Biol Chem 274:18201–18205
Fujikawa K, Kamiya H, Yakushiji H et al (2001) Human MTH1 protein hydrolyzes the oxidized ribonucleotide, 2-hydroxy-ATP. Nucleic Acids Res 29:449–454
Nakabeppu Y, Oka S, Sheng Z et al (2010) 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
Rai P (2010) Oxidation in the nucleotide pool, the DNA damage response and cellular senescence: defective bricks build a defective house. Mutat Res 703:71–81
Ventura I, Russo MT, De Luca G et al (2010) Oxidized purine nucleotides, genome instability and neurodegeneration. Mutat Res 703:59–65
Nakabeppu Y, Kajitani K, Sakamoto K et al (2006) MTH1, an oxidized purine nucleoside triphosphatase, prevents the cytotoxicity and neurotoxicity of oxidized purine nucleotides. DNA Repair 5:761–772
Tsuzuki T, Egashira A, Kura S (2001) Analysis of MTH1 gene function in mice with targeted mutagenesis. Mutat Res 477:71–78
Tsuzuki T, Egashira A, Igarashi H et al (2001) Spontaneous tumorigenesis in mice defective in the MTH1 gene encoding 8-oxo-dGTPase. Proc Natl Acad Sci USA 98:11456–11461
Rai P, Young JJ, Burton DG et al (2011) Enhanced elimination of oxidized guanine nucleotides inhibits oncogenic RAS-induced DNA damage and premature senescence. Oncogene 30:1489–1496
Egashira A, Yamauchi K, Yoshiyama K et al (2002) Mutational specificity of mice defective in the MTH1 and/or the MSH2 genes. DNA Repair 1:881–893
Hori M, Satou K, Harashima H et al (2010) Suppression of mutagenesis by 8-hydroxy-2′-deoxyguanosine 5′-triphosphate (7,8-dihydro-8-oxo-2′-deoxyguanosine 5′-triphosphate) by human MTH1, MTH2, and NUDT5. Free Radic Biol Med 48:1197–1201
Rai P (2012) Human Mut T homolog 1 (MTH1): a roadblock for the tumor-suppressive effects of oncogenic RAS-induced ROS. Small GTPases 3:120–125
Svensson LM, Jemth AS, Desroses M et al (2011) Crystal structure of human MTH1 and the 8-oxo-dGMP product complex. FEBS Lett 585:2617–2621
Josephy PD (2000) The Escherichia coli lacZ reversion mutagenicity assay. Mutat Res 455:71–80
Cai JP, Ishibashi T, Takagi Y et al (2003) Mouse MTH2 protein which prevents mutations caused by 8-oxoguanine nucleotides. Biochem Biophys Res Commun 305:1073–1077
Takagi Y, Setoyama D, Ito R et al (2012) Human MTH3 (NUDT18) protein hydrolyzes oxidized forms of guanosine and deoxyguanosine diphosphates: comparison with MTH1 and MTH2. J Biol Chem 287:21541–21549
Yoshimura K, Ogawa T, Ueda Y et al (2007) AtNUDX1, an 8-oxo-7,8-dihydro-2′-deoxyguanosine 5′-triphosphate pyrophosphohydrolase, is responsible for eliminating oxidized nucleotides in Arabidopsis. Plant Cell Physiol 48:1438–1449
Yu Y, Cai JP, Tu B et al (2009) Proliferating cell nuclear antigen is protected from degradation by forming a complex with MutT Homolog2. J Biol Chem 284:19310–19320
Sanada U, Yonekura S-I, Kikuchi M et al (2011) NDX-1 protein hydrolyses 8-oxo-7,8-dihydrodeoxyguanosine-5′-diphosphate to sanitize oxidized nucleotides and prevent oxidative stress in Caenorhabditis elegans. J Biochem 150:649–657
Yang HJ, Slupska MM, Wei YF et al (2000) Cloning and characterization of a new member of the nudix hydrolases from human and mouse. J Biol Chem 275:8844–8853
Gasmi L, Cartwright JL, McLennan AG (1999) Cloning, expression and characterization of YSA1H, a human adenosine 5′-diphosphosugar pyrophosphatase possessing a MutT motif. Biochem J 344:331–337
Ribeiro JM, Carloto A, Costas MJ et al (2001) Human placenta hydrolases active on free ADP-ribose: an ADP-sugar pyrophosphatase and a specific ADP-ribose pyrophosphatase. Biochim Biophys Acta 1526:86–94
Dunn CA, O’Handley SF, Frick DN et al (1999) Studies on the ADP-ribose pyrophosphatase subfamily of the Nudix hydrolases and tentative identification of trgB, a gene associated with tellurite resistance. J Biol Chem 274:32318–32324
Moreno-Bruna B, Baroja-Fernandez E, Muñoz FJ et al (2001) Adenosine diphosphate sugar pyrophosphatase prevents glycogen biosynthesis in Escherichia coli. Proc Natl Acad Sci USA 98:8128–8132
Muñoz FJ, Baroja-Fernandez E, Moran-Zorzano MT et al (2006) Cloning, expression and characterization of a Nudix hydrolase that catalyzes the hydrolytic breakdown of ADP-glucose linked to starch biosynthesis in Arabidopsis thaliana. Plant Cell Physiol 47:926–934
Muñoz FJ, Baroja-Fernandez E, Ovecka M et al (2008) Plastidial localization of a potato nudix hydrolase of ADP-glucose linked to starch biosynthesis. Plant Cell Physiol 49:1734–1746
Tong L, Lee S, Denu JM (2009) Hydrolase regulates NAD+ metabolites and modulates cellular redox. J Biol Chem 284:11256–11266
Formentini L, Macchiarulo A, Cipriani G et al (2009) Poly(ADP-ribose) catabolism triggers AMP-dependent mitochondrial energy failure. J Biol Chem 284:17668–17676
Ishibashi T, Hayakawa H, Ito R et al (2005) Mammalian enzymes for preventing transcriptional errors caused by oxidative damage. Nucleic Acids Res 33:3779–3784
Ishibashi T, Hayakawa H, Sekiguchi M (2003) A novel mechanism for preventing mutations caused by oxidation of guanine nucleotides. EMBO Rep 4:479–483
Kamiya H, Hori M, Arimori T et al (2009) NUDT5 hydrolyzes oxidized deoxyribonucleoside diphosphates with broad substrate specificity. DNA Repair 8:1250–1254
Arczewska KD, Baumeier C, Kassahun H et al (2011) Caenorhabditis elegans NDX-4 is a MutT-type enzyme that contributes to genomic stability. DNA Repair 10:176–187
Arimori T, Tamaoki H, Nakamura T et al (2011) Diverse substrate recognition and hydrolysis mechanisms of human NUDT5. Nucleic Acids Res 39:8972–8983
Ito R, Sekiguchi M, Setoyama D et al (2011) Cleavage of oxidized guanine nucleotide and ADP sugar by human NUDT5 protein. J Biochem 149:731–738
Zhang LQ, Dai DP, Gan W et al (2012) Lowered nudix type 5 (NUDT5) expression leads to cell cycle retardation in HeLa cells. Mol Cell Biochem 363:377–384
Sheikh S, O’Handley SF, Dunn CA et al (1998) Identification and characterization of the Nudix hydrolase from the archaeon, Methanococcus jannaschii, as a highly specific ADP-ribose pyrophosphatase. J Biol Chem 273:20924–20928
Guranowski A (2000) Specific and nonspecific enzymes involved in the catabolism of mononucleoside and dinucleoside polyphosphates. Pharmacol Ther 87:117–139
Abdelghany HM, Bailey S, Blackburn GM et al (2003) Analysis of the catalytic and binding residues of the diadenosine tetraphosphate pyrophosphohydrolase from Caenorhabditis elegans by site-directed mutagenesis. J Biol Chem 278:4435–4439
Abdelghany HM, Gasmi L, Cartwright JL et al (2001) Cloning, characterisation and crystallisation of a diadenosine 5′,5′′′-P1, P4-tetraphosphate pyrophosphohydrolase from Caenorhabditis elegans. Biochim Biophys Acta 1550:27–36
Bailey S, Sedelnikova SE, Blackburn GM et al (2002) The crystal structure of diadenosine tetraphosphate hydrolase from Caenorhabditis elegans in free and binary complex forms. Structure 10:589–600
McLennan AG (2000) Dinucleoside polyphosphates – friend or foe? Pharmacol Ther 87:73–89
Abdelghany HM (2003) Cloning, expression and mutational analysis of recombinant diadenosine tetraphosphate hydrolase from Caenorhabditis elegans. School of Biological Sciences. University of Liverpool, p 234
Carmi-Levy I, Yannay-Cohen N, Kay G et al (2008) Diadenosine tetraphosphate hydrolase is part of the transcriptional regulation network in immunologically activated mast cells. Mol Cell Biol 28:5777–5784
Lee Y-N, Razin E (2005) Nonconventional involvement of LysRS in the molecular mechanism of USF2 transcriptional activity in FcεRI-activated mast cells. Mol Cell Biol 25:8904–8912
Jansson K, Blomberg A, Sunnerhagen P et al (2010) Evolutionary loss of 8-oxo-G repair components among eukaryotes. Genome Integr 1:12
Hazra TK, Hill JW, Izumi T et al (2001) Multiple DNA glycosylases for repair of 8-oxoguanine and their potential in vivo functions. Prog Nucleic Acid Res Mol Biol 68:193–205
Nunoshiba T, Ishida R, Sasaki M et al (2004) A novel Nudix hydrolase for oxidized purine nucleoside triphosphates encoded by ORFYLR151c (PCD1 gene) in Saccharomyces cerevisiae. Nucleic Acids Res 32:5339–5348
Cartwright JL, Gasmi L, Spiller DG et al (2000) The Saccharomyces cerevisiae PCD1 gene encodes a peroxisomal nudix hydrolase active towards coenzyme A and its derivatives. J Biol Chem 275:32925–32930
Ito D, Yoshimura K, Ishikawa K et al (2012) A comparative analysis of the molecular characteristics of the Arabidopsis CoA pyrophosphohydrolases AtNUDX11, 15, and 15a. Biosci Biotechnol Biochem 76:139–147
Chu C, Alapat D, Wen XP et al (2004) Ectopic expression of murine diphosphoinositol polyphosphate phosphohydrolase 1 attenuates signaling through the ERK1/2 pathway. Cell Signal 16:1045–1059
Li AW, Too CKL, Knee R et al (1997) FGF-2 antisense RNA encodes a nuclear protein with MutT-like antimutator activity. Mol Cell Endocrinol 133:177–182
Tremblay LW, Dunaway-Mariano D, Allen KN (2006) Structure and activity analyses of Escherichia coli K-12 NagD provide insight into the evolution of biochemical function in the haloalkanoic acid dehalogenase superfamily. Biochemistry 45:1183–1193
Kumar D, Abdulovic AL, Viberg J et al (2011) Mechanisms of mutagenesis in vivo due to imbalanced dNTP pools. Nucleic Acids Res 39:1360–1371
Kunz BA, Kohalmi SE, Kunkel TA et al (1994) Deoxyribonucleoside triphosphate levels: a critical factor in the maintenance of genetic stability. Mutat Res 318:1–64
Rampazzo C, Miazzi C, Franzolin E et al (2010) Regulation by degradation, a cellular defense against deoxyribonucleotide pool imbalances. Mutat Res 703:2–10
Steyert SR, Messing SAJ, Amzel LM et al (2008) Identification of Bdellovibrio bacteriovorus HD100 Bd0714 as a nudix dGTPase. J Bacteriol 190:8215–8219
Buchko GW, Edwards TE, Abendroth J et al (2011) Structure of a Nudix hydrolase (MutT) in the Mg2+-bound state from Bartonella henselae, the bacterium responsible for cat scratch fever. Acta Crystallogr Sect F 67:1078–1083
Dos Vultos T, Blazquez J, Rauzier J et al (2006) Identification of nudix hydrolase family members with an antimutator role in Mycobacterium tuberculosis and Mycobacterium smegmatis. J Bacteriol 188:3159–3161
Moreland NJ, Charlier C, Dingley AJ et al (2009) Making sense of a missense mutation: characterization of MutT2, a nudix hydrolase from Mycobacterium tuberculosis, and the G58R mutant encoded in W-Beijing strains of M. tuberculosis. Biochemistry 48:699–708
Osburne MS, Holmbeck BM, Frias-Lopez J et al (2010) UV hyper-resistance in Prochlorococcus MED4 results from a single base pair deletion just upstream of an operon encoding nudix hydrolase and photolyase. Environ Microbiol 12:1978–1988
Yonekura SI, Sanada U, Zhang-Akiyama QM (2010) CiMutT, an asidian MutT homologue, has a 7, 8-dihydro-8-oxo-dGTP pyrophosphohydrolase activity responsible for sanitization of oxidized nucleotides in Ciona intestinalis. Genes Genet Sys 85:287–295
Engelhardt BE, Jordan MI, Srouji JR et al (2011) Genome-scale phylogenetic function annotation of large and diverse protein families. Genome Res 21:1969–1980
Fowler RG, White SJ, Koyama C et al (2003) Interactions among the Escherichia coli mutT, mutM, and mutY damage prevention pathways. DNA Repair 2:159–173
Vidmar JJ, Cupples CG (1993) MutY repair is mutagenic in mutT - strains of Escherichia coli. Can J Microbiol 39:892–894
Messing SAJ, Gabelli SB, Liu QS et al (2009) Structure and biological function of the RNA pyrophosphohydrolase BdRppH from Bdellovibrio bacteriovorus. Structure 17:472–481
Cartwright JL, Britton P, Minnick MF et al (1999) The ialA invasion gene of Bartonella bacilliformis encodes a (di)nucleoside polyphosphate hydrolase of the MutT motif family and has homologs in other invasive bacteria. Biochem Biophys Res Commun 256:474–479
Gaywee J, Xu WL, Radulovic S et al (2002) The Rickettsia prowazekii invasion gene homolog (invA) encodes a Nudix hydrolase active on adenosine (5′)-pentaphospho-(5′)-adenosine. Mol Cell Proteomics 1:179–185
Ismail T, Hart CA, McLennan AG (2003) Regulation of dinucleoside polyphosphate pools by the YgdP and ApaH hydrolases is essential for the ability of Salmonella enterica serovar Typhimurium to invade cultured mammalian cells. J Biol Chem 278:32602–32607
Lundin A, Nilsson C, Gerhard M et al (2003) The NudA protein in the gastric pathogen Helicobacter pylori is an ubiquitous and constitutively expressed dinucleoside polyphosphate hydrolase. J Biol Chem 278:12574–12578
Urick T, I-Chang C, Arena E et al (2005) The pnhA gene of Pasteurella multocida encodes a dinucleoside oligophosphate pyrophosphatase member of the nudix hydrolase superfamily. J Bacteriol 187:5809–5817
Bessman MJ, Walsh JD, Dunn CA et al (2001) The gene ygdP, associated with the invasiveness of Escherichia coli K1, designates a nudix hydrolase, Orf176, active on adenosine (5′)-pentaphospho-(5′)-adenosine (Ap5A). J Biol Chem 276:37834–37838
Edelstein PH, Hu BF, Shinzato T et al (2005) Legionella pneumophila NudA is a nudix hydrolase and virulence factor. Infect Immun 73:6567–6576
Deana A, Celesnik H, Belasco JG (2008) The bacterial enzyme RppH triggers messenger RNA degradation by 5′ pyrophosphate removal. Nature 451:355–359
Butland G, Peregrin-Alvarez JM, Li J et al (2005) Interaction network containing conserved and essential protein complexes in Escherichia coli. Nature 433:531–537
Nazemof N (2009) yciL, yfgB, ygdP and ybcJ are novel genes that affect the process of protein synthesis in Escherichia coli. Dissertation. Carleton University, Ottawa, p 95
Blanchin-Roland S, Blanquet S, Schmitter JM et al (1986) The gene for Escherichia coli diadenosine tetraphosphatase is located immediately clockwise to folA and forms an operon with ksgA. Mol Gen Genet 205:515–522
Li S, Armstrong CM, Bertin N et al (2004) A map of the interactome network of the metazoan C. elegans. Science 303:540–543
Zhang HB, Alramini H, Tran V et al (2011) Nucleus-localized antisense small RNAs with 5′-polyphosphate termini regulate long term transcriptional gene silencing in Entamoeba histolytica G3 strain. J Biol Chem 286:44467–44479
Chen YG, Kowtoniuk WE, Agarwal I et al (2009) LC/MS analysis of cellular RNA reveals NAD-linked RNA. Nat Chem Biol 5:879–881
Kowtoniuk WE, Shen Y, Heemstra JM et al (2009) A chemical screen for biological small molecule-RNA conjugates reveals CoA-linked RNA. Proc Natl Acad Sci USA 106:7768–7773
Bail S, Kiledjian M (2009) Tri- to be mono- for bacterial mRNA decay. Structure 17:317–319
Ghosh T, Peterson B, Tomasevic N et al (2004) Xenopus U8 snoRNA binding protein is a conserved nuclear decapping enzyme. Mol Cell 13:817–828
Taylor MJ, Peculis BA (2008) Evolutionary conservation supports ancient origin for Nudt16, a nuclear-localized, RNA-binding, RNA-decapping enzyme. Nucleic Acids Res 36:6021–6034
Lu G, Zhang J, Li Y et al (2011) hNUDT16: a universal decapping enzyme for small nucleolar RNA and cytoplasmic mRNA. Protein Cell 2:64–73
Peculis BA, Reynolds K, Cleland M (2007) Metal determines efficiency and substrate specificity of the nuclear NUDIX decapping proteins X29 and H29 K (Nudt16). J Biol Chem 282:24792–24805
Song MG, Li Y, Kiledjian M (2010) Multiple mRNA decapping enzymes in mammalian cells. Mol Cell 40:423–432
Iyama T, Abolhassani N, Tsuchimoto D et al (2010) NUDT16 is a (deoxy)inosine diphosphatase, and its deficiency induces accumulation of single-strand breaks in nuclear DNA and growth arrest. Nucleic Acids Res 38:4834–4843
Abolhassani N, Iyama T, Tsuchimoto D et al (2010) NUDT16 and ITPA play a dual protective role in maintaining chromosome stability and cell growth by eliminating dIDP/IDP and dITP/ITP from nucleotide pools in mammals. Nucleic Acids Res 38:2891–2903
Decker CJ, Parker R (2002) mRNA decay enzymes: decappers conserved between yeast and mammals. Proc Natl Acad Sci USA 99:12512–12514
Dunckley T, Parker R (1999) The DCP2 protein is required for mRNA decapping in Saccharomyces cerevisiae and contains a functional MutT motif. EMBO J 18:5411–5422
Piccirillo C, Khanna R, Kiledjian M (2003) Functional characterization of the mammalian mRNA decapping enzyme hDcp2. RNA 9:1138–1147
Geisler S, Coller J (2010) Alternate endings: a new story for mRNA decapping. Mol Cell 40:349–350
Li Y, Song MG, Kiledjian M (2008) Transcript-specific decapping and regulated stability by the human Dcp2 decapping protein. Mol Cell Biol 28:939–948
Parrish S, Hurchalla M, Liu SW et al (2009) The African swine fever virus g5R protein possesses mRNA decapping activity. Virology 393:177–182
Cartwright JL, Safrany ST, Dixon LK et al (2002) The g5R (D250) gene of African swine fever virus encodes a nudix hydrolase that preferentially degrades diphosphoinositol polyphosphates. J Virol 76:1415–1421
Barker CJ, Illies C, Gaboardi GC et al (2009) Inositol pyrophosphates: structure, enzymology and function. Cell Mol Life Sci 66:3851–3871
Burton A, Hu XW, Saiardi A (2009) Are inositol pyrophosphates signalling molecules? J Cell Physiol 220:8–15
Shears SB (2009) Diphosphoinositol polyphosphates: metabolic messengers? Mol Pharmacol 76:236–252
Shears SB, Gokhale NA, Wang HC et al (2011) Diphosphoinositol polyphosphates: what are the mechanisms? Adv Enzyme Regul 51:13–25
McLennan AG (2007) Decapitation: poxvirus makes RNA lose its head. Trends Biochem Sci 32:297–299
Duong-Ly KC, Gabelli SB, Xu WL et al (2011) The nudix hydrolase CDP-Chase, a CDP-choline pyrophosphatase, is an asymmetric dimer with two distinct enzymatic activities. J Bacteriol 193:3175–3185
Cartwright JL, McLennan AG (1999) The Saccharomyces cerevisiae YOR163w gene encodes a diadenosine 5′,5′′′-P1, P6-hexaphosphate hydrolase member of the MutT motif (nudix hydrolase) family. J Biol Chem 274:8604–8610
Ingram SW, Stratemann SA, Barnes LD (1999) Schizosaccharomyces pombe Aps1, a diadenosine 5′,5′′′-P1, P6- hexaphosphate hydrolase that is a member of the nudix (MutT) family of hydrolases: cloning of the gene and characterization of the purified enzyme. Biochemistry 38:3649–3655
Caffrey JJ, Safrany ST, Yang XN et al (2000) Discovery of molecular and catalytic diversity among human diphosphoinositol-polyphosphate phosphohydrolases – an expanding NUDT family. J Biol Chem 275:12730–12736
Hidaka K, Caffrey JJ, Hua L et al (2002) An adjacent pair of human NUDT genes on chromosome X are preferentially expressed in testis and encode two new isoforms of diphosphoinositol polyphosphate phosphohydrolase. J Biol Chem 277:32730–32738
Leslie NR, McLennan AG, Safrany ST (2002) Cloning and characterisation of hAps1 and hAps2, human diadenosine polyphosphate-metabolising Nudix hydrolases. BMC Biochem 3:20
Winward L, Whitfield WGF, McLennan AG et al (2010) Oxidation of the diphosphoinositol polyphosphate phosphohydrolase-like Nudix hydrolase Aps from Drosophila melanogaster induces thermolability – a possible regulatory switch? Int J Biochem Cell Biol 42:1174–1181
Garza JA, Ilangovan U, Hinck AP et al (2009) Kinetic, dynamic, ligand binding properties, and structural models of a dual-substrate specific nudix hydrolase from Schizosaccharomyces pombe. Biochemistry 48:6224–6239
Yang XN, Safrany ST, Shears SB (1999) Site-directed mutagenesis of diphosphoinositol polyphosphate phosphohydrolase, a dual specificity NUDT enzyme that attacks diadenosine polyphosphates and diphosphoinositol polyphosphates. J Biol Chem 274:35434–35440
Bhandari R, Chakraborty A, Snyder SH (2007) Inositol pyrophosphate pyrotechnics. Cell Metab 5:321–323
Lonetti A, Szijgyarto Z, Bosch D et al (2011) Identification of an evolutionarily conserved family of inorganic polyphosphate endopolyphosphatases. J Biol Chem 286:31966–31974
Jankowski V, van der Giet M, Mischak H et al (2009) Dinucleoside polyphosphates: strong endogenous agonists of the purinergic system. Br J Pharmacol 157:1142–1153
Ingram SW, Safrany ST, Barnes LD (2003) Disruption and overexpression of the Schizosaccharomyces pombe aps1 gene, and effects on growth rate, morphology and intracellular diadenosine 5′,5′′′-P1, P5-pentaphosphate and diphosphoinositol polyphosphate concentrations. Biochem J 369:519–528
Hua LV, Hidaka K, Pesesse X et al (2003) Paralogous murine Nudt10 and Nudt11 genes have differential expression patterns but encode identical proteins that are physiologically competent diphosphoinositol polyphosphate phosphohydrolases. Biochem J 373:81–89
Dobrzanska M, Szurmak B, Wyslouch-Cieszynska A et al (2002) Cloning and characterization of the first member of the Nudix family from Arabidopsis thaliana. J Biol Chem 277:50482–50486
Szurmak B, Wyslouch-Cieszynska A, Wszelaka-Rylik M et al (2008) A diadenosine 5′,5″′-P1P4 tetraphosphate (Ap4A) hydrolase from Arabidopsis thaliana that is activated preferentially by Mn2+ ions. Acta Biochim Pol 55:151–160
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McLennan, A.G. Substrate ambiguity among the nudix hydrolases: biologically significant, evolutionary remnant, or both?. Cell. Mol. Life Sci. 70, 373–385 (2013). https://doi.org/10.1007/s00018-012-1210-3
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DOI: https://doi.org/10.1007/s00018-012-1210-3