Structure of Human MTH1, a Nudix Family Hydrolase That Selectively Degrades Oxidized Purine Nucleoside Triphosphates

Oxygen radicals generated through normal cellular respiration processes can cause mutations in genomic and mitochondrial DNA. Human MTH1 hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-dGTP and 2-hydroxy-dATP, to monophosphates, thereby preventing the misincorporation of these oxidized nucleotides during replication. Here we present the solution structure of MTH1 solved by multidimensional heteronuclear NMR spectroscopy. The protein adopts a fold similar to that of Escherichia coli MutT, despite the low sequence similarity between these proteins outside the conserved Nudix motif. The substrate-binding pocket of MTH1, deduced from chemical shift perturbation experiments, is located at essentially the same position as in MutT; however, a pocket-forming helix is largely displaced in MTH1 (∼9 Å) such that the shape of the pocket differs between the two proteins. Detailed analysis of the pocket-forming residues enabled us to identify Asn33 as one of the key residues in MTH1 for discriminating the oxidized form of purine, and mutation of this residue modifies the substrate specificity. We also show that MTH1 catalyzes hydrolysis of 8-oxo-dGTP through nucleophilic substitution of water at the β-phosphate. Oxygen radicals generated through normal cellular respiration processes can cause mutations in genomic and mitochondrial DNA. Human MTH1 hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-dGTP and 2-hydroxy-dATP, to monophosphates, thereby preventing the misincorporation of these oxidized nucleotides during replication. Here we present the solution structure of MTH1 solved by multidimensional heteronuclear NMR spectroscopy. The protein adopts a fold similar to that of Escherichia coli MutT, despite the low sequence similarity between these proteins outside the conserved Nudix motif. The substrate-binding pocket of MTH1, deduced from chemical shift perturbation experiments, is located at essentially the same position as in MutT; however, a pocket-forming helix is largely displaced in MTH1 (∼9 Å) such that the shape of the pocket differs between the two proteins. Detailed analysis of the pocket-forming residues enabled us to identify Asn33 as one of the key residues in MTH1 for discriminating the oxidized form of purine, and mutation of this residue modifies the substrate specificity. We also show that MTH1 catalyzes hydrolysis of 8-oxo-dGTP through nucleophilic substitution of water at the β-phosphate. Cellular DNA continually suffers assault from exogenous and endogenous agents that cause a wide variety of DNA modifications. Such modifications are often detrimental to the cell, leading to mutagenesis and carcinogenesis. Numerous enzymes have the important task of maintaining the integrity of DNA. These enzymes are generally well conserved from bacteria to humans. Oxygen radicals, which are spontaneously generated during normal cellular metabolism or by ionizing radiation or various chemicals, often attack nucleic acids, thereby generating modified bases in DNA (1Boiteux S. Gajewski E. Laval J. Dizdaroglu M. Biochemistry. 1992; 31: 106-110Crossref PubMed Scopus (575) Google Scholar, 2Gajewski E. Rao G. Nackerdien Z. Dizdaroglu M. Biochemistry. 1990; 29: 7876-7882Crossref PubMed Scopus (250) Google Scholar). Among these modified bases, the most abundant species, 8-oxo-7,8-dihydroguanine (8-oxo-G), 1The abbreviations used are: 8-oxo-G, 8-oxo-7,8-dihydroguanine; NOE, nuclear Overhauser effect; NOESY, NOE spectroscopy; TOCSY, total correlation spectroscopy; HSQC, heteronuclear single quantum correlation spectroscopy; r.m.s.d., root mean square deviations; AMPCPP, α,β-methyleneadenosine triphosphate; ADPRase, ADP-ribose pyrophosphatase; 2-OH-dATP, 2-hydroxy-dATP. can pair with both cytosine and adenine with almost equal efficiency and consequently can induce A:T to C:G and G:C to T:A transversion mutations (3Maki H. Sekiguchi M. Nature. 1992; 355: 273-275Crossref PubMed Scopus (792) Google Scholar, 4Cheng K.C. Cahill D.S. Kasai H. Nishimura S. Loeb L.A. J. Biol. Chem. 1992; 267: 166-172Abstract Full Text PDF PubMed Google Scholar, 5Kamiya H. Murata-Kamiya N. Koizume S. Inoue H. Nishimura S. Ohtsuka E. Carcinogenesis. 1995; 16: 883-889Crossref PubMed Scopus (126) Google Scholar). Organisms are equipped with elaborate mechanisms to counteract the mutagenic effects of 8-oxo-G. In Escherichia coli, two glycosylases encoded by the mutM and mutY genes function to prevent mutation caused by the presence of 8-oxo-G in DNA. MutM protein removes 8-oxo-G paired with cytosine, whereas MutY protein removes adenine paired with 8-oxo-G (6Tchou J. Kasai H. Shibutani S. Chung M.H. Laval J. Grollman A.P. Nishimura S. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 4690-4694Crossref PubMed Scopus (693) Google Scholar, 7Michaels M.L. Cruz C. Grollman A.P. Miller J.H. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 7022-7025Crossref PubMed Scopus (550) Google Scholar, 8Michaels M.L. Miller J.H. J. Bacteriol. 1992; 174: 6321-6325Crossref PubMed Scopus (614) Google Scholar, 9Tajiri T. Maki H. Sekiguchi M. Mutat. Res. 1995; 336: 257-267Crossref PubMed Scopus (318) Google Scholar). To prevent further mutation through the presence of 8-oxo-dGTP, MutT hydrolyzes 8-oxo-dGTP to its monophosphate form, thereby preventing the oxidized purine from being misincorporated into genomic DNA. The importance of this enzyme has been underscored by the observation that deficiency of the mutT gene increases the occurrence of A:T to C:G transversion mutations 1000-fold (10Yanofsky C. Cox E.C. Horn V. Proc. Natl. Acad. Sci. U. S. A. 1966; 55: 274-281Crossref PubMed Scopus (213) Google Scholar, 11Akiyama M. Maki H. Sekiguchi M. Horiuchi T. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 3949-3952Crossref PubMed Scopus (90) Google Scholar). The mechanism concerning the coordinated action of MutM, MutY, and MutT, which constitute the so-called “GO system,” has been well characterized in prokaryotes. Protein factors with enzymatic activities similar to those of MutM, MutY, and MutT have been identified in mammals; however, these enzymes show limited sequence similarity to their prokaryotic counterparts (12Bessho T. Tano K. Kasai H. Ohtsuka E. Nishimura S. J. Biol. Chem. 1993; 268: 19416-19421Abstract Full Text PDF PubMed Google Scholar, 13McGoldrick J.P. Yeh Y.C. Solomon M. Essigmann J.M. Lu A.L. Mol. Cell. Biol. 1995; 15: 989-996Crossref PubMed Google Scholar). The mammalian counterpart of MutT, MutT homolog-1 (MTH1), is induced after proliferative activation (14Oda H. Nakabeppu Y. Furuichi M. Sekiguchi M. J. Biol. Chem. 1997; 272: 17843-17850Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar), and is predominantly localized in the cytoplasm and mitochondria (15Kang D. Nishida J. Iyama A. Nakabeppu Y. Furuichi M. Fujiwara T. Sekiguchi M. Takeshige K. J. Biol. Chem. 1995; 270: 14659-14665Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar). Mice lacking the Mth1 gene exhibit an increase in the occurrence of spontaneous carcinogenesis in liver and, to a lesser extent, in lung and stomach, suggesting that an accumulation of 8-oxo-dGTP, which is a substrate of MTH1, may trigger malignant transformation in vivo (16Tsuzuki 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; 98: 11456-11461Crossref PubMed Scopus (262) Google Scholar). The detrimental effect of 8-oxo-dGTP in eukaryotes is also implied from the observation that an increase in the accumulation of 8-oxo-G in DNA, together with an increase in the expression of MTH1, is found not only in human cancer tissue (17Kennedy C.H. Cueto R. Belinsky S.A. Lechner J.F. Pryor W.A. FEBS Lett. 1998; 429: 17-20Crossref PubMed Scopus (77) Google Scholar, 18Iida T. Furuta A. Kawashima M. Nishida J. Nakabeppu Y. Iwaki T. Neuro-oncol. 2001; 3: 73-81PubMed Google Scholar) but also in degenerating neurons, as determined by immunohistochemical analyses (19Shimura-Miura H. Hattori N. Kang D. Miyako K. Nakabeppu Y. Mizuno Y. Ann. Neurol. 1999; 46: 920-924Crossref PubMed Scopus (149) Google Scholar, 20Furuta A. Iida T. Nakabeppu Y. Iwaki T. Neuroreport. 2001; 12: 2895-2899Crossref PubMed Scopus (44) Google Scholar). MTH1, but not E. coli MutT, can hydrolyze in vitro nucleotide triphosphates containing oxidized adenine such as 2-hydroxy-dATP (2-OH-dATP), 2-OH-rATP, 8-oxo-dATP, and 8-oxo-rATP, in addition to those containing oxidized guanines such as 8-oxo-dGTP and 8-oxo-rGTP (21Fujikawa K. Kamiya H. Yakushiji H. Y. Nakabeppu Y. Kasai H. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, K. Kamiya H. Yakushiji H. Nakabeppu Y. Kasai H. Res. 2001; 29: PubMed Scopus Google Scholar). MTH1 enzymatic for for 8-oxo-dGTP, with of and (21Fujikawa K. Kamiya H. Yakushiji H. Y. Nakabeppu Y. 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In this hydrolysis are in the presence of with that an of the is by that of the of or with or is by the one nucleophilic substitution by water at the the nucleophilic substitution at the The that is can determined from NMR of the the to exhibit a chemical shift of the The of are in In the of the NMR of the two at and which to the of and the in the presence of a from the at chemical shift of is similar to effects caused by the of into J. Biol. Chem. 1992; 267: Full Text PDF PubMed Google Scholar). can that the is to and that of the substrate is by water during the further by the in the presence of the of the to of the for the in the presence of The Nudix mutagenesis has that of the conserved residues in the Nudix and are for by MTH1 Y. H. Sekiguchi M. Nakabeppu Y. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). and form an the Nudix helix in structure of MTH1 These residues function to the the same residues in two Nudix MutT J. C. 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In to the Nudix the position of these residues is similar to that of of These that of MTH1 as a The conserved residues in the Nudix to residues and of MTH1, which are located the of the the These residues are important for the Nudix helix the and to a and from from and from mutagenesis has that with residue Y. H. Sekiguchi M. Nakabeppu Y. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). can with however, the expression of is low Y. H. Sekiguchi M. Nakabeppu Y. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar), that the protein is the These that both and may important for maintaining the fold of the The of the Nudix helix the is further by between located at the of the Nudix and both from and from the of In addition to the the of the in the Nudix located at residues to important for a at which is by a between the of and the of and are conserved Nudix has been to in mutagenesis Biol. 2001; Scopus Google Scholar, J.P. T. T. Sekiguchi M. 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The of this residue is in to the of the residue of with the structure of the thereby leading to a of enzyme for of the analyses that two of the pocket-forming residues of MTH1, and to substrate Y. Furuichi M. M. M. S. M. Nakabeppu Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of with increases the for both 8-oxo-dGTP and Y. Furuichi M. M. M. S. M. Nakabeppu Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The of this residue has also been implied from which show that of 8-oxo-dGTP or the and of the to this that is located to the M. F. Y. Yakushiji H. M. M. S. H. Sekiguchi M. Nakabeppu Y. J. Mol. Biol. PubMed Scopus Google Scholar). The in the of induced by 8-oxo-dGTP or is that induced by In to mutation of with effects the of 8-oxo-dGTP and Y. Furuichi M. M. M. S. M. Nakabeppu Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The has of the for 8-oxo-dGTP but almost for 2-OH-dATP, and the also has similar activities with the suggesting that the of the but not is for discriminating the In addition to these key residues identified through structure that Asn33 is important for nucleotide its is in the pocket To Asn33 is in nucleotide we with or The mutation to of the whereas the a of suggesting that the presence of the at this position is also important for the of the 8-oxo-dGTP whereas the mutation The detrimental effect of this mutation may by a between the of the and 8-oxo-dGTP and between the of the In these and mutagenesis that the of and Asn33 an in whereas the of may important for with the purine bases of substrate of MTH1 is its for nucleotides that bases and those that bases, are located at the of the purine to with mutagenesis present has enabled us to identify the and pocket of the of the structure we mutagenesis that that Asn33 also important in To this is the of the structure of a enzyme that is to oxidized proteins that a Nudix have been identified S. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar), substrate have been well characterized for only a of these has that MTH1 is similar but E. coli MutT, with to the structure of the substrate-binding may a for of the Nudix as well as of proteins that oxidized

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