A Novel Nitroimidazole Compound Formed during the Reaction of Peroxynitrite with 2‘,3‘,5‘-Tri-<i>O</i>-Acetyl-Guanosine

Jc, Niles; Js, Wishnok; Tannenbaum,

doi:10.1021/ja004296k

Cited by 58 publications

(62 citation statements)

References 51 publications

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“…Oxazolone is bypassed efficiently and exhibits a mutation frequency similar to that of Iz in vivo (86%) but preferentially generates G3 T transversion mutations (31). In distinct contrast, NI has been observed only as a result of ONOO Ϫ -related chemistry (28,48,49). NI is a chemically stable lesion (when heated to 90°C for 6 h at pH 7, ϳ10 -15% decomposition of an ODN containing NI occurs) (49) and is refractory to repair by Fpg glycosylase (MutM) and endonuclease III in vitro (48).…”

Section: Discussionmentioning

confidence: 99%

“…NI is a chemically stable lesion (when heated to 90°C for 6 h at pH 7, ϳ10 -15% decomposition of an ODN containing NI occurs) (49) and is refractory to repair by Fpg glycosylase (MutM) and endonuclease III in vitro (48). The chemical and biological properties of NI make this lesion a potential biomarker of ONOO Ϫ -mediated oxidation of DNA (28,48).…”

Section: Discussionmentioning

confidence: 99%

“…Several products are formed directly from guanine residues in DNA including 7,8-dihydro-8-oxoguanine (8-oxoG), 8-nitroguanine (8-NO 2 -G), 2-aminoimidazolone (Iz), and 5-guanidino-4-nitroimidazole (NI) ( Fig. 1) (28). The lesions 8-oxoG and 8-NO 2 -G are highly susceptible to further oxidation (27) and yield a variety of additional products (29,30).…”

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In Vivo Bypass Efficiencies and Mutational Signatures of the Guanine Oxidation Products 2-Aminoimidazolone and 5-Guanidino-4-nitroimidazole

Neeley

Delaney

Henderson³

et al. 2004

Journal of Biological Chemistry

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The in vivo mutagenic properties of 2-aminoimidazolone and 5-guanidino-4-nitroimidazole, two products of peroxynitrite oxidation of guanine, are reported. Two oligodeoxynucleotides of identical sequence, but containing either 2-aminoimidazolone or 5-guanidino-4-nitroimidazole at a specific site, were ligated into singlestranded M13mp7L2 bacteriophage genomes. Wild-type AB1157 Escherichia coli cells were transformed with the site-specific 2-aminoimidazolone-and 5-guanidino-4-nitroimidazole-containing genomes, and analysis of the resulting progeny phage allowed determination of the in vivo bypass efficiencies and mutational signatures of the DNA lesions. 2-Aminoimidazolone was efficiently bypassed and 91% mutagenic, producing almost exclusively G to C transversion mutations. In contrast, 5-guanidino-4-nitroimidazole was a strong block to replication and 50% mutagenic, generating G to A, G to T, and to a lesser extent, G to C mutations. The G to A mutation elicited by 5-guanidino-4-nitroimidazole implicates this lesion as a novel source of peroxynitriteinduced transition mutations in vivo. For comparison, the error-prone bypass DNA polymerases were overexpressed in the cells by irradiation with UV light (SOS induction) prior to transformation. SOS induction caused little change in the efficiency of DNA polymerase bypass of 2-aminoimidazolone; however, bypass of 5-guanidino-4-nitroimidazole increased nearly 10-fold. Importantly, the mutation frequencies of both lesions decreased during replication in SOS-induced cells. These data suggest that 2-aminoimidazolone and 5-guanidino-4-nitroimidazole in DNA are substrates for one or more of the SOS-induced Y-family DNA polymerases and demonstrate that 2-aminoimidazolone and 5-guanidino-4-nitroimidazole are potent sources of mutations in vivo.Oxidative damage of DNA is implicated as a cause of aging (1-3), carcinogenesis (4 -6), and a variety of noncancerous diseases such as Alzheimer disease and cardiovascular disease (7) and in the progression to acquired immunodeficiency syndrome in human immunodeficiency virus-infected patients (8). The reactive species responsible for DNA damage are generated by common endogenous processes (9) such as respiration and inflammation (10, 11). During inflammation, an assortment of reactive oxygen and nitrogen intermediates are generated by activated immune system cells (11), and reaction of these molecules with DNA produces dozens of oxidized nucleobase derivatives (12).The . ) and nitrogen dioxide ( ⅐ NO 2 ) (20 -22). These radicals are believed to be responsible for the oxidation and nitration of DNA caused by exposure to ONOO Ϫ (23-25).Because guanine possesses the lowest redox potential of the four DNA nucleobases (E 7 ϭ 1.27 V versus normal hydrogen electrode) (26), it is preferentially oxidized by ONOO Ϫ compared with the other natural nucleobases (27). Several products are formed directly from guanine residues in DNA including 7,8-dihydro-8-oxoguanine (8-oxoG), 8-nitroguanine (8-NO 2 -G), 2-aminoimidazolone (Iz), and 5-guanidino-4-n...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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In Vivo Bypass Efficiencies and Mutational Signatures of the Guanine Oxidation Products 2-Aminoimidazolone and 5-Guanidino-4-nitroimidazole

Neeley

Delaney

Henderson³

et al. 2004

Journal of Biological Chemistry

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“…The pathophysiological action of reactive nitrogen oxides is quite important in the pathogenesis of virus infection, because these molecular species are known to be not only oxidants but also potent nitrating agents for proteins, nucleic acids, and unsaturated membrane lipids (9,10,(17)(18)(19)(20)(21). In this context the genotoxicity of nitrogen oxides is currently of great interest, because reactive nitrogen oxides formed endogenously during infections are highly mutagenic for both invading viruses and hosts (12,16), and cause cell and tissue injury in the host.…”

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confidence: 99%

8-Nitroguanosine formation in viral pneumonia and its implication for pathogenesis

Akaike

Okamoto

Sawa

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

159

149

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For many diseases, mediation of pathogenesis by nitric oxide (NO) has been suggested. In this study, we explored NO-induced viral pathogenesis with a focus on nucleic acid damage as evidenced by 8-nitroguanosine formation in vivo. Wild-type mice and littermate mice deficient in inducible NO synthase (iNOS) were infected with influenza or Sendai virus. Formation of 8-nitroguanosine in virusinfected lungs was assessed immunohistochemically with an antibody specific for 8-nitroguanosine. Extensive nitration of RNA either treated with peroxynitrite or obtained from cultured RAW 264 cells expressing iNOS was readily detected by this antibody. Strong 8-nitroguanosine immunostaining was evident primarily in the cytosol of bronchial and bronchiolar epithelial cells of virus-infected wild-type mice but not iNOS-deficient mice. This staining colocalized with iNOS immunostaining in the lung. 8-Nitroguanosine staining disappeared after addition of exogenous authentic 8-nitroguanosine during the antibody reaction and after pretreatment of tissues with sodium hydrosulfite, which reduces 8-nitroguanosine to 8-aminoguanosine. NO was generated in excess in lungs of wild-type mice but was eliminated in iNOSdeficient mice after virus infection; this result also correlated well with formation of 8-nitroguanosine and 3-nitrotyrosine. One consequence of the lack of iNOS expression was marked improvement in histopathological changes in the lung and the lethality of the infection without effects on cytokine responses and viral clearance. It is intriguing that 8-nitroguanosine markedly stimulated superoxide generation from cytochrome P450 reductase and iNOS in vitro. The present data constitute a demonstration of 8-nitroguanosine formation in vivo and suggest a potential role for NO-induced nitrative stress in viral pathogenesis.

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“…8-oxo-7,8-dihydroguanine (8-oxoG) (23) is considered to be the most important among over 100 oxidized DNA lesions (12,24,25). Other oxidation products of guanine include 5-guanidino-4-nitroimidazole (NI), cyanuric acid (Ca), oxaluric acid (Oa), oxazolone (Oz), imidazolone (Iz), urea (Ua), spiroiminodihydantoin (Sp), and guanidinohydantoin (Gh) (26)(27)(28)(29)(30)(31)(32).…”

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confidence: 99%

Flexible 5-Guanidino-4-nitroimidazole DNA Lesions: Structures and Thermodynamics

et al. 2006

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Abstract5-Guanidino-4-nitroimidazole (NI), derived from guanine oxidation by reactive oxygen and nitrogen species, contains an unusual flexible ring opened structure, with nitro and guanidino groups which possess multiple hydrogen bonding capabilities. In vitro primer extension experiments with bacterial and mammalian polymerases show that NI incorporates C as well as A and G opposite the lesion, depending on the polymerase. In order to elucidate structural and thermodynamic properties of the mutagenic NI lesion, we have investigated the structure of the modified base itself and the NIcontaining nucleoside with high level quantum mechanical calculations, and have employed molecular modeling and molecular dynamics simulations in solution for the lesion in B-DNA duplexes with four partner bases opposite the NI. Our results show that the NI adopts a planar structure at the damaged-base level. However, in the nucleoside and in DNA duplexes, steric hindrance between the guanidino group and its linked sugar causes NI to be non-planar. The NI lesion can adopt both syn and anti conformations on the DNA duplex level, with the guanidino group positioned in the DNA major and minor grooves, respectively; the specific preference depends on the partner base. Based on hydrogen bonding and stacking interactions, groove dimensions, and bending, we find that the least distorted NI modified duplex contains partner C, consistent with incorporation of C opposite NI. However, hydrogen bonding interactions between NI with partner G or A are also found, which would be compatible with the observed mismatches.Reactive oxygen and nitrogen species are products of normal cellular metabolism. In some cases, they are produced specifically to serve essential biological functions, in regulating circulation, energy metabolism, and apoptosis, and they constitute a major defense against pathogens (1,2). However, these highly reactive species also have the capability of damaging DNA. Base lesions are prominent among the resulting forms of DNA damage (3-9). If not removed by repair enzymes, the processing of the damaged DNA by polymerases may cause mutations, which may in turn initiate cancer (10-14). In addition, aging (15)(16)(17)(18)(19), and a variety † This research is supported by NIH Grant CA-75449 to S. B. and NIH Grant ES-11589 to V. S. and N. E. G. Figure S1 shows representative starting models for the MD simulations. Figure S2 shows stereo views of geometry-optimized NI nucleosides. Figure S3 shows RMSD vs time plots of each molecular dynamics simulation. Figures S4 and S5 show stereo views of the central 5-mer of the NI trajectory-average duplex structures and hydrogen bonds between NI and partner base of high energy structures. Figures S6-S8 show the average bend angles, groove dimensions of the NI damaged DNA, and trajectory plots of torsion angles of the NI lesion, respectively. Tables S1-S5 show added force field parameters, torsion angles, simulation box sizes, and numbers of added waters of initial models, and time windows chosen ...

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A Novel Nitroimidazole Compound Formed during the Reaction of Peroxynitrite with 2‘,3‘,5‘-Tri-O-Acetyl-Guanosine

Cited by 58 publications

References 51 publications

In Vivo Bypass Efficiencies and Mutational Signatures of the Guanine Oxidation Products 2-Aminoimidazolone and 5-Guanidino-4-nitroimidazole

In Vivo Bypass Efficiencies and Mutational Signatures of the Guanine Oxidation Products 2-Aminoimidazolone and 5-Guanidino-4-nitroimidazole

8-Nitroguanosine formation in viral pneumonia and its implication for pathogenesis

Flexible 5-Guanidino-4-nitroimidazole DNA Lesions: Structures and Thermodynamics

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