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Nitric oxide and superoxide, which are produced by several cell types, rapidly combine to form peroxynitrite. This reaction can result in nitric oxide scavenging, and thus mitigation of the biological effects of superoxide. Also, superoxide can trap and hence modulate the effects of nitric oxide; superoxide dismutase, by controlling superoxide levels, therefore can influence the reaction pathways open to nitric oxide. The production of peroxynitrite, however, causes its own sequelae of events: Although neither .NO nor superoxide is a strong oxidant, peroxynitrite is a potent and versatile oxidant that can attack a wide range of biological targets. The peroxynitrite anion is relatively stable, but its acid, peroxynitrous acid (HOONO), rearranges to form nitrate with a half-life of approximately 1 s at pH 7, 37 degrees C. HOONO exists as a Boltzmann distribution of rotamers; at 5-37 degrees C HOONO has an apparent acidity constant, pKa,app, of 6.8. Oxidation reactions of HOONO can involve two-electron processes (such as an SN2 displacement) or a one-electron transfer (ET) reaction in which the substrate is oxidized by one electron and peroxynitrite is reduced. These oxidation reactions could involve one of two mechanisms. The first mechanism is homolysis of HOONO to give HO. and .NO2, which initially are held together in a solvent cage. This caged pair of radicals (the "geminate" pair) can either diffuse apart, giving free radicals that can perform oxidations, or react together either to form nitrate or to reform HOONO (a process called cage return). A large amount of cage return can explain the small entropy of activation (Arrhenius A-factor) observed for the decomposition of HOONO. A cage mechanism also can explain the residual yield of nitrate that appears to be formed even in the presence of high concentrations of all of the scavengers studied to date, since scavengers capture only free HO. and .NO2 and not caged radicals. If the cage mechanism is correct, the rate of disappearance of peroxynitrite be slower in solvents of higher viscosity, and we do not find this to be the case. The second mechanism is that an activated isomer of peroxynitrous acid, HOONO*, can be formed in a steady state. The HOONO* mechanism can explain the inability of hydroxyl radical scavengers to completely block either nitrate formation or the oxidation of substrates such as methionine, since HOONO* would be less reactive, and therefore more selective, than the hydroxyl radical itself.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The chemistry of peroxynitrite: a product from the reaction of nitric oxide with superoxide. 776 72

Although DNA damage can have a variety of deleterious effects on cells (e.g., senescence, death, and rapid growth), the base excision repair (BER) pathway combats the effects by removing several types of damaged DNA. Since the first BER step involves cleavage of the bond between the damaged nucleobase and the DNA sugar-phosphate backbone, we have used density functional theory to compare the intrinsic stability of the glycosidic bond in a number of common DNA oxidation, deamination, and alkylation products to the corresponding natural nucleosides. Our calculations predict that the dissociative (SN1) and associative (SN2) pathways are nearly isoenergetic, with the dissociative pathway only slightly favored on the Gibbs reaction surface for all canonical and damaged nucleosides, which suggests that DNA damage does not affect the inherently most favorable deglycosylation pathway. More importantly, with the exception of thymine glycol, all DNA lesions exhibit reduced glycosidic bond stability relative to the undamaged nucleosides. Furthermore, the trend in the magnitude of the deglycosylation barrier reduction directly correlates with the relative nucleobase acidity (at N9 for purines or N1 for pyrimidines), which thereby provides a computationally efficient, qualitative measure of the glycosidic bond stability in DNA damage. The effect of nucleobase activation (protonation) at different sites predicts that the positions leading to the largest reductions in the deglycosylation barrier are typically used by DNA glycosylases to facilitate base excision. Finally, deaza purine derivatives are found to have greater glycosidic bond stability than the canonical counterparts, which suggests that alterations to excision rates measured using these derivatives to probe DNA glycosylase function must be interpreted in reference to the inherent differences in the nucleoside reactivity. Combined with previous studies of the deglycosylation of DNA nucleosides, the current study provides a greater fundamental understanding about the reactivity of the glycosidic bond in damaged DNA, which has direct implications to the function of critical DNA repair enzymes.
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PMID:Glycosidic Bond Cleavage in DNA Nucleosides: Effect of Nucleobase Damage and Activation on the Mechanism and Barrier. 2661 97