Peroxynitrite hydroxyl radical-like

Isomerization of trans-peroxynitrite anion and trans-peroxynitrous acid to nitrate through the putative hydroxyl radical-like intermediates. 

Peroxynitrite is a potent bactericidal agent for E. coli, with an LD50 of 250 tM at pH 7.4 and 37°C (Zhu et al., 1992). Neither 1 mM HjOj nor 10 mU/ml of xanthine oxidase plus xanthine were toxic in the same system. The toxicity was not due to the hydroxyl radical-like reactivity because lipid soluble radical scavengers either had no effect or slightly increased toxicity of peroxynitrite (Zhu... 

Most probably due to the capability of peroxynitrite to yield HO radicals, it was found that the induced effects are comparable to the effects elicited by hydroxyl radicals [263]. A more detailed investigation using spectroscopic methods as well as mass spectrometry (MS) has been published recently [264] Neither NMR nor MS experiments provide any evidence of a peroxynitrite-mediated modification of HA. On the other hand, simultaneously performed ESR experiments give evidence for the generation of C-centered carbon radicals, most probably by the way of hydroxyl radical-like reactivity of peroxynitrite. 

NO can interact with other free radicals most notably, NO reacts with the superoxide anion (O 2) to produce the potent oxidant peroxynitrite (ONOO") (Radi et al., 1991). Although it is a simple molecule, ONOO is chemically complex. It can display hydroxyl radical-like and nitrogen dioxide (NO2) radical-like activity, can oxidize lipids, and can directly nitrate proteins. ONOO" has been shown to nitrate a tyrosine residue on superoxide dismutase (SOD) (Beckman et al., 1992). 

It appears likely that oxidative events including mitochondrial dysfunction play a major role in PD. Among the deleterious agents thought to be involved are peroxynitrite and hydroxyl radicals (Yokoyama et ah,... 

Although hydroxyl radical is commonly assumed to be the most toxic of the oxygen radicals (with little direct evidence), other direct reactions are more likely to be important for understanding the cytotoxicity of peroxynitrite. A second oxidative pathway involves the heterolytic cleavage of peroxynitrite to form a nitronium-like species (N02 ), which is catalyzed hy transition metals (Beckman et al., 1992). Low molecular weight metal complexes as well as metals bound in superoxide dismutase and other proteins catalyze the nitration of a wide range of phenolics, including tyrosine residues in most proteins (Beckman et al., 1992). 

The sites of production of peroxynitrite are more likely to lie in closer proximity to the site of superoxide production as the latter is limited to transfer across the plasma membrane via anion channels, and has a shorter half-life (see above) [18]. It decomposes spontaneously at physiological pH, a process facilitated by the presence of Fe-EDTA and SOD, to yield nitrate (-65%) and nitrogen dioxide and the hydroxyl radical (-35%). Peroxynitrite is not a radical per se, and is less reactive than its protonated form. The pKa of the protonation reaction is 6.8, hence this proceeds efficiently at physiological pH yielding the potent oxidising species, peroxynitrous acid, which correspondingly decomposes to form the hydroxyl radical and nitrogen dioxide shown in Eq. 10 [27] ... 

The precise mechanism by which NO causes glutamase neurotoxicity is unknown. Calcium must be required because of the requirement for NMDA- and glutamate-induced NO formation in brain tissue (Garthwaite etal., 1988). Although both NMDA-receptor agonists and sodium nitroprusside induce specific neurotoxicity as well as cyclic GMP formation in brain tissue (Dawson et al., 1991), it is unlikely that cyclic GMP is the ultimate cause of the neurotoxicity. Instead, NO is most likely involved in producing target cell death. One possible mechanistic pathway is that locally synthesized NO and superoxide anion react with each other to yield peroxynitrite anion (Beckman et al., 1990), which can destroy cell membranes either directly via interaction with cellular thiols (Radi et al., 1991) or indirectly via decomposition to hydroxyl and other free radicals (Beckman et al., 1990). 

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