Transition metals peroxynitrite

Interestingly, that the reactions of peroxynitrite with phenols were accelerated in the presence of ferric and cupric ions [112,114]. Until now, there seems no explanation of transition metal effects in these reactions. We just wonder if it is possible that ferric and cupric ions are able to oxidize peroxynitrite ... 

Thus, physiological free radicals superoxide and nitric oxide produced by phagocytes and nonphagocytes are responsible for the two major pathways of LDL oxidation transition metal-dependent and peroxynitrite-dependent mechanisms. However, there is another mode... 

Thus, the mechanism of MT antioxidant activity might be connected with the possible antioxidant effect of zinc. Zinc is a nontransition metal and therefore, its participation in redox processes is not really expected. The simplest mechanism of zinc antioxidant activity is the competition with transition metal ions capable of initiating free radical-mediated processes. For example, it has recently been shown [342] that zinc inhibited copper- and iron-initiated liposomal peroxidation but had no effect on peroxidative processes initiated by free radicals and peroxynitrite. These findings contradict the earlier results obtained by Coassin et al. [343] who found no inhibitory effects of zinc on microsomal lipid peroxidation in contrast to the inhibitory effects of manganese and cobalt. Yeomans et al. [344] showed that the zinc-histidine complex is able to inhibit copper-induced LDL oxidation, but the antioxidant effect of this complex obviously depended on histidine and not zinc because zinc sulfate was ineffective. We proposed another mode of possible antioxidant effect of zinc [345], It has been found that Zn and Mg aspartates inhibited oxygen radical production by xanthine oxidase, NADPH oxidase, and human blood leukocytes. The antioxidant effect of these salts supposedly was a consequence of the acceleration of spontaneous superoxide dismutation due to increasing medium acidity. 

Mitochondrial function. NO is able to react with transition metals such as iron, including those contained within haem groups. Even at low NO concentrations there is competition between oxygen and NO for reversible binding to cytochrome c oxidase. If mitochondrial 02 is low respiration slows, which may confer anti-apoptotic benefit to the cell. As NO concentration rises and peroxynitrite is formed, electron transport is irreversibly inhibited, there is increased production of superoxide and other reactive oxygen species and apoptosis occurs. 

Fig. 6.13. Reactions of NO in biological systems. NO reacts in biological systems primarily with O2, with the snperoxide anion O2 and with transition metals (Me). The products of the reaction, -NOj, metal-NO adducts (Me-NO) and peroxynitrite (OONO ) react further by nitrosyla-tion of nucleophihc centers. In the ceU, these are espedafly -SH (or thi-olate-S ) groups of peptides and proteins (RS).

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). 

Transition metals like Fe EDTA apparently catalyze the formation of a ni-tronium ion-like species from peroxynitrite by the following reactions... 

Metal-catalyzed nitration by peroxynitrite also provides an alternative explanation to the Haber-Weiss reaction for the role of transition metals in oxidative tissue injury. The rate of peroxynitrite reaction with Fe " EDTA is 5700 M , which is in the same range as the rate of hydrogen peroxide reacting with... 

The cadmium(II) complex corresponding to 9 (M = Cd n = 2) was the first texaphyrin made [6], This aromatic expanded porphyrin was found to differ substantially from various porphyrin complexes and it was noted that its spectral and photophysical properties were such that it might prove useful as a PDT agent. However, it was also appreciated that the poor aqueous solubility and inherent toxicity of this particular metal complex would likely preclude its use in vivo [29-31], Nonetheless, the coordination chemistry of texaphyrins such as 9 was soon generalized to allow for the coordination of late first row transition metal (Mn(II), Co(II), Ni(II), Zn (II), Fe(III)) and trivalent lanthanide cations [26], This, in turn, opened up several possibilities for rational drag development. For instance, the Mn(II) texaphyrin complex was found to act as a peroxynitrite decomposition catalyst [32] and is being studied currently for possible use in treating amyotrophic lateral sclerosis. This work, which is outside the scope of this review, has recently been summarized by Crow [33],... 

One of the most significant common aspects of the chemistry of NO and peroxynitrite is their ability to react in a unique manner with the metal centers of numerous proteins, in particular hemoproteins [10]. We have used myoglobin (Mb) and hemoglobin (Hb) to investigate the diverse reactions that these simple inorganic biomolecules can undergo with different oxidation states of hemoproteins. Mutated forms of Mb and Hb are available [12, 13], and a large number of transition metals ions other than Fe ions have been successfully incorporated in these... 

Hydroxyl radical, HO Three-electron reduction product of O2 generated by Fenton reaction transition metal (iron, copper)-catalyzed Haber-Weiss reaction formed by decomposition of peroxynitrite produced by the reaction of O2 with NO . 

Metalloporphyrins, characterized by a redox-active transitional metal coordinated to a cyclic porphyrin core ligand, mitigate oxidative/nitrosative stress in biological systems. Side-chain substitutions tune redox properties of metalloporphyrins to act as potent superoxide dismutase mimetics, peroxynitrite decomposition catalysts, and redox regulators of transcription factor function. Metalloporphyrins are efficacious in AD models [538],... 

It was shown that tryptophan is also nitrated by peroxynitrite in the absence of transition metals to one predominant isomer of nitrotryptophan, as determined from spectral characteristics and liquid chromatography-mass spectrometry analysis. Typical hydroxyl radical scavengers partially inhibited the nitration" . The yields of the nitration of tyrosine and salicylate by peroxynitrite are significantly improved by the Fe(III)-EDTA complex " ". ... 

NO" to hydroxylamine, peroxynitrite (ONOO") or directly to NO2. Peroxynitrite reacts with peroxynitrous acid giving rise to two NO2 and one O2. Oxidation of nitric monoxide to the nitrosium ion (NO ) requires transition metals or O " radicals. NO" reacts with nucleophilic partners or gives rise to NOj and ONOO". Other pathways also lead directly or indirectly to NO2 (Fig. 10). 

Recently, a novel mechanism for hydroxyl radical production, which is not dependent on the presence of transition metal ions, has been proposed (7). This involves the production of peroxynitrite (ONOO ) arising from the reaction of nitric oxide (NO ) with superoxide (OJ), as shown in the following reactions ... 

Fig. 3. Production of reactive species. (A) ROS can be produced from the weak radical oxygen in the mitochondria and endoplasmic reticulum, by various enzymatic reactions, and from oxyhemoglobin. Normally, nontoxic hydrogen peroxide can give rise to the powerful hydroxyl radical in the presence of transition metals (R5). Oxygen can also be induced to react with biomolecules by transition metals and enzymes. RNS can be produced by reaction of superoxide anion radical with the weak radical nitric oxide. These can react to form the powerful oxidant peroxynitrite/peroxynitrous acid, which can cause formation of other radicals, some with longer lives. See the text for details. SOD, superoxide dismutase. (B) Myeloperoxidase in leukocytes can produce the reactive species hypochlorous acid and tyrosyl radical. Unpaired electrons are indicated by the dense dots and paired electrons by the light ones.

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