Nitric oxide peroxynitrite anion

Superoxide (02 ) is the one electron reduced form of molecular oxygen. It reacts irreversibly and at close to the diffusion limit with nitric oxide (Huie and Padmaja, 1993) to form the powerful oxidant peroxynitrite anion (ONOO ). 

Lipopolysaccharide inhibits FAAH expression without affecting AEA cellular uptake (Maccarrone et al. 2001) conversely, nitric oxide, peroxynitrite and superoxide anions stimulate AEA cellular re-uptake (Maccarrone et al. 2000a), while acute or chronic ethanol inhibits this process (Basavarajappa et al. 2003), without affecting FAAH activity. 

Ca + channels (Chemin et al., 2001), (5) NADA and noladin are rapidly taken up by cells, yet they are either very stable or refractory to enzymatic hydrolysis, respectively (Fezza et al., 2002 Huang et al., 2002), and (6) hpopolysacchatide inhibits FAAH expression without affecting AEA cellular uptake (Maccarrone et al., 2001) conversely, nitric oxide, peroxynitrite, and superoxide anions stimulate AEA cellular reuptake (Maccarrone et al., 2000), whereas acute or chrotuc ethanol treatment inhibits this process (Basavarajappa et al., 2003) without affecting FAAH activity. 

Ohshima H, Yoshie Y, Aniiol S, GUibert I (1998) Antioxidant and pro-oxidant actions of flavonoids effects on DNA damage induced by nitric oxide, peroxynitrite and nitroxyl anion. Free Radic Biol Med 25(9) 1057-1065. doi 10.1016/s0891-5849(98)00141-5... 

Beckman, J.S., Beckman, T.W., Chen, J., Marshall, P.A. and Freeman, B.A. (1990). Apparent hydroxyl radical formation by peroxynitrite implications for endothelial cell injury from nitric oxide and superoxide anion. Proc. Natl Acad. Sci. USA 87, 1620-1624. 

At present, new developments challenge previous ideas concerning the role of nitric oxide in oxidative processes. The capacity of nitric oxide to oxidize substrates by a one-electron transfer mechanism was supported by the suggestion that its reduction potential is positive and relatively high. However, recent determinations based on the combination of quantum mechanical calculations, cyclic voltammetry, and chemical experiments suggest that °(NO/ NO-) = —0.8 0.2 V [56]. This new value of the NO reduction potential apparently denies the possibility for NO to react as a one-electron oxidant with biomolecules. However, it should be noted that such reactions are described in several studies. Thus, Sharpe and Cooper [57] showed that nitric oxide oxidized ferrocytochrome c to ferricytochrome c to form nitroxyl anion. These authors also proposed that the nitroxyl anion formed subsequently reacted with dioxygen, yielding peroxynitrite. If it is true, then Reactions (24) and (25) may represent a new pathway of peroxynitrite formation in mitochondria without the participation of superoxide. 

Nitric oxide also reacts with superoxide to form the stable peroxynitrite anion, which, however, decomposes on protonation [23]. 

It has now been more than a decade since Beckman and his collaborators first disclosed their observations that the combination of two relatively unreactive, yet biologically relevant free radicals, superoxide anion and nitric oxide, would produce a new highly reactive physiologically important reagent. The interaction of these two presumably innocuous species appears to be diffusion controlled and produces a thermally stable peroxy anion, peroxynitrite (equation 1). ... 

The reaction of nitric oxide with superoxide dismutase is a simple reversible equilibrium, whereas the catalytic cycle with superoxide involves a two step sequence. Consequently, superoxide dismutase may be reduced by superoxide and then react with nitric oxide to form nitroxyl anion. Nitroxyl anion may react with molecular oxygen to form peroxynitrite anion (ONOO"). 

The direct reaction of superoxide with nitric oxide is only one of at least four possible pathways that can form peroxynitrite (Fig. 40). For example, superoxide should also efficiently reduce nitrosyldioxyl radical to peroxynitrite. Alternatively, nitric oxide may be reduced to nitroxyl anion, which reacts with oxygen to form peroxynitrite. Superoxide dismutase could even catalyze the formation of peroxynitrite, since reduced (Cu or cuprous) superoxide dismutase can reduce nitric oxide to nitroxyl anion (Murphy and Sies, 1991). Thus, superoxide might first reduce superoxide dismutase to the cuprous form, with nitric oxide reacting with reduced superoxide dismutase to produce nitroxyl anion. A fourth pathway to form peroxynitrite is by the rapid reaction of nitrosonium ion (NO" ) with hydrogen peroxide. This is a convenient synthetic route for experimental studies (Reed et al., 1974), but not likely to be physiologically relevant due to the low concentrations of hydrogen peroxide and the difficulty of oxidizing nitric oxide to nitrosonium ion. 

Four routes to form peroxynitrite from nitric oxide. The reaction of nitric oxide with superoxide is only one mechanism leading to the formation of peroxynitrite. Supetoxide could also reduce the nitrosyidioxyl radical. If nitric oxide is directly reduced to nitroxyl anion, it will react with molecular oxygen to form peroxynitrite. At acidic pH, nitrite may form nitrous acid and nitrosonium ion, which reacts with hydrogen peroxide to form peroxynitrite. 

Fig. (4). Vasodilatory mechanisms of flavonoids. RWPC red wine polyphenolic compounds NO nitric made NOSe nitric oxide synthase endothelial O2 superoxide anions OONO peroxynitrites PKC protein kinase Q AC adenylate cyclase GC guanylate cyclase PDE phosphodiesterase.

Fig. 7.3 Reactions showing the generation of ROS during lipid peroxidation and oxidative stress. Hydroxyl radical ( OH) lipid radical ( lipid), peroxyl radical (lipid-OO ) lipid peroxide (lipid-OOH) nitric oxide ( NO) nitrogen dioxide (N02) peroxynitrite anion (ONOO-) hypochlorous acid (HOC1), and hydrogen peroxide (H202)...

Among the oxygen-derived free radicals, the species of primary concern include superoxide anion (O -), hydrogen peroxide (H202), and hydroxyl radical (OH-). The superoxide is further converted in peroxynitrite (ONOO-) by reacting with nitric oxide. 

Glutathionylated proteins can be formed by the interaction of nitric oxide and protein thiols. For example, exposure of mitochondria to NO can lead to the formation of peroxynitrite, an oxidant, that can cause protein glutathionylation. Protein glutathionylation may also occur via the formation of a nitroso thiol protein (PrSNO) followed by the glutathionylate anion displacement of the nitroxyl anion (NO-) by GSH to form protein glutathionylation as shown in Figure 18.13. 

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