Peroxynitrite anion oxidation

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 ). 

The superoxide anion (O2 ) exhibits numerous physiological toxic effects including endothelial cell damage, increased microvascular permeability, formation of chemotactic factors such as leukotriene B4, recruitment of neutrophils at sites of inflammation, lipid peroxidation and oxidation, release of cytokines, DNA singlestrand damage, and formation of peroxynitrite anion (ONOO-), a potent cytotoxic and proinflammatory molecule generated according to equation 7.210 ... 

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

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"). 

NO to form peroxynitrite (Eq. 18-62).559b Peroxynitrite, in turn, can react with the ubitquitous C02 to give C03 and N02 radicals.559c Peroxynitrite anion also reacts with metalloenzyme centers559"4 and causes nitration and oxidation of aromatic residues in proteins.559d e However, neutrophils contain active superoxide dismutases, and most of the superoxide that is formed is converted quickly to 02 and H202. 

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)...

In addition to oxidants that are generated by the Fenton reaction, superoxide radicals (-02 ) readily react with nitric oxide (NO-), generating peroxynitrite anion (ONOO ) in the following reaction ... 

The protonated form of peroxynitrite anion, peroxynitrous acid, is highly reactive with biologic molecnles. Hence, the production of nitric oxide from nitric oxide synthase (a complex enzyme containing several cofactors, and a heme group that is part of the catalytic site), which catalyzes the formation of NO from oxygen and arginine, can render ceUnlar components such as DNA susceptible to superoxide-mediated damage (1). 

Pryor and coworkers have shown that peroxynitrite-mediated nitrosations and nitrations of phenols are modulated by CO2. The reaction was found to be first order with respect to peroxynitrite and zero order with respect to phenol, showing that an activated intermediate of peroxynitrite, perhaps the peroxynitrite anion-C02 adduct (0=N—OO—C02 ), is involved as the intermediate (equation 57) . At pH higher than 8.0, 4-nitrosophenol is the major product, whereas in acidic media significant amounts of the 2- and 4-nitrophenols were formed. Peroxynitrite also induces biological nitration of tyrosine residues of the proteins. The detection of 3-nitrotyrosine is routinely used as an in vivo marker for the production of the cytotoxic species peroxynitrite (ONOO ). It was shown that nitrite anion (N02 ) formed in situ by the reaction of nitric oxide and hypochlorous acid (HOCl) is similarly able to nitrate phenolic substrates such as tyrosine and 4-hydroxyphenylacetic acid . 

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. 

Foresti, R.f Clark, J. E., Green, C. J. and Motterlini, R. Thiol compounds interact with nitric oxide in regulating heme-oxygenase-1 induction in endothelial cells. Involvement of superoxide and peroxynitrite anions. Journal of Biological Chemistry. 272 18411-18417 1997. 

---