Peroxynitrite anion

The second major finding is that cell protection was also observed against the peroxynitrite anion. Thus, in vivo, the staining increased from 5.2% with the three antioxidants to 43.3% without the antioxidants (giving a PF of 8.3). For the in vitro experiments, the corresponding cell staining was 7.3% and 59.5%, that is, a PF against ONOO- of 8.2 as shown in Table 14.5. 

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]. 

B. Peroxynitrite Anion and Peroxynitrons Acid. Gronnd State Properties.. 8... 

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 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"). 

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

Curiously, the reaction rate becomes zero order with respect to buffer anion at higher buffer concentrations. If the zero-order rate constants for a variety of buffers are plotted versus pH, an apparent pJC is observed at pH 7.9 to 8.0 (Fig. 29). In contrast, the apparent pK observed in phosphate buffer is at 6.8. As described below, we propose that the difference in pK values is due to a slight difference in the Gibbs energies of the cis and trans peroxynitrite anions relative to the corresponding conjugate acid and has important consequences concerning the reactivity of peroxynitrite. 

Highest occupied molecular orbitals for cis- and irans-peroxynitrite anion. The orbitals were calculated with the AMI parameter set using MOPAC 6.0 and the CACHe interface (Textronix Inc., Beaverton, OR). 

Vibrational modes of peroxynitrite anion observable by Raman spectroscopy. A nonlinear molecule with four atoms can have only six independent modes. These consist of three bond stretching modes, two bending modes, and torsion of the OO-NO bond, which will make peroxynitrite nonplanar. 

Reaction of trans-peroxynitrite with superoxide dismutase. The placement of positively charged amino acids around the active site facilitates the attraction of the negatively charged peroxynitrite anion. Because the copper of superoxide dismutase is buried in a pocket shaped to accommodate superoxide, only peroxynitrite in the trans configuration should be able to fit in the active site. Because the predominant form of peroxynitrite is the cis form, the isomerization from the cis to trans geometry limits the reaction of peroxynitrite with superoxide dismutase. 

Additional physical studies and calculations have been performed on peroxy-nitrite (Koppenol and Klasinc, 1993 Kraus, 1994)- Part of the infrared spectrum of peroxynitrite anion in a solid state matrix has been reported (Plumb and Edwards, 1991). 

Kraus, M. (1994). Electronic structure and spectra of the peroxynitrite anion. Chem. Phys. Lett. 222, 513-516. 

Tsai, M. (1991). Raman spectra of peroxynitrite anion. Master s Thesis, University of Alabama at Birmingham. 

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). 

---