Chemical Biology of Peroxynitrite: Kinetics, Diffusion, and Radicals

Abstract

Peroxynitrite is formed by the very fast reaction of nitric oxide and superoxide radicals, a reaction that kinetically competes with other routes that chemically consume or physically sequester the reagents. It can behave either as an endogenous cytotoxin toward host tissues or a cytotoxic effector molecule against invading pathogens, depending on the cellular source and pathophysiological setting. Peroxynitrite is in itself very reactive against a few specific targets that range from efficient detoxification systems, such as peroxiredoxins, to reactions eventually leading to enhanced radical formation (e.g., nitrogen dioxide and carbonate radicals), such as the reaction with carbon dioxide. Thus, the chemical biology of peroxynitrite is dictated by the chemical kinetics of its formation and decay and by the diffusion across membranes of the species involved, including peroxynitrite itself. On the other hand, most durable traces of peroxynitrite passing (such as 3-nitrotyrosine) are derived from radicals formed from peroxynitrite by routes that represent extremely low-yield processes but that have potentially critical biological consequences. Here we have reviewed the chemical kinetics of peroxynitrite as a biochemical transient species in order to estimate its rates of formation and decay and then its steady-state concentration in different intra- or extracellular compartments, trying to provide a quantitative basis for its reactivity; additionally, we have considered diffusion across membranes to locate its possible effects. Finally, we have assessed the most successful attempts to intercept peroxynitrite by pharmacological intervention in their potential to increment the existing biological defenses that routinely deal with this cytotoxin.

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

“…Superoxide dismutase is an endogenous and first-line-of-defense enzyme that eliminates superoxide by catalyzing its dismutation into O 2 and H 2 O 2 (119,120,212,240). Historically, most early synthetic antioxidant compounds were originally developed as SOD mimics, especially because the role of ONOO À and its decomposition products in biology were, at the time, neither accepted nor well defined (106). A greater understanding of the biologic activity of SOD mimics and redox-active compounds paralleled the increased insight into the nature and the role of ROS=RNS in oxidative-stress conditions.…”

Administration of a nitric oxide donor inhibits mglA expression by intracellular Francisella tularensis and counteracts phagosomal escape and subversion of TNF-α secretion

“…Nitration is often detrimental to protein function and is an irreversible modification. Even at low levels it can lead to toxic effects such as pro-oxidant, pro-apoptotic or pro-aggregant properties (Ferrer-Sueta & Radi, 2009). The fact that two ribosomal proteins were found to be nitrated may have contributed to a global effect of decreased de novo protein synthesis.…”

“…For example, NO can react with the superoxide anion to form the even more toxic oxidant peroxynitrite (ONOO 2 ), which is a critical component for the development of severe pathophysiological phenomena such as shock and inflammation (Virág et al, 2003). At the single cell level, ONOO 2 exerts potent apoptotic or necrotic effects via lipid peroxidation, inhibition of mitochondrial respiration, DNA strand breakage and depletion of intracellular energy stores (Ferrer-Sueta & Radi, 2009). Many of the outcomes are directly or indirectly related to effects on its primary targets: inactivation of metalloenzymes (Liochev & Fridovich, 1999).…”

Structural and Molecular Basis of the Peroxynitrite-mediated Nitration and Inactivation of Trypanosoma cruzi Iron-Superoxide Dismutases (Fe-SODs) A and B

“…Under the experimental conditions of Fig. 3, in which biologically relevant micromolar concentrations of enzyme were used, there are two possible mechanisms by which peroxynitrite can generate nitrating intermediates to mediate Fe-SOD tyrosine nitration (64,65): (i) the proton-catalyzed homolysis of peroxynitrous acid (ONOOH, pK a ϭ 6.8) to yield nitrogen dioxide ( ⅐ NO 2 ) and hydroxyl radical ( ⅐ OH) or (ii) the reaction of peroxynitrite anion with the iron center to yield the oxo-Fe complex and ⅐ NO 2 . To define which of the nitration mechanisms was better coupled to enzyme inactivation, we performed peroxynitrite exposures at different pH values and in the presence of CO 2 (Fig.…”