Peroxynitrite, a stealthy biological oxidant

Abstract

Peroxynitrite is the product of the diffusion-controlled reaction of nitric oxide and superoxide radicals. Peroxynitrite, a reactive short-lived peroxide with a pKa of 6.8, is a good oxidant and nucleophile. It also yields secondary free radical intermediates such as nitrogen dioxide and carbonate radicals. Much of nitric oxide- and superoxide-dependent cytotoxicity resides on peroxynitrite, which affects mitochondrial function and triggers cell death via oxidation and nitration reactions. Peroxynitrite is an endogenous toxicant but is also a cytotoxic effector against invading pathogens. The biological chemistry of peroxynitrite is modulated by endogenous antioxidant mechanisms and neutralized by synthetic compounds with peroxynitrite-scavenging capacity.

Keywords: Free Radicals; Nitric Oxide; Oxidative Stress; Peroxynitrite; Superoxide Dismutase (SOD); Superoxide Ion; Tyrosine Nitration.

FIGURE 1.

Peroxynitrite as a mediator of superoxide radical and nitric oxide-dependent oxidative and cytotoxic processes. The figure represents the evolution of our understanding of the biochemically relevant reactions in which peroxynitrite participates. It integrates the initial proposal (24) with what is currently known. Upper, shown in gray is a reproduction of the original scheme in which the commonly accepted mechanism of O₂^⨪-mediated oxidative damage was challenged with an alternative mechanism that considered the participation of ^•NO. The proposal indicated that the reaction of O₂^⨪ with ^•NO yielded peroxynitrite anion, which could then start oxidation reactions directly or via secondary radicals. The original scheme showed two main reactions for peroxynitrite, namely thiol oxidation and homolysis. The lack of absolute certainty at the time regarding the products of the decomposition of peroxynitrous acid led us to write the hydroxyl radical as “^•OH”. Similarly, NX indicated an uncharacterized nitrogen-containing product, later proved to be nitrite. The red arrow connects the early proposal with an updated scheme of the biological chemistry of peroxynitrite. Lower, shown in black are the main accepted reaction pathways of peroxynitrous acid and peroxynitrite anion, namely 1) two-electron oxidation of thiols, 2) homolysis, 3) nucleophilic addition to CO₂ and evolution to radicals, and 4) reaction with transition metal centers. The width of the arrows symbolizes the preferential routes of peroxynitrite consumption in biological systems, underscoring the fact that homolysis is a quantitatively minor process.