Carbon dioxide-catalyzed peroxynitrite reactivity - The resilience of the radical mechanism after two decades of research.

Peroxynitrite, ONOO-, formed in tissues that are simultaneously generating NO• and O2•-, is widely regarded as a major contributor to oxidative stress. Many of the reactions involved are catalyzed by CO2 via formation of an unstable adduct, ONOOC(O)O-, that undergoes O-O bond homolysis to produce NO2• and CO3•- radicals, whose yields are equal at about 0.33 with respect to the ONOO- reactant. Since its inception two decades ago, this radical-based mechanism has been frequently but unsuccessfully challenged. The most recent among these [Serrano-Luginbuehl et al. Chem. Res. Toxicol.31:721-730; 2018] claims that ONOOC(O)O- is stable, predicts a yield of NO2•/CO3•- of less than 0.01 under physiological conditions and, contrary to widely accepted viewpoints, suggests that radical generation is inconsequential to peroxynitrite-induced oxidative damage. Here we review the experimental and theoretical evidence that support the radical model and show this recently proposed alternative mechanism to be incorrect.