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 O ₂ ^•- , is widely regarded as a major contributor to oxidative stress. Many of the reactions involved are catalyzed by CO ₂ via formation of an unstable adduct, ONOOC(O)O ⁻ , that undergoes O-O bond homolysis to produce NO ₂ ^• and CO ₃ ^•– 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 NO ₂ ^• /CO ₃ ^•– 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.