Convergence of Biological Nitration and Nitrosation via Symmetrical Nitrous Anhydride

Current perspective holds that the generation of secondary signaling mediators from nitrite (NO(2)(−)) requires acidification to nitrous acid (HNO(2)) or metal catalysis. Herein, the use of stable isotope-labeled NO(2)(−) and LC-MS/MS analysis of products revealed that NO(2)(−) also participates in fatty acid nitration and thiol S-nitrosation at neutral pH. These reactions occur in the absence of metal centers and are stimulated by nitric oxide ((•)NO) autoxidation via symmetrical dinitrogen trioxide (nitrous anhydride, symN(2)O(3)) formation. While theoretical models have predicted physiological symN(2)O(3) formation, its generation is now demonstrated in aqueous reaction systems, cell models and in viv, with the concerted reactions of (•)NO and NO(2)(−) shown to be critical for symN(2)O(3) formation. These results reveal new mechanisms underlying the NO(2)(−) propagation of (•)NO signaling and the regulation of both biomolecule function and signaling network activity via NO(2)(−)-dependent nitrosation and nitration reactions.