How are nitrosothiols formed de novo in vivo?

The biological mechanisms of de novo formation of cellular nitrosothiols (as opposed to transnitrosation) are reviewed. The approach is to introduce chemical foundations for each mechanism, followed by evidence in biological systems. The general categories include mechanisms involving nitrous acid, NO autoxidation and oxidant stress, redox active and inactive metal ions, and sulfide/persulfide. Important conclusions/speculations are that de novo cellular thiol nitrosation (1) is an oxidative process, and so should be considered within the family of other thiol oxidative modifications, (2) may not involve a single dominant process but depends on the specific conditions, (3) does not involve O2 under at least some conditions, and (4) may serve to provide a "substrate pool" of protein cysteine nitrosothiol which could, through subsequent enzymatic transnitrosation/denitrosation, be "rearranged" to accomplish the specificity and regulatory control required for effective post-translational signaling.