Modeling predicts facile release of nitrite but not nitric oxide from the thionitrate CHSNO with relevance to nitroglycerin bioactivation.

Nitroglycerin is a potent vasodilator in clinical use since the late 1800s. It functions as a prodrug that is bioactivated by formation of an enzyme-based thionitrate, E-Cys-NO. This intermediate reportedly decomposes to release NO and NO but their relative yields remain controversial. Hence, we determined barriers for NO and NO production from the model thionitrate, CHSNO, using comprehensive high-level quantum chemistry calculations [CCSD(T)//MP2/aug-cc-pVTZ]. We find that the sulfenyl nitrite, CHSONO, readily releases NO on (S)O-N bond homolysis but CHSONO formation from CHSNO either by S-NO bond homolysis or concerted rearrangement faces prohibitively high barriers (ΔH/ΔH > 42 kcal/mol). Dramatically lower barriers (ΔH ~ 17-21 kcal/mol) control NO release from CHSNO by gas-phase hydrolysis or nucleophilic attack by OH or CHS on the sulfur atom within the C-S-NO molecular plane. Moreover, attack by either anion along the S-NO bond results in barrierless NO release (ΔH ~ 0 kcal/mol) since a σ-hole (i.e., area of positive electrostatic potential) extends from this bond. Consistent with our high-level calculations, ALDH2 and GAPDH, enzymes implicated in nitroglycerin bioactivation via an E-Cys-NO intermediate, catalyze mainly or exclusively NO release from the prodrug.