Abstract
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(2). This intermediate reportedly decomposes to release NO and NO(2)(-) but their relative yields remain controversial. Hence, we determined barriers for NO and NO(2)(-) production from the model thionitrate, CH(3)SNO(2), using comprehensive high-level quantum chemistry calculations [CCSD(T)//MP2/aug-cc-pVTZ]. We find that the sulfenyl nitrite, CH(3)SONO, readily releases NO on (S)O-N bond homolysis but CH(3)SONO formation from CH(3)SNO(2) either by S-NO(2) bond homolysis or concerted rearrangement faces prohibitively high barriers (ΔH(calc)/ΔH(‡)(calc) > 42 kcal/mol). Dramatically lower barriers (ΔH(‡)(calc) ~ 17-21 kcal/mol) control NO(2)(-) release from CH(3)SNO(2) by gas-phase hydrolysis or nucleophilic attack by OH(-) or CH(3)S(-) on the sulfur atom within the C-S-NO(2) molecular plane. Moreover, attack by either anion along the S-NO(2) bond results in barrierless NO(2)(-) release (ΔH(‡)(calc) ~ 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(2) intermediate, catalyze mainly or exclusively NO(2)(-) release from the prodrug.