Modeling of S-Nitrosothiol-Thiol Reactions of Biological Significance: HNO Production by S-Thiolation Requires a Proton Shuttle and Stabilization of Polar Intermediates.
Nitroxyl (HNO), a reduced form of the important gasotransmitter nitric oxide, exhibits its own unique biological activity. A possible biological pathway of HNO formation is the S-thiolation reaction between thiols and S-nitrosothiols (RSNOs). Our density functional theory (DFT) calculations suggested that S-thiolation proceeds through a proton transfer from the thiol to the RSNO nitrogen atom, which increases electrophilicity of the RSNO sulfur, followed by nucleophilic attack by thiol, yielding a charge-separated zwitterionic intermediate structure RSS+(R)N(H)O-(Zi), which decomposes to yield HNO and disulfide RSSR. In the gas phase, the proton transfer and the S-S bond formation are asynchronous, resulting in a high activation barrier (>40 kcal mol-1), making the reaction infeasible. However, the barrier can decrease below the S-N bond dissociation energy in RSNOs (≈30 kcal mol-1) upon transition into an aqueous environment that stabilizes Zi and provides a proton shuttle to synchronize the proton transfer and the S-S bond formation. These mechanistic features suggest that S-thiolation can easily lend itself to enzymatic catalysis and thus can be a possible route of endogenous HNO production.
Department of Chemistry, Marquette University, 535 N. 14th Street, Milwaukee, WI, 53233, USA.
Lena V
0000-0001-9327-6679
LV
Ivanova
Department of Chemistry, Marquette University, 535 N. 14th Street, Milwaukee, WI, 53233, USA.
Daniel
D
Cibich
Department of Chemistry, Marquette University, 535 N. 14th Street, Milwaukee, WI, 53233, USA.
Gregory
G
Deye
Department of Chemistry, Marquette University, 535 N. 14th Street, Milwaukee, WI, 53233, USA.
Marat R
0000-0002-7559-9666
MR
Talipov
Department of Chemistry, Marquette University, 535 N. 14th Street, Milwaukee, WI, 53233, USA.
Qadir K
0000-0002-8794-8800
QK
Timerghazin
D002384:Catalysis; D006859:Hydrogen / Q000737:chemistry*; D008956:Models, Chemical; D009589:Nitrogen Oxides / Q000138:chemical synthesis*; D009603:Nitroso Compounds / Q000737:chemistry*; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D014867:Water / Q000737:chemistry
D009589:Nitrogen Oxides; D009603:Nitroso Compounds; D013438:Sulfhydryl Compounds; D014867:Water; D006859:Hydrogen; C039900:nitroxyl
S-nitrosothiols; S-thiolation; density functional calculations; nitroxyl; reaction mechanisms