Title

Modeling of S‐Nitrosothiol–Thiol Reactions of Biological Significance: HNO Production by S‐Thiolation Requires a Proton Shuttle and Stabilization of Polar Intermediates

Document Type

Article

Language

eng

Publication Date

2-7-2017

Publisher

Wiley

Source Publication

ChemBioChem

Source ISSN

1439-4227

Abstract

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.

Comments

ChemBioChem, Vol. 18, No. 8 (February 7, 2017). DOI.

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