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

Authors

Lena V. Ivanova, Marquette University
Daniel Cibich, Marquette University
Gregory Deye, Marquette University
Marat R. Talipov, Marquette UniversityFollow
Qadir K. Timerghazin, Marquette UniversityFollow

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

Accepted version. ChemBioChem, Vol. 18, No. 8 (February 7, 2017). DOI. © 2017 Wiley. Used with permission.

Recommended Citation

Ivanova, Lena V.; Cibich, Daniel; Deye, Gregory; Talipov, Marat R.; and Timerghazin, Qadir K., "Modeling of S‐Nitrosothiol–Thiol Reactions of Biological Significance: HNO Production by S‐Thiolation Requires a Proton Shuttle and Stabilization of Polar Intermediates" (2017). Chemistry Faculty Research and Publications. 916.
https://epublications.marquette.edu/chem_fac/916