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Chembiochem. 2017 Apr 18;18(8):726-738. doi: 10.1002/cbic.201600556. Epub 2017 Apr 3.

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

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Department of Chemistry, Marquette University, 535 N. 14th Street, Milwaukee, WI, 53233, USA.


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.


S-nitrosothiols; S-thiolation; density functional calculations; nitroxyl; reaction mechanisms

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