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Modeling of S ‐Nitrosothiol–Thiol Reactions of Biological Significance: HNO Production by S‐Thiolation Requires a Proton Shuttle and Stabilization of Polar Intermediates
Author(s) -
Ivanova Lena V.,
Cibich Daniel,
Deye Gregory,
Talipov Marat R.,
Timerghazin Qadir K.
Publication year - 2017
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201600556
Subject(s) - chemistry , thiol , electrophile , photochemistry , nucleophile , proton , nitroxyl , catalysis , combinatorial chemistry , stereochemistry , organic chemistry , physics , quantum mechanics
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.