Reactivity of nitroxyl-derived sulfinamides

Biochemistry
Gizem Keceli, John P Toscano

Abstract

Sulfinamide [RS(O)NH(2)] formation is known to occur upon exposure of cysteine residues to nitroxyl (HNO), which has received recent attention as a potential heart failure therapeutic. Because this modification can alter protein structure and function, we have examined the reactivity of sulfinamides in several systems, including a small organic molecule, peptides, and a protein. Although it has generally been assumed that this thiol to sulfinamide modification is irreversible, we show that sulfinamides can be reduced back to the free thiol in the presence of excess thiol at physiological pH and temperature. We have examined this sulfinamide reduction both in peptides, where a cyclic intermediate analogous to that proposed for asparagine deamidation reactions potentially can contribute, and in a small organic molecule, where the mechanism is restricted to a direct thiolysis. These studies suggest that the contribution from the cyclic intermediate becomes more important in environments with lower dielectric constants. In addition, although sulfinic acid [RS(O)OH] formation is observed upon prolonged incubations in water, reduction of sulfinamides is found to dominate in the presence of thiols. Finally, studies with the cysteine p...Continue Reading

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Citations

Apr 24, 2014·Chemical Communications : Chem Comm·Guo-Jiang MaoRu-Qin Yu
May 30, 2014·Biochemistry·Gizem Keceli, John P Toscano
Oct 7, 2014·Chemical Communications : Chem Comm·Xiaotong JingLingxin Chen
Oct 1, 2013·Biochemistry·Gizem KeceliJohn P Toscano
Mar 16, 2013·Bioorganic & Medicinal Chemistry Letters·Kazuyuki AizawaNaoki Miyata
Aug 1, 2014·Bioorganic & Medicinal Chemistry Letters·Gizem KeceliJohn P Toscano
Aug 31, 2013·Archives of Biochemistry and Biophysics·Matthew I JacksonJon M Fukuto
Oct 23, 2016·Free Radical Biology & Medicine·Christopher L BiancoJohn P Toscano
Mar 8, 2019·The Journal of General Physiology·Gizem KeceliJohn P Toscano
Jan 25, 2018·Journal of Natural Products·Janusz J PetkowskiSara Seager
Dec 24, 2020·The Journal of Organic Chemistry·Jessica ZarenkiewiczJohn P Toscano

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