Direct and Nitroxyl (HNO)-mediated Reactions of Acyloxy Nitroso Compounds with the Thiol-containing Proteins Glyceraldehyde 3-phosphate Dehydrogenase and Alkyl Hydroperoxide Reductase Subunit C

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2013 Jul 31

PMID 23895568

Citations 9

Authors

Susan Mitroka

Mai E Shoman

Jenna F DuMond

Landon Bellavia

Omar M Aly

Mohamed Abdel-Aziz

Daniel B Kim-Shapiro

S Bruce King

Affiliations

Soon will be listed here.

Abstract

Nitroxyl (HNO) reacts with thiols, and this reactivity requires the use of donors with 1-nitrosocyclohexyl acetate, pivalate, and trifluoroacetate, forming a new group. These acyloxy nitroso compounds inhibit glyceraldehyde 3-phosphate dehydrogenase (GAPDH) by forming a reduction reversible active site disulfide and a reduction irreversible sulfinic acid or sulfinamide modification at Cys244. Addition of these acyloxy nitroso compounds to AhpC C165S yields a sulfinic acid and sulfinamide modification. A potential mechanism for these transformations includes nucleophilic addition of the protein thiol to a nitroso compound to yield an N-hydroxysulfenamide, which reacts with thiol to give disulfide or rearranges to sulfinamides. Known HNO donors produce the unsubstituted protein sulfinamide as the major product, while the acetate and pivalate give substituted sulfinamides that hydrolyze to sulfinic acids. These results suggest that nitroso compounds form a general class of thiol-modifying compounds, allowing their further exploration.

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