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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
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 <i>N</i>-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