BIOCHEMISTRY: An On-Off Cycle

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Science  29 Jul 2005:
Vol. 309, Issue 5735, pp. 671d
DOI: 10.1126/science.309.5735.671d

The mechanisms by which the activities of regulatory enzymes are themselves regulated range from tight-binding inhibitors to covalent modification. Sivaramakrishnan et al.have used a small molecule model in order to explore the chemical feasibility of regulating protein tyrosine phosphatase 1B (PTP1B) by reversible oxidation of its catalytic sulfhydryl. Structural analysis of inhibited PTP1B revealed the presence of a 3-isothiazolidinone adduct, in which the side chain of the active site cysteine had become covalently linked to the amide nitrogen of the next residue. Using a benzene scaffold to juxtapose a β-sulfinyl propionic acid ester and a monosubstituted amide nitrogen, they find that the in situ-generated sulfenic acid (RS-OH) is sufficiently reactive for the heterocycle to form under mild conditions (pH 7.5 and 37°C). In terms of how the corresponding biochemistry occurs, hydrogen peroxide oxidizes the sulfhydryl to the sulfenic acid, and glutathione opens the ring, forming a mixed disulfide that regenerates the free sulfhydryl. These reactions together would then serve as a redox cycle, switching phosphatase activity on and off. — GJC

J. Am. Chem. Soc. 10.1021/ja052599e (2005).

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