Redox Regulation of Protein Tyrosine Phosphatase 1B by Peroxymonophosphate (O3POOH)

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Abstract
Reversible phosphorylation of tyrosine residues serves as a biochemical “switch” that alters the functional properties of many proteins involved in cellular signal transduction processes. Protein tyrosine phosphatases (PTPs) catalyze the removal of phosphoryl groups from tyrosine residues in target proteins, thereby playing a central role in the regulation of diverse cellular processes including glucose metabolism, cell cycle control, and immune responses. Accordingly, small molecules capable of inactivating PTPs may find use as therapeutic agents and tools for the study of diverse signal transduction pathways. In the work reported here, peroxymonophosphate (2-O3POOH) was reported to be an exceptional inactivator of PTP1B, an archetypal member of the PTP enzyme family (KI = 6.6 × 10-7 M and kinact = 0.043 s-1). In this regard, peroxymonophosphate is over 7000 times more potent than hydrogen peroxide, the endogenous regulator of PTP1B. Inactivation of PTP1B by peroxymonophosphate is active site directed and, like that by hydrogen peroxide, is readily reversed by treatment with dithiothreitol (5 mM). Together the findings suggest that peroxymonophosphate oxidizes the active site cysteine residue of PTP1B to the sulfenic acid oxidation state. Importantly, peroxymonophosphate (100 nM) yields substantial inactivation of PTP1B even in the presence of physiologically relevant concentrations of the biological thiol glutathione (1 mM). Collectively, these properties may make peroxymonophosphate a useful tool for probing the role of cysteine-dependent PTPs in various signal transduction pathways. Finally, it is interesting to note that peroxymonophosphate may be biosynthetically accessible via the reaction of endogenous hydrogen peroxide with phosphoryl donors. Peroxymonophosphate possesses key properties expected for the endogenous signaling molecule involved in the redox regulation of PTP activity.