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The oxidative mechanism of action of ortho-quinone inhibitors of protein-tyrosine phosphatase α is mediated by hydrogen peroxide

2004; Elsevier BV; Volume: 429; Issue: 1 Linguagem: Inglês

10.1016/j.abb.2004.05.010

1096-0384

Michael P. Bova, Matthew N. Mattson, Stefan Vasile, Danny Tam, Leslie J. Holsinger, Meire Bremer, Terence Hui, Gerald McMahon, Audie Rice, Jon M. Fukuto,

Bioactive Compounds and Antitumor Agents

Here, we report the identification and characterization of five ortho-quinone inhibitors of PTPα. We observed that the potency of these compounds in biochemical assays was markedly enhanced by the presence of DTT. A kinetic analysis suggested that they were functioning as irreversible inhibitors and that the inhibition was targeted to the catalytic site of PTPα. The inhibition observed by these compounds was sensitive to superoxide dismutase and catalase, suggesting that reactive oxygen species may be mediators of their inhibition. We observed that in the presence of DTT, these compounds would produce up to 2.5 mM hydrogen peroxide (H2O2). The levels of H2O2 produced were sufficient to completely inactivate PTPα. In contrast, without a reducing agent the compounds did not generate H2O2 and showed little activity towards PTPα. In addition, these compounds inhibited PTPα-dependent cell spreading in NIH 3T3 cells at concentrations that were similar to their activity in biochemical assays. The biological implications of these results are discussed as they support growing evidence that H2O2 is a key regulator of PTPs.