Redox regulation of protein tyrosine phosphatase activity by hydroxyl radical

Fan Guo Meng, Zhong Yin Zhang

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Substantial evidence suggests that transient production of reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) is an important signaling event triggered by the activation of various cell surface receptors. Major targets of H2O2 include protein tyrosine phosphatases (PTPs). Oxidation of the active site Cys by H2O 2 abrogates PTP catalytic activity, thereby potentially furnishing a mechanism to ensure optimal tyrosine phosphorylation in response to a variety of physiological stimuli. Unfortunately, H2O2 is poorly reactive in chemical terms and the second order rate constants for the H 2O2-mediated PTP inactivation are ∼ 10 M- 1 s- 1, which is too slow to be compatible with the transient signaling events occurring at the physiological concentrations of H 2O2. We find that hydroxyl radical is produced from H 2O2 solutions in the absence of metal chelating agent by the Fenton reaction. We show that the hydroxyl radical is capable of inactivating the PTPs and the inactivation is active site directed, through oxidation of the catalytic Cys to sulfenic acid, which can be reduced by low molecular weight thiols. We also show that hydroxyl radical is a kinetically more efficient oxidant than H2O2 for inactivating the PTPs. The second-order rate constants for the hydroxyl radical-mediated PTP inactivation are at least 2-3 orders of magnitude higher than those mediated by H2O2 under the same conditions. Thus, hydroxyl radical generated in vivo may serve as a more physiologically relevant oxidizing agent for PTP inactivation. This article is part of a Special Issue entitled: Chemistry and mechanism of phosphatases, diesterases and triesterases.

Original languageEnglish (US)
Pages (from-to)464-469
Number of pages6
JournalBiochimica et Biophysica Acta - Proteins and Proteomics
Volume1834
Issue number1
DOIs
StatePublished - Jan 1 2013

Keywords

  • Hydrogen peroxide
  • Hydroxyl radical
  • Protein tyrosine phosphatase
  • Redox regulation

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Analytical Chemistry
  • Molecular Biology

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