1. Redox Modulation of PTEN Phosphatase Activity by Hydrogen Peroxide and Bisperoxidovanadium Complexes
- Author
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Christoph Rademacher, Sven Hennig, David Bier, Gernot Hahne, Tom N. Grossmann, Tanja Bange, Jonas Hanske, Chang-Uk Lee, Organic Chemistry, and AIMMS
- Subjects
Models, Molecular ,bpV-phen ,disulfides ,Cellular homeostasis ,Protein tyrosine phosphatase ,Oxidative phosphorylation ,protein tyrosine phosphatase ,Catalysis ,law.invention ,Structure-Activity Relationship ,Phosphatase Inhibition ,SDG 3 - Good Health and Well-being ,law ,inhibitors ,Organometallic Compounds ,Humans ,Structure–activity relationship ,PTEN ,Mode of action ,chemistry.chemical_classification ,Reactive oxygen species ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,tumor suppressors ,Chemistry ,PTEN Phosphohydrolase ,Vanadium ,Hydrogen Peroxide ,General Chemistry ,Communications ,Peroxides ,Biochemistry ,biology.protein ,Suppressor ,Oxidation-Reduction - Abstract
PTEN is a dual-specificity protein tyrosine phosphatase. As one of the central tumor suppressors, a thorough regulation of its activity is essential for proper cellular homeostasis. The precise implications of PTEN inhibition by reactive oxygen species (e.g. H2 O2 ) and the subsequent structural consequences remain elusive. To study the effects of PTEN inhibition, bisperoxidovanadium (bpV) complexes serve as important tools with the potential for the treatment of nerve injury or cardiac ischemia. However, their mode of action is unknown, hampering further optimization and preventing therapeutic applications. Based on protein crystallography, mass spectrometry, and NMR spectroscopy, we elucidate the molecular basis of PTEN inhibition by H2O2 and bpV complexes. We show that both molecules inhibit PTEN via oxidative mechanisms resulting in the formation of the same intramolecular disulfide, therefore enabling the reactivation of PTEN under reductive conditions.
- Published
- 2015
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