title: Redox Modulation of PTEN Phosphatase Activity by Hydrogen Peroxide and Bisperoxidovanadium Complexes.
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.
authors.affiliation: Chemical Genomics Centre of the Max Planck Society, Otto-Hahn-Strasse 15, 44227 Dortmund (Germany).|Technical University Dortmund, Department of Chemistry and Chemical Biology, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany).
authors.forename: Chang-Uk
authors.initials: CU
authors.lastname: Lee
authors.affiliation: Chemical Genomics Centre of the Max Planck Society, Otto-Hahn-Strasse 15, 44227 Dortmund (Germany).|Technical University Dortmund, Department of Chemistry and Chemical Biology, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany).
authors.forename: Gernot
authors.initials: G
authors.lastname: Hahne
authors.affiliation: Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14424 Potsdam (Germany).
authors.forename: Jonas
authors.initials: J
authors.lastname: Hanske
authors.affiliation: Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, Dortmund (Germany).
authors.forename: Tanja
authors.initials: T
authors.lastname: Bange
authors.affiliation: Chemical Genomics Centre of the Max Planck Society, Otto-Hahn-Strasse 15, 44227 Dortmund (Germany).
authors.forename: David
authors.initials: D
authors.lastname: Bier
authors.affiliation: Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14424 Potsdam (Germany).
authors.forename: Christoph
authors.initials: C
authors.lastname: Rademacher
authors.affiliation: Chemical Genomics Centre of the Max Planck Society, Otto-Hahn-Strasse 15, 44227 Dortmund (Germany).
authors.forename: Sven
authors.initials: S
authors.lastname: Hennig
authors.affiliation: Chemical Genomics Centre of the Max Planck Society, Otto-Hahn-Strasse 15, 44227 Dortmund (Germany). tom.grossmann@cgc.mpg.de.|Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, Dortmund (Germany). tom.grossmann@cgc.mpg.de.|Technical University Dortmund, Department of Chemistry and Chemical Biology, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany). tom.grossmann@cgc.mpg.de.|VU University Amsterdam, Department of Chemistry & Pharmaceutical Sciences, De Boelelaan 1083, 1081 HV, Amsterdam (The Netherlands). tom.grossmann@cgc.mpg.de.
authors.forename: Tom N
authors.initials: TN
authors.lastname: Grossmann
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D010084:Oxidation-Reduction; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010545:Peroxides / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014639:Vanadium / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D009942:Organometallic Compounds; D010545:Peroxides; D014639:Vanadium; D006861:Hydrogen Peroxide; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: bpV-phen; disulfides; inhibitors; protein tyrosine phosphatase; tumor suppressors