Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 54, Issue 46, Pages 13796-13800Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201506338
Keywords
bpV-phen; disulfides; inhibitors; protein tyrosine phosphatase; tumor suppressors
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Funding
- German Research Foundation (DFG, Emmy Noether program) [RA1944/2-1, GR3592/2-1]
- AstraZeneca
- Bayer CropScience
- Bayer HealthCare
- Boehringer Ingelheim
- Merck KGaA
- Max Planck Society
- Fonds der Chemischen Industrie
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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. H2O2) 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.
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