Antitumor antibiotic fostriecin covalently binds to cysteine-269 residue of protein phosphatase 2A catalytic subunit in mammalian cells.

Abstract	Fostriecin is a phosphate monoester with excellent antitumor activity against mouse leukemia, and it is a potent inhibitor of protein phosphatase (PP) 2A. This compound has been predicted to covalently bind to the Cys269 residue of the PP2A catalytic subunit (PP2Ac) at the alpha,beta-unsaturated lactone via a conjugate addition reaction. However, this binding has not yet been experimentally proven. To confirm such binding, we synthesized biotin-labeled fostriecin (bio-Fos), which has an inhibitory activity against the proliferation of mouse leukemia cells. We showed that fostriecin directly binds to PP2Ac in HeLa S3 cells by pull-down assays using bio-Fos. Moreover, we directly demonstrated that fostriecin covalently binds to the Cys269 residue of PP2Ac by matrix assisted laser desorption/ionization time-of-flight mass spectrometry analysis. From these results, the inhibitory mechanism of fostriecin on PP2A activity is discussed.
Authors	Toshifumi Takeuchi, Noriyuki Takahashi, Kazutomo Ishi, Tomoe Kusayanagi, Kouji Kuramochi, Fumio Sugawara
Journal	Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 17 Issue 23 Pg. 8113-22 (Dec 01 2009) ISSN: 1464-3391 [Electronic] England
PMID	19857968 (Publication Type: Journal Article)
Chemical References	Alkenes Antibiotics, Antineoplastic Polyenes Pyrones Protein Phosphatase 2 Cysteine fostriecin
Topics	Alkenes (pharmacology) Amino Acid Sequence Antibiotics, Antineoplastic (pharmacology) Binding Sites (physiology) Binding, Competitive (physiology) Catalytic Domain (physiology) Cell Survival (physiology) Cysteine (metabolism) HeLa Cells Humans Inhibitory Concentration 50 Magnetic Resonance Spectroscopy Models, Molecular Molecular Sequence Data Polyenes Protein Phosphatase 2 (metabolism) Pyrones (pharmacology) Spectrometry, Mass, Electrospray Ionization Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Spectroscopy, Fourier Transform Infrared

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