title: trans-Beta-nitrostyrene derivatives as slow-binding inhibitors of protein tyrosine phosphatases.
abstract: Protein tyrosine phosphatases (PTPs) catalyze the hydrolysis of phosphotyrosyl (pY) proteins to produce tyrosyl proteins and inorganic phosphate. Specific PTPs inhibitors provide useful tools for studying PTP function in signal transduction processes and potential treatment for human diseases such as diabetes, inflammation, and cancer. In this work, trans-beta-nitrostyrene (TBNS) and its derivatives are found to be slow-binding inhibitors against protein tyrosine phosphatases PTP1B, SHP-1, and Yop with moderate potencies (K(I*) = 1-10 microM). Competition experiments with a substrate (pNPP) and iodoacetate indicate that TBNS is active site-directed. The mechanism of inhibition was investigated by UV-vis absorption spectroscopy, (1)H-(13)C heteronuclear single-quantum correlation NMR spectroscopy, and site-directed mutagenesis. These studies suggested a mechanism in which TBNS acts a pY mimetic and binds to the PTP active site to form an initial noncovalent E.I complex, followed by nucleophilic attack on the TBNS nitro group by Cys-215 of PTP1B to form a reversible, covalent adduct as the tighter E.I* complex. TBNS derivatives represent a new class of neutral pY mimetic inhibitors of PTPs.
authors.affiliation: Department of Chemistry and Ohio State Biochemistry Program, The Ohio State University, 100 West 18th Avenue, Columbus, Ohio 43210, USA.
authors.forename: Junguk
authors.initials: J
authors.lastname: Park
authors.forename: Dehua
authors.initials: D
authors.lastname: Pei
mesh_terms: D001665:Binding Sites; D001667:Binding, Competitive / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007700:Kinetics; D008956:Models, Chemical; D015394:Molecular Structure; D016254:Mutagenesis, Insertional; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013343:Styrenes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D013343:Styrenes; C011955:beta-nitrostyrene; D017027:Protein Tyrosine Phosphatases