How Does Alendronate Inhibit Protein-tyrosine Phosphatases?

摘要: Alendronate (4-amino-1-hydroxybutylidene 1,1-bisphosphonate) is a drug used in the treatment of osteoporosis and other bone diseases. The inhibition protein-tyrosine phosphatases (PTPs) by alendronate suggests that PTPs may be molecular targets. As clear understanding mechanism lacking, our aim was to analyze provide further insight into its therapeutic effect. We show here presence calcium followed first-order kinetic behavior, parameters for process were determined. Evidence presented alendronate/calcium active site-directed. However, this very sensitive assay constituents such as EDTA dithiothreitol. Furthermore, eliminated addition catalase. These observations suggest combination alendronate, metal ions, hydrogen peroxide responsible PTPs. individual effects calcium, or on inactivation CD45 Electrospray ionization mass spectrometry demonstrated PTP1B increased 34 +/- 2 units after enzyme inactivated with alendronate/calcium, due oxidization catalytic cysteine sulfinic acid (Cys-SO2H). inhibited could partially reactivated reducing agents hydroxylamine (NH2OH) N,N'-dimethyl-N, N'-bis(mercaptoacetyl)hydrazine, indicating oxidized forms sulfenic (Cys-SOH). This confirms result oxidation cysteine. relevance oxidative biological system discussed.