P-48 プロテインフォスファターゼ阻害剤トートマイシンの分子形状解析と活性に関する研究(ポスター発表の部)

概要

論文の詳細を見る
Protein phosphatases type 1 (PP1) and type 2A (PP2A) are two of the four major enzymes that dephosphorylate serine/threonine residues of proteins in eukaryotic cells. Recently, these enzymes turned to be specifically inhibited by tautomycin (1). In this paper, we describe the molecular shape-activity relationship of tautomycin and its conformational analyses. We have been establishing a new assay method for PP1 and PP2A inhibitors, in which the activities are monitored by a firefly bioluminescence system. Two forms of tautomycin, i.e. 1a (acid anhydride) and 1b (diacid), were successfully isolated by ODS-HPLC using CH_3CN-H_2O. The large differences of these retention times suggested that the molecular shapes must be quite different in this condition. The determination of PP2A inhibitory activities of 1a and 1b indicated that 1b is the real active form of tautomycin. Four tautomycin derivatives, 6-8 (enone) and 9 (22-deoxy-), were prepared. None of them showed PP2A inhibitory activities, therefore flexibility around C19 to C23 and hydroxyl group at C22 maybe indispensable for PP2A inhibitory activity. Trans-esterification mechanism on alkali degradation of tautomycin (1) was proposed. This mechanism proved that hydroxyl group at C22 is near to C-1' in tautomycin molecule. Preliminary result of molecular dynamic calculation of 1b is also presented.
天然有機化合物討論会の論文
1995-09-01