A Pharmacophore Model of Tautomycin, an Inhibitor of Protein Phosphatases 1 and 2A

Over the last decade there has been a growing realization that phosphatases are extremely important in cellular and organismal functions. Tautomycin, an inhibitor of protein phosphatases (PP) 1 and 2A, was isolated from a culture broth of Streptomyces spiroverticillatus in 1987. The structure that we established in 1990 showed some similarities with that of okadaic acid, and the target protein of okadaic acid had already been found to be protein phosphatase in 1988. Indeed, it was later found that the target proteins of tautomycin were also protein phosphatases. However, this molecule is not a tumor promoter on mouse skin and in rat glandular stomach. These differences in biological activities between tautomycin and the okadaic acid class tumor promoters are interesting topics in structural biology. The three-dimensional structures of the related compound acanthifolicin and the o-bromobenzyl ester derivative of okadaic acid were determined by X-ray crystallography, and the solution-state conformation of okadaic acid was proposed by molecular modelling and NMR. Since tautomycin inhibits specific [ super(3)H]okadaic acid binding to PP-1 and PP-2A, it has been assumed to have similar conformation to that of okadaic acid. In order to define homology in the 3-D structures of both inhibitors, and to provide a pharmacophore model of tautomycin against PP-1 and PP-2A, we performed the conformational analysis of tautomycin in organic solvents, starting from the established absolute configuration of tautomycin.