DIFFERENT MOIETIES OF TAUTOMYCIN INVOLVED IN PROTEIN PHOSPHATASE INHIBITION AND INDUCTION OF APOPTOSIS

The effects of tautomycin and its derivatives on protein phosphatases PP1 and PP2A and their apoptosis-inducing activity toward human leukem ia Jurkat cells were examined, and the relationship between chemical s tructure and function was discussed. Among the compounds we examined, tautomycin was the most potent inhibitor and the most effective induce r of apoptosis. It inhibited PP1 and PP2A enzymatic activity concentra tion-dependently with IC50 values of 20 and 75 pM, respectively, in th e presence of 0.01% Brij-35, and an LC50 value of 1 mu M. Esterificati on of the anhydride moiety of tautomycin markedly increased the IC50 f or the protein phosphatases. The C-1-C-7, fragment of tautomycin had n o inhibitory effect, but the fragment containing the C-22-C-26 moiety was inhibitory. These results suggest that the C-22-C-26 moiety is ess ential for inhibition of protein phosphatase activity and that the anh ydride moiety enhances the inhibition. However, the esterification of the anhydride did not decrease, nor did the inclusion of the C-22-C-26 moiety increase the apoptosis inducing activity. On the other hand, t he C-1-C-18 moiety of tautomycin was essential for induction of apopto sis, and the conformation and the arrangement of functionalities of th e C-18-C-26 carbon chain affected the apoptosis activity. However, mod ification of C-1-C-18, C-1-C-21, or C-1-C-26 compounds had little effe ct on phosphatase inhibitory activity. Our results strongly suggest th at different moieties of tautomycin are involved in protein phosphatas e inhibition and induction of apoptosis. (C) 1998 Elsevier Science Inc .