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 leukemia Jurkat cells were examined, and the relationship between chemical structure and function was discussed. Among the compounds we examined, tautomycin was the most potent inhibitor and the most effective inducer of apoptosis. It inhibited PP1 and PP2A enzymatic activity concentration-dependently with IC50 values of 20 and 75 pM, respectively, in the presence of 0.01% Brij-35, and an LC50 value of 1 mu M. Esterification of the anhydride moiety of tautomycin markedly increased the IC50 for the protein phosphatases. The C-1-C-7, fragment of tautomycin had no 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 essential for inhibition of protein phosphatase activity and that the anhydride 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, the C-1-C-18 moiety of tautomycin was essential for induction of apoptosis, and the conformation and the arrangement of functionalities of the C-18-C-26 carbon chain affected the apoptosis activity. However, modification of C-1-C-18, C-1-C-21, or C-1-C-26 compounds had little effect on phosphatase inhibitory activity. Our results strongly suggest that different moieties of tautomycin are involved in protein phosphatase inhibition and induction of apoptosis. (C) 1998 Elsevier Science Inc.