Kawamura T, Matsuzawa S, Mizuno Y, Kikuchi K, Oikawa H, Oikawa M, Ubukata M, Ichihara A
Section of Biochemistry, Institute of Immunological Science, Hokkaido University, Sapporo, Japan.
Biochem Pharmacol. 1998 Apr 1;55(7):995-1003. doi: 10.1016/s0006-2952(97)00539-x.
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 microM. Esterification of the anhydride moiety of tautomycin markedly increased the IC50 for the protein phosphatases. The C1'-C7' fragment of tautomycin had no inhibitory effect, but the fragment containing the C22-C26 moiety was inhibitory. These results suggest that the C22-C26 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 C22-C26 moiety increase the apoptosis-inducing activity. On the other hand, the C1-C18 moiety of tautomycin was essential for induction of apoptosis, and the conformation and the arrangement of functionalities of the C18-C26 carbon chain affected the apoptosis activity. However, modification of C1-C18, C1-C21, or C1-C26 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.
研究了陶诺霉素及其衍生物对蛋白磷酸酶PP1和PP2A的影响以及它们对人白血病Jurkat细胞的凋亡诱导活性，并探讨了化学结构与功能之间的关系。在我们研究的化合物中，陶诺霉素是最有效的抑制剂和凋亡诱导剂。在存在0.01% Brij - 35的情况下，它浓度依赖性地抑制PP1和PP2A的酶活性，IC50值分别为20和75 pM，LC50值为1 microM。陶诺霉素酸酐部分的酯化显著增加了对蛋白磷酸酶的IC50值。陶诺霉素的C1'-C7'片段没有抑制作用，但含有C22-C26部分的片段具有抑制作用。这些结果表明，C22-C26部分对于抑制蛋白磷酸酶活性至关重要，而酸酐部分增强了抑制作用。然而，酸酐的酯化并没有降低凋亡诱导活性，包含C22-C26部分也没有增加凋亡诱导活性。另一方面，陶诺霉素的C1-C18部分对于诱导凋亡至关重要，C18-C26碳链的构象和官能团排列影响凋亡活性。然而，对C1-C18、C1-C21或C1-C26化合物的修饰对磷酸酶抑制活性影响很小。我们的结果强烈表明，陶诺霉素的不同部分参与了蛋白磷酸酶抑制和凋亡诱导过程。
