Chemical biology study on protein phosphatases and their specific inhibitors.

蛋白磷酸酶及其特异性抑制剂的化学生物学研究。

基本信息

批准号：
12045268
负责人：
OSADA Hiroyuki
金额：
$ 12.67万
依托单位：
RIKEN
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

Proteins involved in the signal transduction are regulated by phosphorylation/dephosphorylation during a process of proliferation, differentiation and apoptosis.Many selective inhibitors for protein kinases have been developed, however development of selective phosphatase inhibitors has not been achieved yet.To resolve this problem, I have tried to develop phosphatase inhibitors.1.4-isovavenaciolide was isolated as an inhibitor of the VHR protein tyrosine phosphatase. As 4-isoavenaciolide possesses a reactive exo-methylene moiety, it is possible that 4-isoavenaciolide inhibits VHR through the direct modification of a cysteine residue in the catalytic site.Since dual-specificity phosphatases have a consensus CXXXXXR motif in the catalytic site, dual-specificity phosphatases are sensitive to 4-isoavenaciolide.2.Phoslactomycins (PLMs) produced by Streptomyces, are potent and selective inhibitors of serine threonine phosphatases, PP2A.Incorporation studies with stable isotope labeling cyclohexanecarboxylic acid (CHC) indicated that the six PLM analoges (PLM A-F) made by Streptomyces sp.HK-803 are all biosynthesized from a CHC starter unit.Hydroxylation of the CHC-derived side chain of PLM B and a subsequent esterification produces the remaining PLM analogs.The entire 75 kb PLM biosynthetic gene cluster of the producing strain was cloned, sequenced and analyzed.Thecluster contains six genes (plml-7) which comprise the loading domain and seven extension modules of the type I modular PLM polyketide synthase.

在增殖，分化和凋亡过程中，已经开发了蛋白激酶的许多选择性抑制剂，但在选择性磷酸酶抑制剂的发展尚未达到此问题。为了解决此问题，我已经尝试隔离phastatasase.1.1.11. VHR蛋白酪氨酸磷酸酶的抑制剂。 As 4-isoavenaciolide possesses a reactive exo-methylene moiety, it is possible that 4-isoavenaciolide inhibits VHR through the direct modification of a cysteine residue in the catalytic site.Since dual-specificity phosphatases have a consensus CXXXXXR motif in the catalytic site, dual-specificity phosphatases are sensitive to 4-异叶烯丙基。2。链霉菌产生的短乳霉菌素（PLMS）是丝氨酸苏氨酸磷酸酶的有效抑制剂，PP2A。与稳定的同位素标记稳定的同位素标记的构成研究，该研究均由Cyclohexanecylicic（CHC）指示了所有六个PLMMMMATER-03 EYTRETS（CHC）（plmms）（plmms）。从CHC启动器单元进行的生物合成。PLM B的CHC衍生侧链的羟基化和随后的酯化产生剩余的PLM类似物。整个75 KB PLM PLM生物合成基因簇的生产菌株的生产菌株的生产菌株均可生产，序列和分析。 I型模块化PLM聚酮化合酶合酶的模块。