Chemical biology study on protein phosphatases and their specific inhibitors.

参与信号转导的蛋白质在增殖、分化和凋亡的过程中受到磷酸化/去磷酸化的调节。许多选择性的蛋白激酶抑制剂已经被开发出来，但是选择性的磷酸酶抑制剂的开发还没有实现。为了解决这个问题，我试图开发磷酸酶抑制剂。1.4-异伐那西汀被分离作为VHR蛋白酪氨酸磷酸酶的抑制剂。由于4-异燕麦内酯具有一个反应性的外亚甲基部分，因此4-异燕麦内酯可能通过直接修饰催化位点的半胱氨酸残基来抑制VHR。由于双特异性磷酸酶在催化位点具有一个共有的CXXXXXR基序，因此双特异性磷酸酶对4-异燕麦内酯敏感。是丝氨酸苏氨酸磷酸酶的有效和选择性抑制剂，PP 2A.用稳定同位素标记环己烷羧酸（CHC）的掺入研究表明，由链霉菌HK-803产生的六种PLM类似物（PLM A-F）都是从CHC起始单元生物合成的。对该菌株75 kb的PLM生物合成基因簇进行了克隆、测序和分析，该基因簇包含6个基因（plml-7），它们分别包含PLM聚酮合酶I型模块的装载结构域和7个延伸模块。

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.