Chemical biology study on protein phosphatases and their specific inhibitors.

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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.