Development of small-molecular-bioprobes and proteomic analyses of signal transduction factors.

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To elucidate biological functions, there are two ways of analysis. One is the information and structure based analysis such as genome science or structural biology. The other is the chemical biology based analysis, in which proteins essential for biological process are identified using their specific inhibitors. The purposes of the present research project are to generate chemicals ("bioprobes") useful for the latter type of study, which regulate the signal transduction pathway in cells, to identify biological target molecules of the bioprobes and to mine and analyze novel molecular targets. We have conducted the project for these purposes and have obtained many important results as follows.1.Identification of molecular targets and characterization of bioprobes using proteomic analysis(1)Development of photo-crosslinked small molecule microarrays to identify specific interacting molecules for target proteins in high throughput manner. Angew.Chem.Int.Ed.(2005)(2)Elucidation of the bindi … More ng mechanism of phoslactomycin to its specific molecular target, protein phosphatase 2A.FEBS Lett.(2005)(3)Identification of a mitochondria specific heat shock protein, Hsp60 as a target molecule for epolactaene and elucidation of the mechanism to inhibit HSP60's chaperone activity. Biochem.J.(2005)2.Exploitation of novel bioprobes for the study of cellular signal transduction pathway(1)Identification of the pathway and the gene cluster in an actinomycete for the biosynthesis of PP2A specific inhibitor, phoslactomycins, and development of a method to enhance the selective production of phoslactomycins in vivo. Tetrahedron (2003),J.Biol.Chem.(2003)(2)Isolation and characterization of novel compounds, RK805 and epoxytwinol A as novel angiogenesis inhibitors. Tetrahedron (2004),Chem.Commun.(2005)3.Molecular biology on novel molecular targets(1)Elucidation of the mechanism of ubiquitin-proteasome dependent degradation of a cell cycle regulatory protein kinase, Weel. Proc.Natl.Acad.Sci.USA(2004) Less