Structure and function of key biomacromolecules.
My research focuses on the structure-function relationships of the key macromolecules that are involved in various biological processes. Three-dimensional structures of the interested macromolecules have been determined at atomic resolution by a single crystal X-ray diffraction method. Site-directed mutageneses and enzyme kinetics measurements have been used to interpret the structure-function relationships. Currently, I have two research projects.
The first project is structural analysis of enzymes in the methyl cycle. In biological systems, there are a myriad of reactions in which methyl groups are transferred from a few types of methyl donor molecules to a wide variety of methyl acceptor molecules. Among biological methyl group donors, S-adenosylmethionine (AdoMet) is the most widely used in methylation reactions. Methylation reactions mediated by AdoMet are increasingly being recognized as significant control factors in the regulation of variety of cellular functions. The 3D structures of several enzymes that are involved in the methyl cycle have been determined. On the basis of the 3D structures, the catalytic mechanisms of the enzymes have been proposed. Using site-directed mutagenesis and kinetics measurements, the proposed mechanisms have further studied. The 3D structures have been used to design potential inhibitors, and some of the inhibitors have been synthesized.
The second project is a study on the anticancer drug actinomycin D (AMD) by X-ray crystallography, chemical synthesis, and inhibition measurement. Crystal structures of DNA-AMD complexes have been determined in his laboratory. On the basis of the crystal structures, the AMD molecule has been modified in order to reduce its cytotoxicity and/or increase its selectivity against certain tumor cells. For a long-range plan, crystallographic and chemical and biological methods will be used to design various sequence-specific DNA binders which can define unique DNA sequences in humans. The ultimate goal is to develop agents that recognize 16 base sequences.