| Budget Amount *help |
¥48,230,000 (Direct Cost: ¥37,100,000、Indirect Cost: ¥11,130,000)
Fiscal Year 2007: ¥14,170,000 (Direct Cost: ¥10,900,000、Indirect Cost: ¥3,270,000)
Fiscal Year 2006: ¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000)
Fiscal Year 2005: ¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000)
Fiscal Year 2004: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
|
|---|
| Research Abstract |
We have been working on the conformational changes and vibration movement of protein structure of xanthine oxidoreductase that potentially produces active oxygen species. Outline of the significant results as follows : 1) We have assigned the atom ligands and their geometries of the molybdenum atom of the MoCo center in the catalytic center of xanthine oxidoreductase by X-ray crystallographic analysis. In contrast to the previous reports, comparison between the electron densities of the sulfo and desulfo forms indicated that the oxygen atom locates at the apical position while the sulfo atom locates at the equatorial position. These results account for the hydride transfer mechanism during hydroxylation reaction proposed in the structure of reaction intermediate of the enzyme with slow substrate of FYX-051. We also proposed the role of amino acid residues located in the active site cavities in the hydroxylation of purine substrates by site directed mutagenesis experiments. 2) We have revealed the overall mechanism of the conversion from the dehydrogenase to the oxidase revealed by the three-dimensional structures analysis, and have published the invited review papers. 3) In order to account for the different effects of inhibitors on the mammalian and bacterial enzymes observed in the anti-gout drugs, we have determined the molecular dynamics by computer simulation analysis. The results suggested that the dynamics of the hydrophobic peptide exist in the cavity differ significantly between bacterial and mammalian enzymes. 4) We have constructed transgenic mouse that produces large amount of superoxide compare to the normal enzyme. Analyses of phenotype are still under way. We have analyzed the effects of inhibitors of xanthine oxidoreductase on the ALS model mouse, it was found that some of the inhibitors are quite effective for therapeutic usage.
|
