32 非メバロン酸経路とその特異的阻害剤(口頭発表の部)

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Several eubacteria including Escherichia coli utilize an alternative mevalonate-independent pathway (nonmevalonate pathway) for the biosynthesis of isopentenyl diphosphate. In the nonmevalonate pathway, 2-C-methyl-D-erythritol or its 4-phosphate which was proposed to be formed from 1-deoxy-D-xylulose 5-phosphate (DXP) via intramolecular rearrangement followed by a reduction process is one of the biosynthetic precursors of isopentenyl diphosphate. To clone the gene(s) responsible for the synthesis of 2-C-methyl-D-erythritol 4-phosphate (MEP), we prepared and selected E. coli mutants with an obligatory requirement for 2-C-methylerythritol for growth and survival. All the DNA fragments which complemented the defect in synthesizing MEP of these mutants contained the yaeM gene which located at 4.2 min on the chromosomal map of E. coli. The gene product showed significant homologies to hypothetical proteins with unknown functions present in several eubacteria. The yaeM gene product overexpressed in E. coli was found to catalyze the formation of MEP from DXP in the presence of NADPH. These data clearly show that the yaeM gene encodes a novel enzyme, designated DXP reductoisomerase, which synthesizes MEP from DXP in a single step by intramolecular rearrangement and reduction. Since the nonmevalonate pathway is absent in mammals, all the enzymes involved in this pathway are considered to be new targets for screening of antibacterial substances. Therefore, we attempted by database search to find antibiotics active against E. coli and Bacillus subtilis with the nonmevalonate pathway, but inactive against Staphylococcus aureus possessing the mevalonate pathway with an expectation that such inhibitors might have already been reported as antibacterial substances. As a result, fosmidomycin showing the expected antibacterial spectrum came up as a candidate for an inhibitor of the nonmevalonate pathway. In this presentation we describe inhibitory effects of fosmidomycin on DXP reductoisomerase.
1999-09-01

32 非メバロン酸経路とその特異的阻害剤(口頭発表の部)

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