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[摘要]：1-Deoxy-D-xylulose 5-phosphate (DXP) reductoisomerase (DXR) is an NADPH-dependent enzyme catalyzing the rearrangement and reduction of DXP to methyl-D-erythritol 4-phosphate ( MEP). Two mechanisms for this enzymatic reaction have been proposed, involving either an alpha-ketol rearrangement or a retroaldol/aldol rearrangement. In this study, a fluorinated product analogue, FCH2-MEP, was synthesized as a possible mechanism-based inactivator for DXR if the retroaldol/aldol mechanism is operative. FCH2-MEP was found to be a weak competitive inhibitor, and thus was unable to discriminate between the mechanisms. This result is due to the inability of the targeted enzyme, DXR, to oxidize FCH2-MEP to the aldehyde intermediate that is common to both mechanisms. While FCH2-MEP failed to act as a mechanism-based inactivator, the insight gained from this study will assist in the future design of inhibitors of DXR. (c) 2007 Elsevier Ltd. All rights reserved. |
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