Synthesis and analysis of a fluorinated product analogue as an inhibitor for 1-deoxy-D-xylulose 5-phosphate reductoisomerase.
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, FCH(2)-MEP, was synthesized as a possible mechanism-based inactivator for DXR if the retroaldol/aldol mechanism is operative. FCH(2)-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 FCH(2)-MEP to the aldehyde intermediate that is common to both mechanisms. While FCH(2)-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.
Munos
Jeffrey W
JW
Division of Medicinal Chemistry, College of Pharmacy, and Department of Chemistry and Biochemistry, University of Texas, Austin, TX 78712, USA.
Pu
Xiaotao
X
Liu
Hung-wen
HW
D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors* / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004896:Erythritol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000187:drug effects; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000187:drug effects
D004791:Enzyme Inhibitors; C531868:FCH(2)-methyl-D-erythritol 4-phosphate; D009097:Multienzyme Complexes; D010088:Oxidoreductases; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases; D004896:Erythritol