1-Deoxy-D-xylulose 5-phosphate synthase catalyzes a novel random sequential mechanism |
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Authors: | Brammer Leighanne A Smith Jessica M Wade Herschel Meyers Caren Freel |
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Affiliation: | Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. |
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Abstract: | Emerging resistance of human pathogens to anti-infective agents make it necessary to develop new agents to treat infection. The methylerythritol phosphate pathway has been identified as an anti-infective target, as this essential isoprenoid biosynthetic pathway is widespread in human pathogens but absent in humans. The first enzyme of the pathway, 1-deoxy-D-xylulose 5-phosphate (DXP) synthase, catalyzes the formation of DXP via condensation of D-glyceraldehyde 3-phosphate (D-GAP) and pyruvate in a thiamine diphosphate-dependent manner. Structural analysis has revealed a unique domain arrangement suggesting opportunities for the selective targeting of DXP synthase; however, reports on the kinetic mechanism are conflicting. Here, we present the results of tryptophan fluorescence binding and kinetic analyses of DXP synthase and propose a new model for substrate binding and mechanism. Our results are consistent with a random sequential kinetic mechanism, which is unprecedented in this enzyme class. |
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Keywords: | Enzyme Catalysis Enzyme Inhibitors Enzyme Mechanisms Fluorescence Ligand Binding Protein 1-Deoxy-D-xylulose 5-Phosphate Synthase DXP Synthase DXS Methylerythritol Phosphate Pathway Thiamine Diphosphate |
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