1. 1-Deoxy-D-xylulose 5-phosphate synthase catalyzes a novel random sequential mechanism.
- Author
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Brammer LA, Smith JM, Wade H, and Meyers CF
- Subjects
- Aldose-Ketose Isomerases genetics, Aldose-Ketose Isomerases metabolism, Catalysis, Drug Resistance, Bacterial physiology, Escherichia coli genetics, Escherichia coli Proteins genetics, Escherichia coli Proteins metabolism, Humans, Kinetics, Multienzyme Complexes genetics, Multienzyme Complexes metabolism, Oxidoreductases genetics, Oxidoreductases metabolism, Protein Structure, Tertiary, Aldose-Ketose Isomerases chemistry, Escherichia coli enzymology, Escherichia coli Proteins chemistry, Models, Chemical, Multienzyme Complexes chemistry, Oxidoreductases chemistry
- 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.
- Published
- 2011
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