1-Deoxy-D-xylulose 5-phosphate synthase catalyzes a novel random sequential mechanism

Leighanne A. Brammer, Jessica M. Smith, Herschel Wade, Caren L Meyers

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)36522-36531
Number of pages10
JournalJournal of Biological Chemistry
Volume286
Issue number42
DOIs
StatePublished - Oct 21 2011

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Pathogens
Kinetics
Glyceraldehyde 3-Phosphate
Thiamine Pyrophosphate
Biosynthetic Pathways
Terpenes
Enzymes
Anti-Infective Agents
Pyruvic Acid
Structural analysis
Tryptophan
Condensation
Fluorescence
Phosphates
Substrates
Infection
xylulose-5-phosphate
deoxyxylulose-5-phosphate synthase

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

1-Deoxy-D-xylulose 5-phosphate synthase catalyzes a novel random sequential mechanism. / Brammer, Leighanne A.; Smith, Jessica M.; Wade, Herschel; Meyers, Caren L.

In: Journal of Biological Chemistry, Vol. 286, No. 42, 21.10.2011, p. 36522-36531.

Research output: Contribution to journalArticle

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