Hydroxybenzaldoximes Are D -GAP-Competitive Inhibitors of E. coli 1-Deoxy- D -Xylulose-5-Phosphate Synthase

David Bartee, Francine Morris, Amer Al-Khouja, Caren L. Freel Meyers

Research output: Contribution to journalArticlepeer-review

Abstract

1-Deoxy-D-xylulose 5-phosphate (DXP) synthase is the first enzyme in the methylerythritol phosphate pathway to essential isoprenoids in pathogenic bacteria and apicomplexan parasites. In bacterial pathogens, DXP lies at a metabolic branch point, serving also as a precursor in the biosynthesis of vitamins B1 and B6, which are critical for central metabolism. In an effort to identify new bisubstrate analogue inhibitors that exploit the large active site and distinct mechanism of DXP synthase, a library of aryl mixed oximes was prepared and evaluated. Trihydroxybenzaldoximes emerged as reversible, low-micromolar inhibitors, competitive against D-glyceraldehyde 3-phosphate (D-GAP) and either uncompetitive or noncompetitive against pyruvate. Hydroxybenzaldoximes are the first class of D-GAP-competitive DXP synthase inhibitors, offering new tools for mechanistic studies of DXP synthase and a new direction for the development of antimicrobial agents targeting isoprenoid biosynthesis.

Original languageEnglish (US)
Pages (from-to)1771-1781
Number of pages11
JournalChemBioChem
Volume16
Issue number12
DOIs
StatePublished - Aug 1 2015

Keywords

  • DXP synthase
  • MEP pathway
  • biosynthesis
  • inhibitors
  • isoprenoids
  • thiamin diphosphate

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

Fingerprint Dive into the research topics of 'Hydroxybenzaldoximes Are D -GAP-Competitive Inhibitors of E. coli 1-Deoxy- D -Xylulose-5-Phosphate Synthase'. Together they form a unique fingerprint.

Cite this