Nanomolar inhibition of the enterobactin biosynthesis enzyme, EntE: synthesis, substituent effects, and additivity

Bioorg Med Chem Lett. 2006 Jul 15;16(14):3802-5. doi: 10.1016/j.bmcl.2006.04.024. Epub 2006 May 5.

Abstract

2,3-Dihydroxybenzohydroxamoyl adenylate (I) was prepared as a potential product analog inhibitor of EntE (EC# 2.7.7.58), a 2,3-dihydroxybenzoate AMP ligase from Escherichia coli that is required for the biosynthesis of enterobactin. This compound, obtained by the aqueous reaction of imidazole-activated adenosine 5'-phosphate and 2,3-dihydroxybenzohydroxamic acid, is a competitive inhibitor with a Ki value of 4.5 x 10(-9)M. Deletion of the catecholic 3-OH group of (I), in compound (II), reduced inhibitory activity by a factor of 3.5, whereas, removal of both the 3-OH and 2-OH groups, in (III), reduced inhibitory activity by a factor of approximately 2000. Acetohydroxamoyl adenylate (IV), in which the entire catechol moiety of (I) is replaced by a hydrogen atom, gave <or= 10% inhibition at 6 x 10(-4)M, indicating a reduction in affinity by more than 10(5). The binding free energy of (I) is nearly equivalent to the sum of the corresponding values for adenosine 5'-phosphate and 2,3-dihydroxybenzoate.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Monophosphate / analogs & derivatives*
  • Adenosine Monophosphate / chemical synthesis
  • Adenosine Monophosphate / chemistry
  • Adenosine Monophosphate / metabolism
  • Adenosine Monophosphate / pharmacology
  • Binding, Competitive
  • Catechols / chemistry
  • Enterobactin / biosynthesis*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology
  • Escherichia coli / enzymology
  • Escherichia coli Proteins / antagonists & inhibitors*
  • Hydrogen / chemistry
  • Hydroxamic Acids / chemistry
  • Hydroxybenzoates / chemical synthesis*
  • Hydroxybenzoates / chemistry
  • Hydroxybenzoates / pharmacology
  • Imidazoles / chemistry
  • Ligases / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • 2,3-dihydroxybenzohydroxamoyl adenylate
  • Catechols
  • Enzyme Inhibitors
  • Escherichia coli Proteins
  • Hydroxamic Acids
  • Hydroxybenzoates
  • Imidazoles
  • Enterobactin
  • Adenosine Monophosphate
  • 2,3-dihydroxybenzoic acid
  • imidazole
  • Hydrogen
  • Ligases
  • 2,3-dihydroxybenzoate-AMP ligase, E coli
  • benzohydroxamic acid
  • catechol