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

Bioorg. Med. Chem. Lett.2006 Jul 15;16(14):3802-5. Epub 2006 May 05
Brian P Callahan 1 , Joseph V Lomino , Richard Wolfenden
Brian P Callahan 1 , Joseph V Lomino , Richard Wolfenden

[No authors listed]

Author information
  • 1 Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599-7260, USA. callahan@wadsworth.org

摘要


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 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.

基因