Studies of inhibitor binding to the [4Fe-4S] cluster of quinolinate synthase

Angew Chem Int Ed Engl. 2012 Jul 27;51(31):7711-4. doi: 10.1002/anie.201202261. Epub 2012 Jun 19.

Abstract

Stop for NadA! A [4Fe-4S] enzyme, NadA, catalyzes the formation of quinolinic acid in de novo nicotinamide adenine dinucleotide (NAD) biosynthesis. A structural analogue of an intermediate, 4,5-dithiohydroxyphthalic acid (DTHPA), has an in vivo NAD biosynthesis inhibiting activity in E. coli. The inhibitory effect can be explained by the coordination of DTHPA thiolate groups to a unique Fe site of the NadA [4Fe-4S] cluster.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkyl and Aryl Transferases / antagonists & inhibitors*
  • Alkyl and Aryl Transferases / metabolism
  • Binding Sites / drug effects
  • Dihydroxyacetone Phosphate / chemistry
  • Dihydroxyacetone Phosphate / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Escherichia coli Proteins / antagonists & inhibitors*
  • Escherichia coli Proteins / metabolism
  • Iron-Sulfur Proteins / antagonists & inhibitors*
  • Iron-Sulfur Proteins / metabolism
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Escherichia coli Proteins
  • Iron-Sulfur Proteins
  • Dihydroxyacetone Phosphate
  • Alkyl and Aryl Transferases
  • quinolinate synthase, E coli