PDBsum entry 3log

Isomerase

PDB id: 3log

Contents

Protein chains

435 a.a.

Ligands

SIN ×5

GOL ×5

CO3

Metals

_NA

Waters ×1624

References listed in PDB file

Key reference

• Title: Inhibition studies of mycobacterium tuberculosis salicylate synthase (mbti).
• Authors: A.Manos-Turvey, E.M.Bulloch, P.J.Rutledge, E.N.Baker, J.S.Lott, R.J.Payne.
• Ref.: Chemmedchem, 2010, 5, 1067-1079.
• PubMed id: 20512795

Abstract

Mycobacterium tuberculosis salicylate synthase (MbtI), a member of the chorismate-utilizing enzyme family, catalyses the first committed step in the biosynthesis of the siderophore mycobactin T. This complex secondary metabolite is essential for both virulence and survival of M. tuberculosis, the etiological agent of tuberculosis (TB). It is therefore anticipated that inhibitors of this enzyme may serve as TB therapies with a novel mode of action. Herein we describe the first inhibition study of M. tuberculosis MbtI using a library of functionalized benzoate-based inhibitors designed to mimic the substrate (chorismate) and intermediate (isochorismate) of the MbtI-catalyzed reaction. The most potent inhibitors prepared were those designed to mimic the enzyme intermediate, isochorismate. These compounds, based on a 2,3-dihydroxybenzoate scaffold, proved to be low-micromolar inhibitors of MbtI. The most potent inhibitors in this series possessed hydrophobic enol ether side chains at C3 in place of the enol-pyruvyl side chain found in chorismate and isochorismate.