title: A study of the structure-activity relationship for diazaborine inhibition of Escherichia coli enoyl-ACP reductase.
abstract: Enoyl acyl carrier protein (ACP) reductase catalyses the last reductive step of fatty acid biosynthesis, reducing the enoyl group of a growing fatty acid chain attached to ACP to its acyl product using NAD(P)H as the cofactor. This enzyme is the target for the diazaborine class of antibacterial agents, the biocide triclosan, and one of the targets for the front-line anti-tuberculosis drug isoniazid. The structures of complexes of Escherichia coli enoyl-ACP reductase (ENR) from crystals grown in the presence of NAD+ and a family of diazaborine compounds have been determined. Analysis of the structures has revealed that a mobile loop in the structure of the binary complex with NAD+ becomes ordered on binding diazaborine/NAD+ but displays a different conformation in the two subunits of the asymmetric unit. The work presented here reveals how, for one of the ordered conformations adopted by the mobile loop, the mode of diazaborine binding correlates well with the activity profiles of the diazaborine family. Additionally, diazaborine binding provides insights into the pocket on the enzyme surface occupied by the growing fatty acid chain.
authors.affiliation: Krebs Institute for Research, Department of Molecular Biology and Biotechnology, University of Sheffield, UK.
authors.forename: C W
authors.initials: CW
authors.lastname: Levy
authors.forename: C
authors.initials: C
authors.lastname: Baldock
authors.forename: A J
authors.initials: AJ
authors.lastname: Wallace
authors.forename: S
authors.initials: S
authors.lastname: Sedelnikova
authors.forename: R C
authors.initials: RC
authors.lastname: Viner
authors.forename: J M
authors.initials: JM
authors.lastname: Clough
authors.forename: A R
authors.initials: AR
authors.lastname: Stuitje
authors.forename: A R
authors.initials: AR
authors.lastname: Slabas
authors.forename: D W
authors.initials: DW
authors.lastname: Rice
authors.forename: J B
authors.initials: JB
authors.lastname: Rafferty
mesh_terms: D001665:Binding Sites; D001896:Boron Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology*; D008958:Models, Molecular; D009243:NAD / Q000378:metabolism; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D021122:Protein Subunits; D013329:Structure-Activity Relationship; D014260:Triclosan / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D001896:Boron Compounds; D004791:Enzyme Inhibitors; D021122:Protein Subunits; D009243:NAD; D014260:Triclosan; D010088:Oxidoreductases; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)