A study of the structure-activity relationship for diazaborine inhibition of Escherichia coli enoyl-ACP reductase

Enoyl acyl carrier protein (ACP) reductase catalyses the last reductive ste p of fatty acid biosynthesis, reducing the enoyl group of a growing fatty a cid 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 anti bacterial age nts, the biocide triclosan, and one of the targets for the frontline anti-t uberculosis drug isoniazid. The structures of complexes of Escherichia coli enoyl-ACP reductase (ENR) from crystals grown in the presence of NAD(+) an d a family of diazaborine compounds have been determined. Analysis of the s tructures has revealed that a mobile loop in the structure of the binary co mplex with NAD+ becomes ordered on binding diazaborine/NAD(+) but displays a different conformation in the two subunits of the asymmetric unit. The wo rk presented here reveals how, for one of the ordered conformations adopted by the mobile loop, the mode of diazaborine binding correlates well with t he activity profiles of the diazaborine family. Additionally, diazaborine b inding provides insights into the pocket on the enzyme surface occupied by the growing fatty acid chain. (C) 2001 Academic Press.