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Science 20 December 1996:
Vol. 274. no. 5295, pp. 2107 - 2110
DOI: 10.1126/science.274.5295.2107
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Reports

A Mechanism of Drug Action Revealed by Structural Studies of Enoyl Reductase

Clair Baldock, John B. Rafferty, Svetlana E. Sedelnikova, Patrick J. Baker, Antoine R. Stuitje, Antoni R. Slabas, Timothy R. Hawkes, David W. Rice *

Enoyl reductase (ENR), an enzyme involved in fatty acid biosynthesis, is the target for antibacterial diazaborines and the front-line antituberculosis drug isoniazid. Analysis of the structures of complexes of Escherichia coli ENR with nicotinamide adenine dinucleotide and either thienodiazaborine or benzodiazaborine revealed the formation of a covalent bond between the 2' hydroxyl of the nicotinamide ribose and a boron atom in the drugs to generate a tight, noncovalently bound bisubstrate analog. This analysis has implications for the structure-based design of inhibitors of ENR, and similarities to other oxidoreductases suggest that mimicking this molecular linkage may have generic applications in other areas of medicinal chemistry.

C. Baldock, J. B. Rafferty, S. E. Sedelnikova, P. J. Baker, D. W. Rice, Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield S10 2TN, UK.
A. R. Stuitje, Department of Genetics, Institute of Molecular Biological Studies (IMBW), Vrije Universiteit, Biocenter Amsterdam, De Boelelaan 1087, 1081 HV Amsterdam, Netherlands.
A. R. Slabas, Department of Biological Sciences, University of Durham, Durham DH1 3LE, UK.
T. R. Hawkes, Department of Exploratory Plant Sciences, Zeneca Agrochemicals, Jealott's Hill Research Station, Bracknell, Berkshire RG12 6EY, UK.
*   To whom correspondence should be addressed. E-mail: D.Rice{at}sheffield.ac.uk

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