A Mechanism of Drug Action Revealed by Structural Studies of Enoyl Reductase-Reference-Cited by-同舟云学术

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

Published:1996-12-20 Issue:5295 Volume:274 Page:2107-2110
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Baldock Clair¹,Rafferty John B.¹,Sedelnikova Svetlana E.¹,Baker Patrick J.¹,Stuitje Antoine R.²,Slabas Antoni R.³,Hawkes Timothy R.⁴,Rice David W.¹

Affiliation:

1. 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.

2. A. R. Stuitje, Department of Genetics, Institute of Molecular Biological Studies (IMBW), Vrije Universiteit, Biocenter Amsterdam, De Boelelaan 1087, 1081 HV Amsterdam, Netherlands.

3. A. R. Slabas, Department of Biological Sciences, University of Durham, Durham DH1 3LE, UK.

4. T. R. Hawkes, Department of Exploratory Plant Sciences, Zeneca Agrochemicals, Jealott's Hill Research Station, Bracknell, Berkshire RG12 6EY, UK.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Reference30 articles.

1. inhA , a Gene Encoding a Target for Isoniazid and Ethionamide in Mycobacterium tuberculosis

2. Dessen A., Quémard A., Blanchard J. S., Jacobs W. R., Sacchettini J. C., ibid. 267, 1638 (1995).

3. Bergler H., et al., J. Biol. Chem. 269, 5493 (1994).

4. Cole S. T., Trends Microbiol. 2, 411 (1994).

5. Högenauer G., Woisetschläger M., Nature 293, 662 (1981).

Cited by 233 articles. 订阅此论文施引文献订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献

1. Design of antibacterial agents;Molecular Medical Microbiology;2024

2. Click processes orthogonal to CuAAC and SuFEx forge selectively modifiable fluorescent linkers;Nature Chemistry;2023-12-13

3. Modular synthesis of 1,2-azaborines via ring-opening BN-isostere benzannulation;Nature Chemistry;2023-10-02

4. Expanding the Role of Boron in New Drug Chemotypes: Properties, Chemistry, Pharmaceutical Potential of Hemiboronic Naphthoids;Journal of Medicinal Chemistry;2023-09-26

5. Sulfonyl Diazaborine ‘Click’ Chemistry Enables Rapid and Efficient Bioorthogonal Labeling**;Chemistry – A European Journal;2023-06-14