A mechanism of drug action revealed by structural ...[Science. 1996]

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1: Science. 1996 Dec 20;274(5295):2107-10. Links

A mechanism of drug action revealed by structural studies of enoyl reductase.

Baldock C, Rafferty JB, Sedelnikova SE, Baker PJ, Stuitje AR, Slabas AR, Hawkes TR, Rice DW.

Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield S10 2TN, UK. D.Rice@sheffield.ac.uk

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.

PMID: 8953047 [PubMed - indexed for MEDLINE]

A study of the structure-activity relationship for diazaborine inhibition of Escherichia coli enoyl-ACP reductase.
J Mol Biol. 2001 May 25; 309(1):171-80.

[J Mol Biol. 2001]
Structural basis and mechanism of enoyl reductase inhibition by triclosan.
J Mol Biol. 1999 Jul 23; 290(4):859-65.

[J Mol Biol. 1999]
ReviewMechanism of action of diazaborines.
Biochem Pharmacol. 1998 May 15; 55(10):1541-9.

[Biochem Pharmacol. 1998]
The enoyl-[acyl-carrier-protein] reductase (FabI) of Escherichia coli, which catalyzes a key regulatory step in fatty acid biosynthesis, accepts NADH and NADPH as cofactors and is inhibited by palmitoyl-CoA.
Eur J Biochem. 1996 Dec 15; 242(3):689-94.

[Eur J Biochem. 1996]
ReviewInhibitors of FabI, an enzyme drug target in the bacterial fatty acid biosynthesis pathway.
Acc Chem Res. 2008 Jan; 41(1):11-20.

[Acc Chem Res. 2008]
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Cited by 13 PubMed Central articles

Design and synthesis of aryl ether inhibitors of the Bacillus anthracis enoyl-ACP reductase.
Tipparaju SK, Mulhearn DC, Klein GM, Chen Y, Tapadar S, Bishop MH, Yang S, Chen J, Ghassemi M, Santarsiero BD, et al. ChemMedChem. 2008 Aug; 3(8):1250-68.

[ChemMedChem. 2008]
Synthesis and in vitro antimycobacterial activity of B-ring modified diaryl ether InhA inhibitors.
am Ende CW, Knudson SE, Liu N, Childs J, Sullivan TJ, Boyne M, Xu H, Gegina Y, Knudson DL, Johnson F, et al. Bioorg Med Chem Lett. 2008 May 15; 18(10):3029-33. Epub 2008 Apr 18.

[Bioorg Med Chem Lett. 2008]
Crystal structure of enoyl-acyl carrier protein reductase (FabK) from Streptococcus pneumoniae reveals the binding mode of an inhibitor.
Saito J, Yamada M, Watanabe T, Iida M, Kitagawa H, Takahata S, Ozawa T, Takeuchi Y, Ohsawa F. Protein Sci. 2008 Apr; 17(4):691-9. Epub 2008 Feb 27.

[Protein Sci. 2008]
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Structures reported by this article

X-Ray Structure Of Escherichia Coli Enoyl Reductase With Bound Nad

PDB: 1DFI

Source: Escherichia coli

Method: X-Ray Diffraction | Resolution: 2.09 Å
» See all 3 structures...

Patient Drug Information

Isoniazid (Nydrazid® , Rifamate® (as a combination product containing Isoniazid and Rifampin), Rifater® (as a combination product containing Isoniazid, Pyrazinamide, and Rifampin))
Isoniazid is used alone or with other drugs to treat tuberculosis (TB) and to prevent it in people who have had contact with tuberculosis bacteria. It eliminates only active (growing) bacteria. Since the bacteria may exi...
Source: AHFS Consumer Medication Information

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