A Mechanism of Drug Action Revealed by Structural Studies of Enoyl Reductase
- 20 December 1996
- journal article
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 274 (5295) , 2107-2110
- https://doi.org/10.1126/science.274.5295.2107
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.Keywords
This publication has 24 references indexed in Scilit:
- Design and synthesis of bisubstrate analogues for 3-hydroxy-3-methyl-glutaryl coenzyme a reductaseBioorganic & Medicinal Chemistry Letters, 1996
- Mechanism-Based Inhibition of Human Steroid 5α-Reductase by Finasteride: Enzyme-Catalyzed Formation of NADP−Dihydrofinasteride, a Potent Bisubstrate Analog InhibitorJournal of the American Chemical Society, 1996
- LIGPLOT: a program to generate schematic diagrams of protein-ligand interactionsProtein Engineering, Design and Selection, 1995
- Mycobacterium tuberculosis: drug-resistance mechanismsTrends in Microbiology, 1994
- Sequences of the envM gene and of two mutated alleles in Escherichia coliJournal of General Microbiology, 1992
- MOLSCRIPT: a program to produce both detailed and schematic plots of protein structuresJournal of Applied Crystallography, 1991
- The MIDAS display systemJournal of Molecular Graphics, 1988
- An efficient general-purpose least-squares refinement program for macromolecular structuresActa Crystallographica Section A Foundations of Crystallography, 1987
- Strategy for data collection from protein crystals using a multiwire counter area detector diffractometerJournal of Applied Crystallography, 1985
- A diazaborine derivative inhibits lipopolysaccharide biosynthesisNature, 1981