A MECHANISM OF DRUG-ACTION REVEALED BY STRUCTURAL STUDIES OF ENOYL REDUCTASE

Enoyl reductase (ENR), an enzyme involved in fatty acid biosynthesis, is the target for antibacterial diazaborines and the front-line antitu berculosis 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 cov alent bond between the 2' hydroxyl of the nicotinamide ribose and a bo ron atom in the drugs to generate a tight, noncovalently bound bisubst rate analog. This analysis has implications for the structure-based de sign of inhibitors of ENR, and similarities to other oxidoreductases s uggest that mimicking this molecular linkage may have generic applicat ions in other areas of medicinal chemistry.