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 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.
Baldock
C
C
Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield S10 2TN, UK. D.Rice@sheffield.ac.uk
Rafferty
J B
JB
Sedelnikova
S E
SE
Baker
P J
PJ
Stuitje
A R
AR
Slabas
A R
AR
Hawkes
T R
TR
Rice
D W
DW
D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D001896:Boron Compounds / Q000378:metabolism* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D004352:Drug Resistance, Microbial; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology; D029968:Escherichia coli Proteins; D054889:Fatty Acid Synthase, Type II; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D008958:Models, Molecular; D009243:NAD / Q000378:metabolism*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D017433:Protein Structure, Secondary
D000900:Anti-Bacterial Agents; D001896:Boron Compounds; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D009243:NAD; D010088:Oxidoreductases; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); C493924:fabI protein, E coli; D064429:Fatty Acid Synthases; D054889:Fatty Acid Synthase, Type II