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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anti-Bacterial Agents / metabolism*
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Anti-Bacterial Agents / pharmacology
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Binding Sites
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Boron Compounds / metabolism*
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Boron Compounds / pharmacology
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Crystallography, X-Ray
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Drug Design
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Drug Resistance, Microbial
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Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)
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Enzyme Inhibitors / metabolism*
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Enzyme Inhibitors / pharmacology
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Escherichia coli / enzymology
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Escherichia coli Proteins
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Fatty Acid Synthase, Type II
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Fatty Acid Synthases / antagonists & inhibitors
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Fatty Acid Synthases / chemistry*
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Fatty Acid Synthases / metabolism
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Hydrogen Bonding
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Models, Molecular
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NAD / metabolism*
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Oxidoreductases / antagonists & inhibitors
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Oxidoreductases / chemistry*
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Oxidoreductases / metabolism
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Protein Conformation
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Protein Structure, Secondary
Substances
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Anti-Bacterial Agents
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Boron Compounds
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Enzyme Inhibitors
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Escherichia coli Proteins
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NAD
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Oxidoreductases
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Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)
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fabI protein, E coli
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Fatty Acid Synthases
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Fatty Acid Synthase, Type II