Structural Basis for the Variation in Triclosan Affinity to Enoyl Reductases

Bacteria synthesize fatty acids in a dissociated type pathway different from that in humans. Enoyl acyl carrier protein reductase, which catalyzes the final step of fatty acid elongation, has been validated as a potential anti-microbial drug target. Triclosan is known to inhibit this enzyme effectiv...

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Bibliographic Details
Published in:Journal of molecular biology 2004-10, Vol.343 (1), p.147-155
Main Authors: Pidugu, Lakshmi Swarnamukhi, Kapoor, Mili, Surolia, Namita, Surolia, Avadhesha, Suguna, Kaza
Format: Article
Language:English
Subjects:
Brassica - enzymology
Crystallography, X-Ray
Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)
enoyl-ACP reductase
FAS-II
Genetic Variation
Hydrogen Bonding
Models, Molecular
Molecular Structure
NAD - metabolism
NADH
Oxidoreductases - metabolism
Protein Binding
Protein Structure, Tertiary
structural comparison
Structure-Activity Relationship
Substrate Specificity
triclosan
Triclosan - chemistry
Water - chemistry
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Summary:Bacteria synthesize fatty acids in a dissociated type pathway different from that in humans. Enoyl acyl carrier protein reductase, which catalyzes the final step of fatty acid elongation, has been validated as a potential anti-microbial drug target. Triclosan is known to inhibit this enzyme effectively. Precise characterization of the mode of triclosan binding is required to develop highly specific inhibitors. With this in view, interactions between triclosan, the cofactor NADH/NAD + and the enzyme from five different species, one plant and four of microbial origin, have been examined in the available crystal structures. A comparison of these structures shows major structural differences at the substrate/inhibitor/cofactor-binding loop. The analysis reveals that the conformation of this flexible loop and the binding affinities of triclosan to each of these enzymes are strongly correlated.
ISSN:0022-2836
1089-8638
DOI:10.1016/j.jmb.2004.08.033