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Science 17 March 1995:
Vol. 267. no. 5204, pp. 1638 - 1641
DOI: 10.1126/science.7886450
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Articles

Science, Vol 267, Issue 5204, 1638-1641
Copyright © 1995 by American Association for the Advancement of Science

articles

Crystal structure and function of the isoniazid target of Mycobacterium tuberculosis

A Dessen, A Quemard, JS Blanchard, WR Jacobs Jr, and JC Sacchettini

Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461.

Resistance to isoniazid in Mycobacterium tuberculosis can be mediated by substitution of alanine for serine 94 in the InhA protein, the drug's primary target. InhA was shown to catalyze the beta-nicotinamide adenine dinucleotide (NADH)-specific reduction of 2-trans-enoyl-acyl carrier protein, an essential step in fatty acid elongation. Kinetic analyses suggested that isoniazid resistance is due to a decreased affinity of the mutant protein for NADH. The three-dimensional structures of wild-type and mutant InhA, refined to 2.2 and 2.7 angstroms, respectively, revealed that drug resistance is directly related to a perturbation in the hydrogen-bonding network that stabilizes NADH binding.


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