Crystal Structure and Function of the Isoniazid Target of Mycobacterium tuberculosis

American Association for the Advancement of Science (AAAS) - Tập 267 Số 5204 - Trang 1638-1641 - 1995
Andréa Dessen1, Annaı̈k Quémard2, John S. Blanchard1, William R. Jacobs2, James C. Sacchettini1
1Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA
2Departments of Microbiology and Immunology and Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Tóm tắt

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 β-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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