title: Crystal structure and function of the isoniazid target of Mycobacterium tuberculosis.
abstract: 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.
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461.
authors.forename: A
authors.initials: A
authors.lastname: Dessen
authors.forename: A
authors.initials: A
authors.lastname: Quémard
authors.forename: J S
authors.initials: JS
authors.lastname: Blanchard
authors.forename: W R
authors.initials: WR
authors.lastname: Jacobs
authors.forename: J C
authors.initials: JC
authors.lastname: Sacchettini
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D001665:Binding Sites; D003196:Computer Graphics; D003460:Crystallization; D018360:Crystallography, X-Ray; D004352:Drug Resistance, Microbial; D006860:Hydrogen Bonding; D007538:Isoniazid / Q000494:pharmacology*; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000737:chemistry* / Q000187:drug effects; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D010088:Oxidoreductases; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary
chemical_list: D001426:Bacterial Proteins; D009243:NAD; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium; D007538:Isoniazid