Crystal structure and function of the isoniazid target of Mycobacterium tuberculosis

Andréa Dessen, Annaïk Quémard, John S. Blanchard, William R. Jacobs, James C. Sacchettini

Research output: Contribution to journalArticle

358 Citations (Scopus)

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 β-nicotinamide adenine dinucleotide (NADH)-specific reduction of 2-transenoyl-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.

Original languageEnglish (US)
Pages (from-to)1638-1641
Number of pages4
JournalScience
Volume267
Issue number5204
StatePublished - 1995

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Isoniazid
Mycobacterium tuberculosis
NAD
Acyl Carrier Protein
Mutant Proteins
Hydrogen Bonding
Drug Resistance
Alanine
Serine
Fatty Acids
Pharmaceutical Preparations
Proteins

ASJC Scopus subject areas

  • General

Cite this

Crystal structure and function of the isoniazid target of Mycobacterium tuberculosis. / Dessen, Andréa; Quémard, Annaïk; Blanchard, John S.; Jacobs, William R.; Sacchettini, James C.

In: Science, Vol. 267, No. 5204, 1995, p. 1638-1641.

Research output: Contribution to journalArticle

Dessen, A, Quémard, A, Blanchard, JS, Jacobs, WR & Sacchettini, JC 1995, 'Crystal structure and function of the isoniazid target of Mycobacterium tuberculosis', Science, vol. 267, no. 5204, pp. 1638-1641.
Dessen, Andréa ; Quémard, Annaïk ; Blanchard, John S. ; Jacobs, William R. ; Sacchettini, James C. / Crystal structure and function of the isoniazid target of Mycobacterium tuberculosis. In: Science. 1995 ; Vol. 267, No. 5204. pp. 1638-1641.
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