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Science 2 January 1998:
Vol. 279. no. 5347, pp. 98 - 102
DOI: 10.1126/science.279.5347.98
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Reports

Modification of the NADH of the Isoniazid Target (InhA) from Mycobacterium tuberculosis

Denise A. Rozwarski, Gregory A. Grant, Derek H. R. Barton, William R. Jacobs Jr., James C. Sacchettini *

The preferred antitubercular drug isoniazid specifically targets a long-chain enoyl-acyl carrier protein reductase (InhA), an enzyme essential for mycolic acid biosynthesis in Mycobacterium tuberculosis. Despite the widespread use of this drug for more than 40 years, its precise mode of action has remained obscure. Data from x-ray crystallography and mass spectrometry reveal that the mechanism of isoniazid action against InhA is covalent attachment of the activated form of the drug to the nicotinamide ring of nicotinamide adenine dinucleotide bound within the active site of InhA.

D. A. Rozwarski, Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
G. A. Grant, Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110, USA.
D. H. R. Barton, Department of Chemistry, Texas A&M University, College Station, TX 77843, USA.
W. R. Jacobs Jr., Department of Microbiology and Immunology and Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
J. C. Sacchettini, Department of Biochemistry and Biophysics and Department of Chemistry, Texas A&M University, College Station, TX 77843, USA.
*   To whom correspondence should be addressed.

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