Crystal structure and function of the isoniazid ta...[Science. 1995]

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1: Science. 1995 Mar 17;267(5204):1638-41. Links

Crystal structure and function of the isoniazid target of Mycobacterium tuberculosis.

Dessen A, Quémard A, Blanchard JS, Jacobs WR Jr, Sacchettini JC.

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.

PMID: 7886450 [PubMed - indexed for MEDLINE]

Crystallographic and pre-steady-state kinetics studies on binding of NADH to wild-type and isoniazid-resistant enoyl-ACP(CoA) reductase enzymes from Mycobacterium tuberculosis.
J Mol Biol. 2006 Jun 9; 359(3):646-66. Epub 2006 Apr 21.

[J Mol Biol. 2006]
Enzymatic characterization of the target for isoniazid in Mycobacterium tuberculosis.
Biochemistry. 1995 Jul 4; 34(26):8235-41.

[Biochemistry. 1995]
Modification of the NADH of the isoniazid target (InhA) from Mycobacterium tuberculosis.
Science. 1998 Jan 2; 279(5347):98-102.

[Science. 1998]
ReviewMechanisms for isoniazid action and resistance.
Novartis Found Symp. 1998; 217:209-20; discussion 220-1.

[Novartis Found Symp. 1998]
ReviewSlow-onset inhibition of 2-trans-enoyl-ACP (CoA) reductase from Mycobacterium tuberculosis by an inorganic complex.
Curr Pharm Des. 2006; 12(19):2409-24.

[Curr Pharm Des. 2006]
» See reviews... | » See all...

Cited by 43 PubMed Central articles

Mycothiol biosynthesis is essential for ethionamide susceptibility in Mycobacterium tuberculosis.
Vilchèze C, Av-Gay Y, Attarian R, Liu Z, Hazbón MH, Colangeli R, Chen B, Liu W, Alland D, Sacchettini JC, et al. Mol Microbiol. 2008 Sep; 69(5):1316-29. Epub 2008 Jul 21.

[Mol Microbiol. 2008]
Function of heterologous Mycobacterium tuberculosis InhA, a type 2 fatty acid synthase enzyme involved in extending C20 fatty acids to C60-to-C90 mycolic acids, during de novo lipoic acid synthesis in Saccharomyces cerevisiae.
Gurvitz A, Hiltunen JK, Kastaniotis AJ. Appl Environ Microbiol. 2008 Aug; 74(16):5078-85. Epub 2008 Jun 13.

[Appl Environ Microbiol. 2008]
Crystal structure of enoyl-acyl carrier protein reductase (FabK) from Streptococcus pneumoniae reveals the binding mode of an inhibitor.
Saito J, Yamada M, Watanabe T, Iida M, Kitagawa H, Takahata S, Ozawa T, Takeuchi Y, Ohsawa F. Protein Sci. 2008 Apr; 17(4):691-9. Epub 2008 Feb 27.

[Protein Sci. 2008]
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Structures reported by this article

Long Fatty Acid Chain Enoyl-Acp Reductase (Inha) In Complex With An Isonicotinic-Acyl-Nadh Inhibitor

PDB: 1ZID

Source: Mycobacterium tuberculosis

Method: X-Ray Diffraction | Resolution: 2.7 Å
» See all 3 structures...

Patient Drug Information

Isoniazid (Nydrazid® , Rifamate® (as a combination product containing Isoniazid and Rifampin), Rifater® (as a combination product containing Isoniazid, Pyrazinamide, and Rifampin))
Isoniazid is used alone or with other drugs to treat tuberculosis (TB) and to prevent it in people who have had contact with tuberculosis bacteria. It eliminates only active (growing) bacteria. Since the bacteria may exi...
Source: AHFS Consumer Medication Information

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