CRYSTAL-STRUCTURE AND FUNCTION OF THE ISONIAZID TARGET OF MYCOBACTERIUM-TUBERCULOSIS

被引：387

作者：

DESSEN, A

QUEMARD, A

BLANCHARD, JS

JACOBS, WR

SACCHETTINI, JC

机构：

[1] YESHIVA UNIV ALBERT EINSTEIN COLL MED, DEPT BIOCHEM, BRONX, NY 10461 USA

[2] YESHIVA UNIV ALBERT EINSTEIN COLL MED, DEPT MICROBIOL, BRONX, NY 10461 USA

[3] YESHIVA UNIV ALBERT EINSTEIN COLL MED, DEPT IMMUNOL, BRONX, NY 10461 USA

[4] YESHIVA UNIV ALBERT EINSTEIN COLL MED, HOWARD HUGHES MED INST, BRONX, NY 10461 USA

来源：

SCIENCE | 1995年 / 267卷 / 5204期

关键词：

D O I：

10.1126/science.7886450

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：1638 / 1641

页数：4

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