Crystal Structures of Mycobacterium tuberculosis KasA Show Mode of Action within Cell Wall Biosynthesis and its Inhibition by Thiolactomycin

被引：66

作者：

Luckner, Sylvia R. ^{[1
]}

Machutta, Carl A. ^{[2
]}

Tonge, Peter J. ^{[2
]}

Kisker, Caroline ^{[1
]}

机构：

[1] Univ Wurzburg, Rudolf Virchow Ctr Expt Biomed, Inst Biol Struct, Wurzburg, Germany

[2] SUNY Stony Brook, Inst Chem Biol & Drug Discovery, Dept Chem, Stony Brook, NY 11794 USA

来源：

STRUCTURE | 2009年 / 17卷 / 07期

基金：

美国国家卫生研究院;

关键词：

MYCOLIC ACID BIOSYNTHESIS; FATTY-ACID; ENOYL REDUCTASE; PROTEINS; GROWTH; ENZYME;

D O I：

10.1016/j.str.2009.04.012

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Mycobacteria have a unique cell wall consisting of mycolic acids, very-long-chain lipids that provide protection and allow the bacteria to persist within human macrophages. Inhibition of cell wall biosynthesis is fatal for the organism and a starting point for the discovery and development of novel antibiotics. We determined the crystal structures of KasA, a key enzyme involved in the biosynthesis of long-chain fatty acids, in its apo-form and bound to the natural product inhibitor thiolactomycin. Detailed insights into the interaction of the inhibitor with KasA and the identification of a polyethylene glycol molecule that mimics a fatty acid substrate of approximately 40 carbon atoms length, represent the first atomic view of a mycobacterial enzyme involved in the synthesis of long-chain fatty acids and provide a robust platform for the development of novel thiolactomycin analogs with high affinity for KasA.

引用

页码：1004 / 1013

页数：10