FadA5 a thiolase from Mycobacterium tuberculosis: a steroid-binding pocket reveals the potential for drug development against tuberculosis.
FadA5 a thiolase from Mycobacterium tuberculosis: a steroid-binding pocket reveals the potential for drug development against tuberculosis.
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DOI：
10.1016/j.str.2014.10.010
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发表时间：
2015-01-06
期刊：
影响因子：
5.7
通讯作者：
Kisker, Caroline
中科院分区：
文献类型：
--
作者：
Schaefer, Christin M.;Lu, Rui;Nesbitt, Natasha M.;Schiebel, Johannes;Sampson, Nicole S.;Kisker, Caroline
除艾滋病毒外，结核病(TB)是传染病中死亡的主要原因。由于耐药结核分枝杆菌(Mtb)菌株数量的增加，开发新的抗结核药物的迫切性是显而易见的。最近，参与胆固醇输入和代谢的蛋白质被发现是治疗结核病的有效靶点。FadA5是结核分枝杆菌的一种硫解酶，它在释放关键代谢产物的情况下催化胆固醇侧链降解的β氧化反应的最后一步，在结核病感染的慢性阶段起着重要作用。为了了解FadA5的结构和机制，我们在切割反应的不同阶段表征了该酶，并将类固醇结合到结合口袋上。与人类硫解酶的结构比较表明，应该有可能特异性地靶向FadA5，而类固醇结合的结构为开发FadA5的抑制剂提供了坚实的基础。
With the exception of HIV, tuberculosis (TB) is the leading cause of mortality among infectious diseases. The urgent need to develop new anti-tubercular drugs is apparent due to the increasing number of drug resistant Mycobacterium tuberculosis (Mtb) strains. Proteins involved in cholesterol import and metabolism have recently been discovered as potent targets against TB. FadA5, a thiolase from Mtb, is catalyzing the last step of the β-oxidation reaction of the cholesterol side-chain degradation under release of critical metabolites and was shown to be of importance during the chronic stage of TB infections. To gain structural and mechanistic insight on FadA5 we characterized the enzyme in different stages of the cleavage reaction and with a steroid bound to the binding pocket. Structural comparisons to human thiolases revealed that it should be possible to target FadA5 specifically and the steroid-bound structure provides a solid basis for the development of inhibitors against FadA5.
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DOI：
10.1107/s090744491003982x
发表时间：
2011-04
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
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发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
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