通过先基因替代来操纵西西林变异体:异环替代突变体的结构,形状和活性
Albert A Bowers1, Michael G Acker, Alexander Koglin
1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Journal of the American Chemical Society
|May 12, 2010
概括
谷菌种ATCC 14579通过广泛的翻译后修改产生硫类抗生素. 氨酸和氨酸扫描显示,改变三醇胺核心或宏循环刚性取消了抗生素的活性.
科学领域:
- 微生物学 微生物学
- 生物化学 生物化学
- 结构生物学 结构生物学
背景情况:
- 谷菌种ATCC 14579通过对前的广泛的翻译后修改,合成硫类的子类型 - - 硫类抗生素.
- 前的最后14个残留物中的13个经历了修饰,导致了复杂的生化变化级联.
研究的目的:
- 通过对前的氨酸和氨酸扫描来研究硫素抗生素的结构-活性关系.
- 为了确定主要的残留物和结构特征,对于形成和抗生素活性的西林变体必不可少.
主要方法:
- 在Bacillus cereus的一种淘汰菌株中引入前基因变异.
- 对14个原始残留物的氨酸扫描和对6个氨酸残留物的氨酸扫描.
- 使用高分辨率核磁共振 (NMR) 光谱和抗生素活性测定分析突变化合物的分析.
主要成果:
- 特定的突变 (S1A,S10A) 阻止了成熟的支架的形成,表明它们在形成核中的关键作用.
- 在氨酸和氨酸扫描中,氨酸11替代是阻止成熟支架生产的唯一突变.
- 异环的丧失或宏环环的结构刚性降低导致了抗生素活性的丧失.
结论:
- 三醇胺核心和宏循环刚性对硫素抗生素活性至关重要.
- 即使是微小的破坏,例如单个异环的损失,也会对这些复杂分子的结构完整性和生物功能产生重大影响.
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