多基基和非核糖体抗生素:模块化和多功能性
1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. christopher_walsh@hms.harvard.edu
概括
定制酶指导生物活性多基 (PK) 和非核糖体 (NRP) 自然产品的形成. 重新编程这些酶为新型抗生素提供了途径.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 自然产品化学 自然产品化学
背景情况:
- 多基 (PK) 和非核糖体 (NRP) 是由大型多模块酶复合体合成的复杂自然产物.
- 由基因集群编码的定制酶引入了对生物活动至关重要的结构修改.
- 这些修改包括循环化,氧化和交叉链接,导致不同的分子架构.
研究的目的:
- 阐明定制酶在PK和NRP天然产品生物合成中的作用.
- 探索重新编程这些酶途径的潜力,以发现新的抗生素.
主要方法:
- 对编码PK和NRP组装线的基因集群和相关的定制酶的分析.
- 研究循环和氧化反应的酶机制.
- 酶模块化和基质允许性的生物信息分析.
主要成果:
- 定制酶在PK和NRP生物合成期间引入循环制约,包括异环化 (thiazoles, oxazoles) 和宏环化.
- 装配线后的酶氧化产生复杂的,交叉链接的架构.
- 有证据表明,模块化和酶允许性允许途径重编程.
结论:
- 定制酶对于产生PK和NRP天然产品的生物活性构成至关重要.
- 这些生物合成途径的固有模块化和灵活性为设计具有增强性质的新型抗生素提供了机会.
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