对二醇乳架的组合生物合成定制的O-甲基化区域选择性的合理重新编程
Xiaojing Wang1,2,3, Chen Wang1,2, Lixin Duan2,4
1Biotechnology Research Institute , Chinese Academy of Agricultural Sciences , 12 Zhongguancun South Street , Beijing 100081 , P.R. China.
Journal of the American Chemical Society
|February 16, 2019
概括
我们使用工程化O-甲基转移酶 (OMT) 开发了高效的生物合成和生物催化方法, 这些工程酶为药物发现和开发提供可调节的区域选择性.
科学领域:
- 生物催化和代谢工程
- 自然产品药物发现
- 酶工程
背景情况:
- O-甲基化对小分子天然产品的药理动力学和药理动力学 (PK/ PD) 特性产生显著影响.
- 有效的O-甲基转移酶 (OMT) 生物催化剂具有基质杂交性和可调节的区域选择性,对于药物发现和开发至关重要.
- 需要可扩展和可持续的生产方法来实现OMT催化合成.
研究的目的:
- 建立高效的生物合成和生物催化平台,用于生产非天然的O-甲基化聚化物.
- 通过结构导向工程来证明OMT区域选择性的重新编程.
- 研究工程区域选择性和基质可塑性之间的关系.
主要方法:
- 使用了一对具有直角区域特异性的真菌OMT.
- 采用合理的,结构导向的活性部位腔工程来修改酶区域选择性.
- 开发了生物合成和生物催化生产平台.
主要成果:
- 成功产生非自然的O-甲基化二醇乳多基.
- 证明工程OMT表现出重新编程的区域选择性.
- 描述了工程区域选择性和基质可塑性之间的相互作用.
结论:
- 工程OMT为药物发现提供了强大的工具.
- 这些生物催化平台促进了生物活性支架的PK/PD优化.
- 这些发现为非自然产品的组合生物合成定制提供了指导.
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