通过生物合成指导和定制酶催化剂发现迪利兰型美类药物
Zhaolun Sun1, Mengyue Wu1, Boyuan Zhong1
1State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Journal of the American Chemical Society
|October 25, 2024
概括
研究人员使用生物合成洞察力发现了23种新的真菌甲, 这项工作扩大了对真菌天然产品及其潜在的抗炎和杀虫作用的了解.
科学领域:
- 自然产品化学
- 菌类代谢学
- 酵素学
背景情况:
- 迪利兰类型的美类化合物 (DMs) 是罕见的真菌代谢物,具有复杂的6/ 6/5/5环系统.
- 关于DM的化学多样性和生物合成的知识有限,只有11个已知的化合物.
研究的目的:
- 开发一个工作流程来发现和多样化DM.
- 探索DM形成中的生物合成途径和酶机制.
- 识别具有潜在生物活动的新型DM.
主要方法:
- 菌类二次代谢物基因群的基因组挖掘.
- 使用先进分析技术进行代谢物分析.
- 定制酶催化,包括异质表达和体外测试.
- 结晶学和突变性研究以阐明酶机制.
主要成果:
- 包括7个前所未有的脚手架.
- 描述DhiD,一个α-酸依赖的氧化酶,催化立体分离环收缩.
- 描述DhiH,一个P450细胞染色体,有助于结构多样性.
- 在DM修改中证明DhiD的催化灵活性.
- 生物测试显示分离的化合物具有抗炎和杀虫作用.
结论:
- 开发的工作流程显著扩大了已知的DM的化学多样性.
- 在DM生物合成中,DhiD和DhiH起着至关重要的作用,展示了酶的多功能性.
- 已发现的DM是开发新的抗炎和杀虫剂的有希望的来源.
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