基于P450选择性氧化的天然产物化学-酶法合成进展

程中玉; 李付琸

doi:10.12211/2096-8280.2024-017

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基于P450选择性氧化的天然产物化学-酶法合成进展

特约评述 | 更新时间：2025-03-19

- 基于P450选择性氧化的天然产物化学-酶法合成进展
- Recent advances in chemoenzymatic synthesis of natural products via site- selective P450 oxidation
- 合成生物学 2024年5卷第5期页码：960-980
- 作者机构：
  
  复旦大学药学院，天然药物学系，上海 201203
- 作者简介：
  
  [ "程中玉（1998—），男，研究助理。研究方向为活性天然产物化学-酶法合成。 E-mail：zhongyu_cheng@fudan.edu.cn" ]
  [ "李付琸（1990—），男，青年研究员，博士生导师。研究方向为酶催化反应开发，活性天然产物化学-酶法合成等。 E-mail：lifuzhuo@fudan.edu.cn" ]
- 基金信息：
  
  国家自然科学基金(22301041);上海市自然科学基金(23ZR1412900)
- DOI：10.12211/2096-8280.2024-017
  中图分类号： Q629
- 收稿：2024-02-04，
  
  修回：2024-05-21，
  
  纸质出版：2024-10-31
- 稿件说明：
移动端阅览
程中玉，李付琸. 基于P450选择性氧化的天然产物化学-酶法合成进展［J］. 合成生物学， 2024， 5（5）： 960-980

CHENG Zhongyu， LI Fuzhuo. Recent advances in chemoenzymatic synthesis of natural products via site- selective P450 oxidation［J］. Synthetic Biology Journal， 2024， 5（5）： 960-980
程中玉，李付琸. 基于P450选择性氧化的天然产物化学-酶法合成进展［J］. 合成生物学， 2024， 5（5）： 960-980 DOI： 10.12211/2096-8280.2024-017.

CHENG Zhongyu， LI Fuzhuo. Recent advances in chemoenzymatic synthesis of natural products via site- selective P450 oxidation［J］. Synthetic Biology Journal， 2024， 5（5）： 960-980 DOI： 10.12211/2096-8280.2024-017.

摘要

随着基因挖掘、生物信息学、酶工程等多学科的交叉融合与协同创新，将绿色高效的酶催化反应与现代有机合成方法相结合的化学-酶法合成策略逐渐发展成为合成活性天然产物、药物分子和其他具有重要价值的有机分子的有力工具。其中细胞色素单加氧酶P450能够选择性地实现惰性C—H氧化这一经典的挑战性化学转化，为活性天然产物的高效合成提供了新的思路，成为合成科学领域的研究热点之一。本文以结构类型进行分类，综述了P450选择性氧化在甾体、萜类以及其他类型天然产物化学-酶法合成中的应用进展，并分析了相应的酶催化反应在提高目标产物合成效率方面起到的关键作用。此外，还讨论了该领域目前所面临的挑战，例如主要集中在对酶天然功能的利用，并缺乏对反应位点的准确预测等；同时从酶资源挖掘、酶的改造等多个角度出发展望了未来能够为这些挑战提供解决方案的研究方向和新兴技术，包括高通量筛选技术、AI辅助酶工程等等。

Abstract

Although bioactive natural products have played significant roles in pharmaceutical research

their application potential is still limited by low isolated yields and structural modification challenges. To overcome these obstacles

developing environmentally friendly and highly efficient synthetic strategies offers exceptional approaches to obtain complex bioactive natural products and their analogs. Driven by advancements in microbial genetics and enzyme engineering

chemoenzymatic strategies

which merge enzymatic and synthetic transformations

are steadily emerging as potent tools in the synthesis of bioactive natural products

pharmaceutical components and other valuable molecules. These fashionable strategies offer not only advantages of chemical synthesis

such as simplicity

flexibility and scalability

but also those of biosynthesis

including environmental friendliness

high selectivity and efficiency. This will establish a linkage into the next-generation synthesis which is expected to break the boundary between chemistry and biology. Versatile cytochrome monooxygenases

P450s

can achieve inert C—H bond selective oxidation in mild and green conditions

a classically challenging organic transformation

providing novel retrosynthetic plans for complex natural products and becoming one of the hotspots in synthetic science. This review summarizes the recent applications of chemoenzymatic synthesis of natural products using P450-catalyzed site-selective oxidations as critical steps to improve the synthetic efficiency and avoid unnecessary functional group transformations and protection/deprotection steps

categorizing the case studies by structure features

such as steroids

terpenoids

and other types of natural products. At the end of this review

the current challenges in this field

such as heavily relying on the native activities of enzymes

are also analyzed and discussed

along with emerging research directions and technologies in new enzyme mining and enzyme engineering that may provide solutions to these challenges in the future. With constantly cross fusion of biosynthesis

chemical synthesis

synthetic biology

protein engineering

machine learning and other research field

P450-catalyzed site-selective oxidations will be becoming routine tools for synthetic chemists.

关键词

Keywords

references

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