放线菌聚酮类化合物生物合成体系重构研究进展

谢皇; 郑义蕾; 苏依婷; 阮静怡; 李永泉

doi:10.12211/2096-8280.2023-087

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放线菌聚酮类化合物生物合成体系重构研究进展

特约评述 | 更新时间：2025-03-19

- 放线菌聚酮类化合物生物合成体系重构研究进展
- An overview on reconstructing the biosynthetic system of actinomycetes for polyketides production
- 合成生物学 2024年5卷第3期页码：612-630
- 作者机构：
  
  1.浙江大学药物生物技术研究所，浙江杭州 310058
  2.浙江省微生物生化与代谢工程重点实验室，浙江杭州 310058
- 作者简介：
  
  [ "谢皇（1997—），男，博士研究生。研究方向为微生物次级代谢产物调控，底盘构建与天然产物的异源表达。E-mail：xiehuang@zju.edu.cn" ]
  [ "郑义蕾（1996—），男，博士研究生。研究方向为微生物异源生物合成，微生物次级代谢的生物化学机理。E-mail：yl_zheng@zju.edu.cn" ]
  [ "李永泉（1962—），男，博士，浙江大学求是特聘教授。研究方向为微生物合成生物学、微生物次级代谢调控和微生物制药。E-mail：lyq@zju.edu.cn" ]
- 基金信息：
  
  国家自然科学基金(32170057);国家重点研发计划(2019YFA09005400)
- DOI：10.12211/2096-8280.2023-087
  中图分类号： Q939.97
- 收稿：2023-11-28，
  
  修回：2024-01-16，
  
  纸质出版：2024-06-30
- 稿件说明：
移动端阅览
谢皇，郑义蕾，苏依婷，阮静怡，李永泉. 放线菌聚酮类化合物生物合成体系重构研究进展［J］. 合成生物学， 2024， 5（3）： 612-630

XIE Huang， ZHENG Yilei， SU Yiting， RUAN Jingyi， LI Yongquan. An overview on reconstructing the biosynthetic system of actinomycetes for polyketides production［J］. Synthetic Biology Journal， 2024， 5（3）： 612-630
谢皇，郑义蕾，苏依婷，阮静怡，李永泉. 放线菌聚酮类化合物生物合成体系重构研究进展［J］. 合成生物学， 2024， 5（3）： 612-630 DOI： 10.12211/2096-8280.2023-087.

XIE Huang， ZHENG Yilei， SU Yiting， RUAN Jingyi， LI Yongquan. An overview on reconstructing the biosynthetic system of actinomycetes for polyketides production［J］. Synthetic Biology Journal， 2024， 5（3）： 612-630 DOI： 10.12211/2096-8280.2023-087.

摘要

放线菌因其丰富的次级代谢产物而成为候选药物发掘的宝贵资源库，其蕴含的活性化合物包含聚酮类、非核糖体肽类、氨基糖苷类、萜类等，其中聚酮类化合物占比最大。大环内酯是聚酮类化合物的典型，常常被用作抗生素、抗肿瘤剂、免疫抑制剂、抗寄生虫剂等，具有重要的生物学意义。本文立足聚酮类大环内酯的生物合成过程，提出了从基因组重塑、调控通路重组、组合代谢工程及聚酮类化合物结构的衍生与多样化等多角度，实现放线菌聚酮类生物合成体系的优化，为工业规模生产聚酮类药物及其新型衍生物提供技术支撑。通过这种多维度的方法，结合最新的合成生物学使能技术，遵循绿色、环保、高效和可持续的策略，可以更有效地优化和增强放线菌中聚酮类化合物的生产，为未来药物的开发和生产提供新的可能性。

Abstract

Actinomycetes

enriched with secondary metabolites

have emerged as a resource for drug discovery. These organisms predominantly harbor bioactive compounds such as polyketides

non-ribosomal peptides

aminoglycosides

and terpenes

with polyketides representing the most diverse class. Polyketides are divided into three major categories based on polyketide synthase: type Ⅰ

type Ⅱ

and type Ⅲ

in which type Ⅰ polyketides are most widely distributed and abundant

with macrocyclic lactone compounds serving as their archetypal representatives. Macrocyclic lactone compounds

frequently utilized as antibiotics

anti-cancer agents

immunosuppressants

and antiparasitic agents

hold immense biological significance. This review comments the biosynthetic process of macrolides

and strategies for biosynthesizing actinomycete polyketides are proposed

which encompass genome remodeling

regulatory pathway recombination

combinatorial metabolic engineering

and the modifications of polyketide structures. By knocking out competing gene clusters and superfluous genomic islands

augmenting the supply of precursors

and enhancing precursor supply and lipid stream processing

researchers can obtain genome-minimized and optimized industrial chassis

followed with manipulations such as promoter engineering

regulatory factor engineering

overexpression of the rate-limiting enzyme genes

enhanced substrate transport and tolerance

targeted modifications of the key enzymes

rational design of polyketides

etc

. Furthermore

the optimized chassis and biosynthetic gene clusters are integrated to develop robust strains for multi-omics analyses and fermentation process optimization

which can be guided by rapidly developed synthetic biology enabling technologies and artificial intelligence

to develop a

high-quality

efficient polyketides biosynthesis system. These advancements can offer robust technical support for the large-scale production of polyketides pharmaceuticals and their derivatives.

关键词

Keywords

references

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