放线菌聚酮类化合物生物合成体系重构研究进展

doi:10.12211/2096-8280.2023-087

合成生物学 ›› 2024, Vol. 5 ›› Issue (3): 612-630.DOI: 10.12211/2096-8280.2023-087

放线菌聚酮类化合物生物合成体系重构研究进展

谢皇¹^,², 郑义蕾¹^,², 苏依婷¹^,², 阮静怡¹^,², 李永泉¹^,²

^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

收稿日期:2023-11-28 修回日期:2024-01-16 出版日期:2024-06-30 发布日期:2024-07-12
通讯作者: 李永泉
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
基金资助:
国家自然科学基金(32170057);国家重点研发计划(2019YFA09005400)

An overview on reconstructing the biosynthetic system of actinomycetes for polyketides production

Huang XIE¹^,², Yilei ZHENG¹^,², Yiting SU¹^,², Jingyi RUAN¹^,², Yongquan LI¹^,²

^1.Institute of Pharmaceutical Biotechnology，Zhejiang University，Hangzhou 310058，Zhejiang，China
^2.Zhejiang Provincial Key Laboratory for Microbial Biochemistry and Metabolic Engineering，Hangzhou 310058，Zhejiang，China

Received:2023-11-28 Revised:2024-01-16 Online:2024-06-30 Published:2024-07-12
Contact: Yongquan LI

摘要/Abstract

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。

关键词: 放线菌, 聚酮, 菌种重构, 产量, 代谢工程, 合成生物学

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.

Key words: actinomycetes, polyketide, strain reconstruction, production, metabolic engineering, synthetic biology

中图分类号:

Q939.97

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.

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

图/表 6

图1 不同聚酮类化合物的结构及其主要产生菌株和分子潜在用途

Fig. 1 Structures of different polyketides, their primary producer strains and the potential use of these molecules

图2 非达霉素生物合成基因簇的模块化组装（图中展示了不同延长单元的缩合和修饰，形成了糖苷配体骨架，然后通过不同的后修饰酶进行催化进一步形成非达霉素）

Fig. 2 Assembly of the gene clusters for fidaxomicin biosynthesis(Condensations and modifications of different extender units to form fidaxomicin aglycone are illustrated, which is further processed with different post-modifications to form fidaxomicin.)

图3 基于多组学和生物信息学方法的基因组分析工作流程

Fig. 3 Schematic representation for the genomic analysis based on multi-omics and bioinformatics analyses

图4 放线菌体内影响次级代谢的各层级调控和修饰降解作用

Fig. 4 Various regulation on secondary metabolism and modification and degradation of the metabolites in actinomycetes

图5 放线菌聚酮类化合物及同系物杂质

Fig. 5 Polyketide fidaxomicin, FK506, midecamycin A1 and their derivatives

图6 聚酮合酶的理性设计

Fig. 6 Rational design for polyketide synthase

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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

An overview on reconstructing the biosynthetic system of actinomycetes for polyketides production

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