合成生物学 ›› 2024, Vol. 5 ›› Issue (3): 561-570.DOI: 10.12211/2096-8280.2023-093

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聚酮化合物非天然延伸单元的生物合成与结构改造应用

张俊1, 金诗雪2, 云倩2, 瞿旭东1   

  1. 1.上海交通大学张江高等研究院,上海 201204
    2.复旦大学药学院,上海 201203
  • 收稿日期:2023-11-30 修回日期:2024-01-08 出版日期:2024-06-30 发布日期:2024-07-12
  • 通讯作者: 瞿旭东
  • 作者简介:张俊(1992—),女,博士后。研究方向为聚酮化合物的生物合成与结构改造。E-mail:zhangjun2021@sjtu.edu.cn
    瞿旭东(1980—),男,教授,博士生导师。研究方向为天然产物生物合成与生物催化,通过生物合成与化学合成结合的方式,发展针对各类天然产物骨架的普适、高效的合成与编辑策略,用于拓展结构多样性和提高药物的生产效率,实现对天然产物资源的深度开发及天然药物的高效创制。E-mail:quxd19@sjtu.edu.cn
  • 基金资助:
    国家自然科学基金青年科学基金(32200033)

Biosynthesis of the unnatural extender units with polyketides and their structural modifications for applications in medicines

Jun ZHANG1, Shixue JIN2, Qian YUN2, Xudong QU1   

  1. 1.Zhangjiang Institute for Advanced Study,Shanghai Jiao Tong University,Shanghai 201204,China
    2.School of Pharmacy,Fudan University,Shanghai 201203,China
  • Received:2023-11-30 Revised:2024-01-08 Online:2024-06-30 Published:2024-07-12
  • Contact: Xudong QU

摘要:

聚酮天然产物包括10 000多种具有广泛生物活性的分子,是获批临床药物中最著名的类别之一。已知活性先导化合物通常需要经过结构修饰改良其吸收、分布、代谢和排泄等特性,从而促进成药开发,但针对聚酮化合物的结构修饰极具挑战,需要应对聚酮骨架中大量的立体中心以及多个惰性碳原子,导致化学合成手段难以对聚酮骨架进行精准和高效的衍生化,因此,通过合成生物学方法实现其结构优化就成为了研究者们关注的热点。自然界中,绝大多数聚酮化合物主要由简单的乙酸盐和丙酸盐结构单元通过聚酮合酶组装而成,而少数存在的具有特殊结构单元的聚酮案例给了研究者以灵感——通过设置和引入非天然结构单元从而有选择性地高效改造聚酮结构。聚酮骨架的生物合成有赖于一个起始单元与多个延伸单元的组装,因此,通过人工设计延伸单元向聚酮引入预期结构被认为是精准高效改造聚酮的有力突破点。本文在此总结了近十年来报道的聚酮非天然延伸单元的三种重要的酶促合成方法,通过挖掘新颖的延伸单元合成酶并探索其底物宽泛性,或利用酶工程手段改造延伸单元合成酶的底物催化范围,获得了大量自然界不存在的延伸单元。此外,本文还归纳了利用非天然延伸单元对聚酮结构进行改造的案例,借助聚酮的天然合成途径或利用改造的合成途径达到预期目的。最后,作者讨论了该研究领域内存在的一些制约因素以及可优化的研究方向,包括聚酮合酶对非天然延伸单元的兼容性问题、非天然延伸单元的前体供给等。近年来,利用非天然延伸单元改造聚酮结构的研究兴趣和热度日益高涨,本文绘制了一份基于延伸单元改造聚酮结构研究的简明清晰的图谱,期望为加速聚酮类药物的高效开发打下坚实基础。

关键词: 天然产物, 聚酮化合物, 聚酮合酶, 延伸单元, 生物合成, 酶工程

Abstract:

The natural products polyketides include over 10 000 molecules with a wide range of bioactivities and are among the most prominent classes of approved clinical agents. Usually, active lead compounds require structural modifications to improve their assimilation, distribution, metabolism, and excretion as well as to facilitate the drug development process. However, due to the large number of stereocenters and inert carbon atoms, it is challenging for chemical synthesis to accurately and efficiently derive polyketide scaffolds, making their biological synthesis for structural optimization of the polyketides a hot topic. In nature, the majority of polyketides are assembled from simple the building blocks acetate and propionate catalyzed by polyketide synthases, but a few polyketides with special building blocks provide inspiration for researchers to introduce unnatural building blocks selectively into the scaffolds of polyketides for their structure modifications. Polyketides can be built with predictable biosynthetic logic, each module of a modular polyketide synthase elongates the product backbone with two carbons by synergetic actions of its three essential domains: ketosynthase, acyltransferase and acyl carrier protein. The acyltransferase domain selects for and loads a carboxyacyl-Coenzyme A extender unit for the phosphopantetheinyl modification of the acyl carrier protein domain, whereas the ketosynthase domain then uses the extender unit to elongate the growing polyketide intermediate, before passing it to the following module. Given the hierarchical domain and module organization of the type Ⅰ modular PKSs that make these molecules, gene sequences and product structures are directly connected such that changes can be introduced site-selectively into the molecule by targeting building blocks and promiscuous acyltransferase domain with the corresponding domain. Besides, the biosynthesis of polyketide scaffolds depends on the assembly of a starter unit and variable extender units, therefore, introducing anticipated structures into the polyketides through incorporating the artificial extender units is considered as a powerful breakthrough for precise and effective modifications of the polyketides. This review summarizes three important enzymatic synthesis methods for unnatural polyketides extender units reported within the past decade. As results, a large number of unnatural extender units have been obtained through mining novel extender unit synthetase and exploring their substrates, or using enzyme engineering methods to modify the substrate spectrum. Also, this review comments on the cases of modifying polyketide structures using unnatural extender units to achieve the desired derivatives either through the natural synthetic pathway of polyketides or by utilizing modified synthetic pathways. Finally, we discuss some challenges existing in this research field and potential solutions for better applications of polyketides, including the compatibility issue of polyketides synthase with unnatural extender units, precursor supply for unnatural extender units, and etc. In recent years, interest and enthusiasm for the modifications of polyketides using unnatural extender moieties have increased dramatically, and our review draws a concise and clear map for the research of polyketide structure modifications by artificial extender units, with an expectation of laying a solid foundation for accelerating the development of polyketides drugs.

Key words: natural products, polyketides, polyketide synthase, extender units, biosynthesis, enzyme engineering

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