聚酮化合物非天然延伸单元的生物合成与结构改造应用  

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

作　　者：张俊[1] 金诗雪 云倩 瞿旭东 ZHANG Jun;JIN Shixue;YUN Qian;QU Xudong(Zhangjiang Institute for Advanced Study,Shanghai Jiao Tong University,Shanghai 201204,China;School of Pharmacy,Fudan University,Shanghai 201203,China)

机构地区：[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

出　　处：《合成生物学》2024年第3期561-570,共10页Synthetic Biology Journal

基　　金：国家自然科学基金青年科学基金(32200033)。

摘　　要：聚酮天然产物包括10000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。The natural products polyketides include over 10000 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 typeⅠmodular 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 p

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 

分 类 号：R915[医药卫生—微生物与生化药学]