细菌聚酮合酶间的杂合方式及其生物合成逻辑

doi:10.12211/2096-8280.2023-090

摘要/Abstract

摘要：

聚酮化合物（Polyketides）是一类来源广泛、结构多样的活性天然产物，聚酮合酶（Polyketide Synthase， PKS）负责聚酮骨架的生物合成。细菌次级代谢中PKS广泛存在，不同类型的PKS在组成和生物合成机制上各为不同，从而产生截然不同的聚酮骨架。根据细菌PKS功能和生物合成途径的不同，可以将其分为I型、II型和III型。PKS通常能与其它生物合成酶系杂合以产生结构更为复杂的天然产物。同时，不同类型PKS之间也可以形成多种内部杂合，产生更多样的聚酮骨架。本文总结和比较PKS间的内部杂合，包括I型PKS内部杂合、I型/II型PKS杂合以及I型/III型PKS杂合，归纳各种杂合基因簇的形成方式及其杂合特征。通过比较杂合聚酮化合物的生物合成机制并讨论杂合聚酮工程化改造的进展，我们展望了多种潜在的聚酮杂合模式，合理假设存在合成过程相反的I型/II型PKS杂合模式，或随着化合物的挖掘发现迄今未报道的II型/III型PKS杂合模式等，指出可以充分和全面地利用细菌基因组信息，通过酶和基因的生物勘探，发现更多更特殊的PKS杂合化合物等一系列针对新颖聚酮化合物进行基因组挖掘的方向，同时也提出了工程化改造trans-AT PKS在cis-AT模块中实现不同寻常的骨架修饰等多种PKS的工程化改造想法，为后续PKS内部杂合基因簇挖掘和表征提供一些新思路。

关键词: 天然产物, 聚酮化合物, 聚酮合酶, 聚酮内部杂合

Abstract:

Polyketides are a class of natural products from a wide variety of organisms. In bacteria, diverse skeletons of polyketides lead to different biological properties, including anti-bacterial, anti-fungal, anti-tumor and immunomodulation. Polyketide synthases (PKSs) are responsible for the biosynthesis of polyketides through successive Claisen condensations of short-chain fatty acids. PKSs are classified into type I, type II and type III, producing different polyketide scaffolds. Bacterial PKSs often hybridize with other biosynthetic enzymes to form PKS hybrids, such as PKS-NRPS or PKS-Ripps, exhibiting more complex and unique structural features. Additionally, different types of PKS can also form inter-PKS hybrids to generate different skeletons. In this review, we summarize recent advances in the structures and the biosynthetic mechanisms of inter-PKS hybrids, including type I PKS internal hybrids, type I/II PKS hybrids and type I/III PKS hybrids with the following context: (1) In atypical type I PKSs, some modules may iteratively catalyze multiple rounds of carbon chain growth, resulting in iterative/non-iterative PKS hybrids; (2) trans-AT PKS and cis-AT PKS can also form PKS hybrids, in which kirromycin is a representative example; (3) Type I PKSs synthesize unique starter units for type II PKSs to produce polyketide scaffolds with the corresponding alkyl groups; (4) Type III PKSs can condense malonyl-CoA to form different aromatic acids through multiple tailoring steps, and the aromatic acids subsequently act as the starter unit or extender unit into type I PKS assembly lines. By elucidating the biosynthetic gene clusters and biosynthetic pathways of inter-PKS hybrids, the reconstructions of inter-PKS hybrids for creating pharmaceutically important analogues have been possible. Thus, this review also forecasts the discovery of new inter-PKS hybrids and the engineering of their biosynthetic machineries, to gain more insights into the biosynthetic power for the production of diverse molecules. By comparing the biosynthetic mechanisms of PKS and discussing the progress of engineering modification, we prospected a variety of potential inter-PKS hybrid models, pointed out the direction of genome mining of novel polyketides, and provided ideas for engineering modification of PKS. Through further in-depth and systematic study of various inter-PKS hybrids in bacteria, it is expected to reveal more natural phenomena and laws, generating a large number of new natural products through adaptive transformation, laying a material foundation for the research and development of microbial drugs.

Key words: natural products, polyketides, polyketide synthases, inter-PKS hybrids

中图分类号:

Q939.92

张瑞, 金文铮, 陈依军. 细菌聚酮合酶间的杂合方式及其生物合成逻辑[J]. 合成生物学, DOI: 10.12211/2096-8280.2023-090.

Rui ZHANG, Wenzheng JIN, Yijun CHEN. Bacterial Inter-PKS Hybrids and the Biosynthetic Logic of Related Compounds[J]. Synthetic Biology Journal, DOI: 10.12211/2096-8280.2023-090.

图/表 7

图1 临床使用的经典聚酮类药物［1］

Fig. 1 Classic polyketides in clinical use[1]

图2 不同类型PKS的生物合成的基本逻辑［11］

Fig. 2 Basic biosynthetic logics of different polyketide synthases[11]

图3 Aureothin的生物合成机制［41］

Fig. 3 The biosynthetic mechanism of Aureothin[41]

图4 cis-AT PKS和trans-AT PKS的生物合成逻辑［54］

Fig. 4 Biosynthetic mechanisms of cis-AT PKS and trans-AT PKS[54]

图5 II型PKS和I/II型杂合PKS对应产物的化学结构由聚酮合酶的起始单元引入的基团以红色加粗显示

Fig. 5 The structures of products of type II PKS and type I/II PKS hybrids (a) Tetracenomycin (b) Hedamycin (c) ShellmycinThe moieties from starter units in polyketidess are highlighted in red.

图6 Hedamycin的生物合成途径［71］

Fig. 6 The biosynthetic pathway of Hedamycin[71]

图7 I/III型杂合PKS杂合聚酮的生物合成途径

Fig. 7 The biosynthetic pathways of Type I/III PKS hybrids

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