细菌聚酮合酶间的杂合方式及聚酮化合物生物合成逻辑

doi:10.12211/2096-8280.2023-090

摘要/Abstract

摘要：

聚酮化合物（polyketide）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不相同，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通常能与其他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，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的工程化改造设想，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 isolated from a wide variety of species. In bacteria, diverse skeletons of polyketides lead to different biological functions, including anti-bacteria, anti-fungi, 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 complicated and unique structures. 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 biosynthetic mechanisms of bacterial 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, and the synthesis of kirromycin is a representative example; (3) Type Ⅰ PKSs synthesize unique starter units for type Ⅱ PKSs to produce polyketide scaffolds with the 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 the type Ⅰ PKS assembly line. By elucidating the biosynthetic gene clusters and biosynthetic pathways of inter-PKS hybrids, the reconstructions of inter-PKS hybrids for synthesizing pharmaceutically important analogues are possible. This review also comments the discovery of new inter-PKS hybrids and the engineering of their biosynthetic machineries, to gain more insights into their biosynthetic potential for the production of diverse molecules. By comparing the biosynthetic mechanisms of PKS and discussing the progress of engineering modifications, we prospect a variety of potential inter-PKS hybrid models, highlight the direction for the genome mining of novel polyketides, and provide insights for the engineering modifications of PKS. Through further in-depth and systematic studies on various inter-PKS hybrids in bacteria, it is expected to reveal more natural conundrums, generating a large number of new natural products through adaptive transformation for the research and development of microbial drugs.

Key words: natural products, polyketide, polyketide synthase, 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聚酮化合物生物合成逻辑[J]. 合成生物学, 2024, 5(3): 548-560.

Rui ZHANG, Wenzheng JIN, Yijun CHEN. Bacterial inter-PKS hybrids and the biosynthetic algorithm of polyketides[J]. Synthetic Biology Journal, 2024, 5(3): 548-560.

图/表 7

图1 临床使用的经典聚酮类药物［1］

Fig. 1 Classic polyketides for 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 algorithm for different polyketide synthases[11]

图3 Aureothin的生物合成机制［41］MCoA—丙二酰辅酶A；mMCoA—甲基丙二酰辅酶

Fig. 3 Biosynthetic mechanism of Aureothin[41]MCoA—malonyl CoA; mMCoA—methylmalonyl-CoA

图4 cis-AT PKS和trans-AT PKS的生物催化逻辑［54］

Fig. 4 Biocatalytic 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 Structures of products synthesized under the catalysis of type Ⅱ PKS and type Ⅰ/Ⅱ PKS hybrids(The moieties from starter units in polyketidess are highlighted in red.)

图6 Hedamycin的生物合成途径［71］

Fig. 6 Biosynthetic pathway for Hedamycin[71]

图7 Ⅰ/Ⅲ型杂合PKS杂合聚酮的生物合成途径

Fig. 7 Biocatalytic pathways of Type Ⅰ/Ⅲ PKS hybrids

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