自抗性基因导向的活性天然产物挖掘

doi:10.12211/2096-8280.2023-099

合成生物学

• 特约评述 •

自抗性基因导向的活性天然产物挖掘

宋永相¹^,²^,³, 张秀凤¹^,²^,³, 李艳芹¹^,²^,³, 肖华¹^,²^,³, 闫岩¹^,²^,³

^1. 中国科学院热带海洋生物资源与生态重点实验室，广东省海洋药物重点实验室，中国科学院南海生态环境工程创新研究院，中国科学院南海海洋研究所，广东广州 510301
^2. 三亚海洋生态环境工程研究院，亚洲湾科学城，海南三亚 572000
^3. 中国科学院大学，北京　100049

收稿日期:2023-12-01 修回日期:2024-03-08 出版日期:2024-09-06 发布日期:2024-07-12
通讯作者: 闫岩
作者简介:宋永相（1980—），男，博士，副研究员。研究方向为海洋微生物活性物质的发掘与应用。E-mail：songx@scsio.ac.cn
闫岩（1986—），男，博士，研究员。研究方向为海洋活性天然产物的挖掘与合成生物学智造。E-mail：yyan@scsio.ac.cn
基金资助:
海南省科技计划三亚崖州湾科技城联合项目(2021CXLH0013);国家自然科学基金(32000044);国家重点研发计划(2022YFC2805000)

Resistance-gene directed discovery of bioactive natural products

Yongxiang SONG¹^,²^,³, Xiufeng ZHANG¹^,²^,³, Yanqin LI¹^,²^,³, Hua XIAO¹^,²^,³, Yan YAN¹^,²^,³

^1. Key Laboratory of Tropical Marine Bio-resources and Ecology，Guangdong Key Laboratory of Marine Materia Medica，Innovation Academy of South China Sea Ecology and Environmental Engineering，South China Sea Institute of Oceanology，Chinese Academy of Sciences，Guangzhou 510301，Guangdong，China
^2. Sanya Institute of Ocean Eco-Environmental Engineering，SCSIO，Yazhou Scientific Bay，Sanya 100101，Hainan，China
^3. University of Chinese Academy of Sciences，Beijing 100049，China

Received:2023-12-01 Revised:2024-03-08 Online:2024-09-06 Published:2024-07-12
Contact: Yan YAN

摘要/Abstract

摘要：

天然产物是医药与农药的重要来源。基因组测序和生物信息学分析技术的飞速发展，揭示了大量功能未知的天然产物生物合成基因簇，利用生物信息学工具，从这些庞大的基因簇数据中挖掘活性天然产物已经成为发现新型天然药物的重要途径。天然产物的生产者们利用自抗性基因所表达的自抗性酶来保护自身，这种自抗性酶是体内一些初级代谢途径中管家酶的变体，不但对于活性天然产物具有较好的耐受性，还可以在生产活性天然产物的同时确保宿主体内代谢的正常进行。因而，自抗性基因指导的天然产物研究有效地将活性导向和基因组导向的天然产物发掘策略桥连起来，为精准发掘具有目标活性的新型天然产物提供了有效策略。本综述就利用自抗性基因作为探针进行天然产物发掘的代表性研究工作进行了整理和总结，并对研究趋势进行了展望，主要包括：①对于活性已知的天然产物，利用其自抗性基因来定位生物合成基因簇的研究；②以天然产物生物合成基因簇中的自抗性基因为线索，预测产物的作用靶点的研究；③利用天然产物自抗性机制，将具有已知作用机制的活性分子进行快速排重的研究；④利用自抗性基因与天然产物及其活性的内在联系，以目标靶点导向的活性天然产物基因组挖掘；⑤自抗性基因导向的基因组数据挖掘工具的发展情况。

关键词: 天然产物, 自抗性基因, 基因组挖掘, 生物合成, 基因簇

Abstract:

Natural products play a crucial role as sources of therapeutic agents for human health and agricultural pesticides. With the development of sequencing technologies, genome mining employing various bioinformatic tools has become an important approach to discovering novel natural products. Due to a staggering amount of cryptic natural product biosynthetic gene clusters available, prioritizing those capable of generating the most potent bioactive molecules has gained paramount significance. To avoid self-damage, some bioactive molecule producers employ self-resistance enzymes, which are slightly mutated versions of the original metabolic enzymes. These mutated enzymes maintain the original functions but are insensitive to the bioactive compound. The presence of a self-resistance enzyme in a natural product biosynthetic gene cluster serves as a predictive indicator of the biological activity of the compound it generates. On the other hand, the biosynthetic gene cluster of a natural product could be located using both structure and activity information as probes. Meanwhile, the accumulating knowledge of antibiotic resistance mechanisms has facilitated the discovery of novel antibiotics. Dereplication of natural products with known resistance mechanisms has been achieved using indicator strains expressing the resistance genes. While these approaches successfully utilized self-resistance genes to connect molecules to biological activities, a more impactful application is to accurately link biological activity and genomic information through target-guided mining of natural products. The concept is to use a self-resistance gene as a predictive tool to prioritize and identify biosynthetic gene clusters encoding compounds that inhibit specific targets. Recent breakthroughs in self-resistance gene identification have bridged the gap between activity-guided and genome-driven approaches for natural product discovery and functional assignment. This review summarizes recent representative studies on bioactive natural product discovery guided by self-resistance genes, as well as future trends. These include the following five points: 1) locating biosynthetic gene clusters based on self-resistance genes, 2) predicting the target of secondary metabolites through self-resistance genes, 3) rapid dereplication of bioactive compounds with known reaction mechanisms from self-resistance mechanisms, 4) genome mining of bioactive natural products guided by the target and the internal relationship with self-resistance genes, and 5) the development of genome data mining tools directed by self-resistance genes.

Key words: natural products, self-resistance gene, genome mining, biosynthesis, biosynthetic gene clusters

中图分类号:

Q819

宋永相, 张秀凤, 李艳芹, 肖华, 闫岩. 自抗性基因导向的活性天然产物挖掘[J]. 合成生物学, DOI: 10.12211/2096-8280.2023-099.

Yongxiang SONG, Xiufeng ZHANG, Yanqin LI, Hua XIAO, Yan YAN. Resistance-gene directed discovery of bioactive natural products[J]. Synthetic Biology Journal, DOI: 10.12211/2096-8280.2023-099.

图/表 8

图1 天然产物发掘的策略流程图

Fig. 1 Workflow of natural product discovery

图2 天然产物生物合成基因与自抗性基因的连锁

Fig. 2 Co-localization of biosynthetic core enzyme encoding genes and self-resistance genes

图3 自抗性基因指导的生物合成基因簇定位：生物合成基因簇中的蓝色开放阅读框表示生物合成母核基因，红色开放阅读框表示与天然产物作用靶点同源的自抗性基因，灰色开放阅读框表示其它相关的生物合成基因

Fig. 3 Self-resistance-gene directed localization of natural product biosynthetic gene clusters (BGCs) with a known target: the biosynthetic core genes are shown in blue, self-resistance genes in red, and other related genes in grey

图4 抗性基因导向的作用机制与分子靶点确定：生物合成基因簇（BGC）中的蓝色开放阅读框表示生物合成母核基因，红色开放阅读框表示与天然产物作用靶点同源的自抗性基因，灰色开放阅读框表示其它相关的生物合成基因

Fig. 4 Determination of the target of natural products through resistance genes: biosynthetic core genes are shown in blue, self-resistance genes in red, and other related genes in grey

图5 基于自抗性基因的天然产物排重流程图：（1）构建表达已知抗生素抗性基因的载体；（2）将表达抗性基因的载体导入大肠杆菌中构建抗性基因指示菌株；（3）构建多种指示菌株，并组合成为指示菌株文库；（4）将提前准备好的含有目标菌株发酵产物的培养基进行指示菌株的接种；（5）培养指示菌株，并通过指示菌株的生长状况来判断发酵产物的种类，并对已知的产物进行排重；（6）分离获得具有新型作用机制的天然产物

Fig. 5 Workflow of resistance gene directed dereplication of natural products: (1) Construction of vectors expressing a known antibiotic resistance gene; (2) Construction of strains capable of indicating the presence of known bioactive compounds; (3) Construction of a library of indicator strains; (4) Inoculation of the indicator strains to media containing bioactive natural products; (5) Identification of natural products with new modes of action; (6) Isolation of natural products with new modes of action

图6 目标靶点导向的活性天然产物挖掘：生物合成基因簇中的蓝色开放阅读框表示生物合成母核基因，红色开放阅读框表示与天然产物作用靶点同源的自抗性基因，灰色开放阅读框表示其它相关的生物合成基因

Fig. 6 Discovery of bioactive natural products guided by resistance genes: biosynthetic core genes are shown in blue, self-resistance genes in red, and other related genes in grey

图7 天然产物生物合成基因簇中 “假”的自抗性基因：生物合成基因簇中的蓝色开放阅读框表示生物合成母核基因，红色开放阅读框表示与天然产物作用靶点同源的自抗性基因，灰色开放阅读框表示其它相关的生物合成基因

Fig. 7 The "false positive" resistance genes in biosynthetic gene clusters of natural products: biosynthetic core genes are shown in blue, self-resistance genes in red, and other related genes in grey

图8 自抗性基因与进化树分析相结合的基因组挖掘：在71个具有多样化的糖肽类生物合成基因簇中，corbomycin与complestatin的生物合成基因簇中的自抗性基因特征与已知的抗性基因vanY和vanHAX处于不同的进化树分支

Fig. 8 Discovery of new antibiotics guided by resistance gene phylogeny: the glycopeptide self-resistance determinants of complestatin and corbomycin are distinctive to known determinant vanY and vanHAX among 71 glycopeptide BGCs

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自抗性基因导向的活性天然产物挖掘

Resistance-gene directed discovery of bioactive natural products

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