Resistance-gene directed discovery of bioactive natural products

SONG Yongxiang; ZHANG Xiufeng; LI Yanqin; XIAO Hua; YAN Yan

doi:10.12211/2096-8280.2023-099

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Resistance-gene directed discovery of bioactive natural products

Invited Review | 更新时间：2025-03-19

- Resistance-gene directed discovery of bioactive natural products
- Synthetic Biology Journal Vol. 5, Issue 3, Pages: 474-491(2024)
- 作者机构：
  
  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，海南三亚 572000
  3.中国科学院大学，北京 100049
- 作者简介：
- 基金信息：
- DOI：10.12211/2096-8280.2023-099
  CLC： Q819
- Received：01 December 2023，
  
  Revised：2024-03-08，
  
  Published：30 June 2024
- 稿件说明：
移动端阅览
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， 2024， 5（3）： 474-491

SONG Yongxiang， ZHANG Xiufeng， LI Yanqin， XIAO Hua， YAN Yan. Resistance-gene directed discovery of bioactive natural products［J］. Synthetic Biology Journal， 2024， 5（3）： 474-491
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， 2024， 5（3）： 474-491 DOI： 10.12211/2096-8280.2023-099.

SONG Yongxiang， ZHANG Xiufeng， LI Yanqin， XIAO Hua， YAN Yan. Resistance-gene directed discovery of bioactive natural products［J］. Synthetic Biology Journal， 2024， 5（3）： 474-491 DOI： 10.12211/2096-8280.2023-099.

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。本文对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。

Abstract

Natural products play a crucial role as sources of therapeutic agents for human being and agricultural pesticides. With the development of sequencing technologies

genome mining employing various bioinformatic tools has become an important approach for discovering more natural products. Due to the large number of natural product biosynthetic gene clusters

screening those capable of generating the most potent bioactive molecules has gained significance. To avoid self-destruction

some bioactive molecule producers have evolved with self-resistance enzymes

which are slightly mutated versions of original enzymes

but not sensitive to the bioactive compounds. The presence of self-resistance enzymes in the biosynthetic gene cluster of natural products serves as an indicator for the biosynthesis of bioactive compounds. On the other hand

the biosynthetic gene clusters of natural products could be located using information with their structures and activities as probes

. the accumulating knowledge on antibiotic resistance mechanisms has facilitated the discovery of new antibiotics. Moreover

dereplication of natural products with known resistance mechanisms has been achieved by using indicator strains expressing the resistance genes. While these approaches have successfully utilized self-resistance genes to connect molecules with their biological activities

a more impactful application is to accurately link biological activity with genomic information through target-guided mining of natural products. The concept is to use a self-resistance gene as a predictive tool to screen and identify biosynthetic gene clusters encoding compounds that inhibit specific targets. Recent breakthroughs in self-resistance gene ide

ntification have bridged the gap between activity-guided and genome-driven approaches for natural product discovery and functional assignment. This review summarizes progress in bioactive natural product discovery guided by self-resistance genes

as well as its applications

which include the following points: 1) locating biosynthetic gene clusters based on self-resistance genes

2) predicting the targets of secondary metabolites through self-resistance genes

3) rapid dereplication of bioactive compounds with self-resistance mechanisms

4) genome mining of bioactive natural products guided by the target and the internal connection with self-resistance genes

and 5) the development of genome data mining tools directed by self-resistance genes.

关键词

Keywords

references

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