虫生真菌非核糖体多肽活性产物生物合成潜力预测

张礼文; István MOLNÁR; 徐玉泉

doi:10.12211/2096-8280.2021-005

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虫生真菌非核糖体多肽活性产物生物合成潜力预测

研究论文 | 更新时间：2026-03-18

- 虫生真菌非核糖体多肽活性产物生物合成潜力预测
- Potential biosynthesis of nonribosomal peptides by hypocrealean entomopathogenic fungi
- 合成生物学 2021年2卷第5期页码：815-825
- 作者机构：
  
  1.中国农业科学院生物技术研究所，北京 100081
  2.美国亚利桑那大学西南天然产物研究中心，亚利桑那州图森 85706，美国
- 作者简介：
  
  张礼文（1985—），女，副研究员。研究方向为从真菌中挖掘具有农用生物活性的次生代谢产物及其合成基因元件，再用于组合生物合成新骨架、改进活性的化合物。
  István Molnár（1963—），男，研究员，博士生导师。研究方向为真菌天然产物生物合成与组合合成生物学。
  徐玉泉（1971—），男，研究员，博士生导师。研究方向为发现真菌合成的新型生物活性天然产物，阐明其生物合成机制，利用合成生物学的方法对目标产物进行高效生物合成及结构修饰。
- 基金信息：
  
  国家自然科学基金(32070064;31870076;32070053);中国农业科学院基本科研业务费专项(Y2020XK20);中国农业科学院科技创新工程
- DOI：10.12211/2096-8280.2021-005
  中图分类号： Q74
- 收稿：2021-01-12，
  
  修回：2021-04-16，
  
  纸质出版：2021-10-31
- 稿件说明：
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张礼文， István MOLNÁR，徐玉泉. 虫生真菌非核糖体多肽活性产物生物合成潜力预测［J］. 合成生物学， 2021， 2（5）： 815-825

ZHANG Liwen， István MOLNÀR， XU Yuquan. Potential biosynthesis of nonribosomal peptides by hypocrealean entomopathogenic fungi［J］. Synthetic Biology Journal， 2021， 2（5）： 815-825
张礼文， István MOLNÁR，徐玉泉. 虫生真菌非核糖体多肽活性产物生物合成潜力预测［J］. 合成生物学， 2021， 2（5）： 815-825 DOI： 10.12211/2096-8280.2021-005.

ZHANG Liwen， István MOLNÀR， XU Yuquan. Potential biosynthesis of nonribosomal peptides by hypocrealean entomopathogenic fungi［J］. Synthetic Biology Journal， 2021， 2（5）： 815-825 DOI： 10.12211/2096-8280.2021-005.

摘要

肉座菌目虫生真菌合成的非核糖体多肽类天然产物具有抗菌、杀虫、抗癌、调节免疫等生物活性，在临床和农业等领域有重要应用价值。近年来，随着真菌基因组测序数量的迅速增加、注释和分析工具的不断进步，人们发现真菌基因组中存在大量产物未知的天然产物合成基因。准确有效地预测这些基因的功能，筛选最有潜力合成新颖天然产物的基因簇，可以提高天然产物挖掘的效率。本研究选取40株肉座菌目虫生真菌基因组，系统分析了编码非核糖体多肽合成酶的基因及基因簇。基于隐马尔可夫模型，预测了445个模块型非核糖体多肽合成酶和1243个类非核糖体多肽合成酶；通过提取腺苷酰化结构域，构建序列相似性网络，以已知功能的非核糖体多肽合成酶作为标签，利用马尔可夫聚类算法，分析了非核糖体多肽产物的主要类别，发现了可能合成线性多肽、环缩肽、脂多肽、生物碱等新型结构化合物的基因簇。研究结果不仅揭示了肉座菌目虫生真菌合成非核糖体多肽活性产物的巨大潜力，而且为通过激活沉默基因簇挖掘新产物、利用合成生物学手段改造合成途径提供参考。

Abstract

Nonribosomal peptide natural products synthesized by Hypocrealean entomopathogenic fungi have antibacterial

insecticidal

anticancer

immunomodulatory and other biological activities

with high potential for application in clinical or agricultural fields. These bi

oactive compounds are synthesized by nonribosomal peptide synthetases (NRPSs) and tailored by additional enzymes that are encoded by clustered genes. In addition to the 20 amino acids

non-canonical amino acids as well as

-hydroxy acids can also be incorporated into nonribosomal peptides as structural units

and these

together with further modifications

empower an almost unlimited structural diversity. The rapid increase in the number of sequenced fungal genomes shows that there exists a large number of nonribosomal peptide biosynthetic gene clusters with unknown functions. Accurate and effective prediction of the functions of these "orphan" biosynthetic gene clusters can help to select those clusters that have potential to synthesize novel natural products

and increase the efficiency of natural product genome mining. In this study

we systematically analyzed the genes encoding NRPSs and their gene clusters in the genomes of 40 strains from Hypocrealean entomopathogenic fungi. Genes encoding NRPSs were predicted and categorized based on the hidden Markov models for adenylation

condensation and thiolation domains to reveal 445 modular NRPSs and 1243 NRPS-like proteins. A sequence similarity network based on the amino acid sequences of adenylation domains of these synthetases was constructed. Using adenylation domains from known NRPSs as references

we analyzed the main categories of predicted nonribosomal peptide products using the Markov clustering algorithm. We identified several biosynthetic gene clusters that potentially yield known bioactive compounds or their congeners. In addition

biosynthetic gene clusters that may be able to produce new bioactive compounds belonging to the linear peptide

cyclic peptide

lipopeptide

and alkaloid structural classes were also discovered. The results reveal a great potential of Hypocrealean entomopathogenic fungi to synthesize nonribosomal peptides

and provide insight for genome mining to identify new products by activating silent gene clusters or mo

difying biosynthetic pathways by synthetic biology methods.

关键词

Keywords

references

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