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中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志
中国生物工程杂志  2022, Vol. 42 Issue (6): 86-101    DOI: 10.13523/j.cb.2201015
综述     
合成生物学指导下芽孢杆菌合成环脂肽的研究进展*
靳佳琦,闻建平()
天津大学化工学院 系统生物工程教育部重点实验室 天津 300072
Research Progress of Cyclic Lipopeptides Synthesized by Bacillus under the Guidance of Synthetic Biology
JIN Jia-qi,WEN Jian-ping()
Key Laboratory of Systems Bioengineering of Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China
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摘要：

近年来,合成生物学借助工程化在人工生命系统的设计与构建方面取得了长足进展,特别是“细胞工厂”的开发和应用为天然产物的合成带来了深刻变革。环脂肽是一类新型的天然表面活性剂,因其特殊的结构和功能亦可作为抗生素使用。目前,合成环脂肽最理想的微生物底盘是芽孢杆菌。因此,许多研究者致力于通过合成生物学技术来提升芽孢杆菌作为环脂肽细胞工厂的性能。首先,对芽孢杆菌中环脂肽的非核糖体肽合成途径进行概述;其次,重点介绍与环脂肽合成相关的调控因子;再次,从底盘细胞的选择、基因编辑工具的开发、合成路径的优化及发酵过程的优化等四个方面对合成生物学指导下环脂肽的相关研究进展进行总结;最后,讨论环脂肽合成中可能存在的挑战,并就未来研究趋势进行展望,以期为高效环脂肽细胞工厂的开发提供参考。
关键词： 环脂肽;  非核糖体肽合成途径;  调控因子;  合成路径优化;  发酵过程优化    
Abstract:

In recent years, synthetic biology has made great progress in the design and construction of artificial life systems with the help of engineering ideas. In particular, the development and application of “cell factories” have brought profound changes to the synthesis of natural products. Cyclic lipopeptides are new natural surfactants. They can also be used as antibiotics because of their special structures and functions. At present, Bacillus are the most ideal microbial chassis for cyclic lipopeptides synthesis. Therefore, many researchers are devoted to improving the performance of Bacillus as cyclic lipopeptides cell factories through synthetic biology techniques. In this paper, the non-ribosomal peptide synthesis pathway of cyclic lipopeptides synthesized by Bacillus is first reviewed. Second, the regulatory factors related to the synthesis of cyclic lipopeptides are introduced. Third, the research progress of cyclic lipopeptides synthesis under the guidance of synthetic biology are summarized from the aspects including the selection of chassis cells, the development of gene editing tools, the optimization of synthesis pathway and the optimization of fermentation process. Finally, the possible challenges in cyclic lipopeptides synthesis are discussed and the future research trends are prospected. These will provide reference for the development of efficient cyclic lipopeptides cell factories.
Key words: Cyclic lipopeptides    Non-ribosomal peptide synthesis pathway    Regulatory factors    Synthesis pathway optimization    Fermentation process optimization
收稿日期: 2022-01-13 出版日期: 2022-07-07
ZTFLH:  Q939  
基金资助: *国家重点研发计划(2018YFA0902201)
通讯作者: 闻建平     E-mail: jpwen@tju.edu.cn
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引用本文:

靳佳琦,闻建平. 合成生物学指导下芽孢杆菌合成环脂肽的研究进展*[J]. 中国生物工程杂志, 2022, 42(6): 86-101.

JIN Jia-qi,WEN Jian-ping. Research Progress of Cyclic Lipopeptides Synthesized by Bacillus under the Guidance of Synthetic Biology. China Biotechnology, 2022, 42(6): 86-101.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.2201015    或    https://manu60.magtech.com.cn/biotech/CN/Y2022/V42/I6/86

图1  环脂肽家族分类
图2  肽链延伸机制及丰原素的生物合成过程[36-37]
图3  环脂肽合成的关键调控因子[28,51⇓-53]
底盘细胞 环脂肽 参考文献
B. subtilis EA-CB0015 表面活性素、伊枯草菌素、丰原素 [7]
B. subtilis BBK-1 表面活性素、杆菌抗霉素L、制磷脂菌素 [80]
B. subtilis S499 表面活性素、伊枯草菌素、丰原素 [81]
B. subtilis pB2-L 表面活性素、制磷脂菌素 [82]
B. subtilis ATCC21332 表面活性素、丰原素 [83]
B. subtilis B3 丰原素、伊枯草菌素 [84]
B. subtilis THY-7 表面活性素 [85]
B. subtilis DSM7T 表面活性素 [86]
B. subtilis MT45 表面活性素 [87]
B. subtilis fmbJ 丰原素 [88]
B. subtilis NCD-2 丰原素 [89]
B. velezensis P45 表面活性素、伊枯草菌素、丰原素 [90]
B. velezensis BA-26 表面活性素、伊枯草菌素 [91]
B. amyloliquefaciens fmbJ 表面活性素、杆菌抗霉素D、丰原素 [60]
B. amyloliquefaciens FZB42 表面活性素、杆菌抗霉素D、丰原素 [92]
B. amyloliquefaciens BC32-1 表面活性素、伊枯草菌素、丰原素 [93]
B. amyloliquefaciens C06 杆菌抗霉素D、丰原素 [94]
B. amyloliquefaciens fmb-60 丰原素 [95]
B. amyloliquefaciens BA-16-8 丰原素 [96]
B. pumilus HY1 表面活性素 [97]
表1  芽孢杆菌底盘细胞及其合成的环脂肽类型
基因编辑工具 原理 步骤 主要特点 应用
Cre/loxP(Cre/
loxP重组技术)		 Cre重组酶介导两个loxP位点间的特异性重组 宿主范围广、特异性强、效率高;但是需要引入识别位点 基因敲除、激活和易位;loxP位点的突变可实现多基因敲除
TALEN(类转录激活因子效应物核酸酶技术) TALE识别并结合目标序列,Fok I发挥切割活性,诱发DNA损伤修复机制 同源重组频率高,遗传稳定性好,基因改造效率高,可实现无标记敲除;但工具载体不易构建,多基因敲除存在挑战 基因的敲除、转录与修饰
CRISPR(规律间隔成簇短回文重复序列编辑技术) sgRNA引导Cas9或dCas9对靶位点切割,从而实现基因定向编辑 稳定性、特异性、生物编辑性良好,可同时敲除多个靶基因;但存在修复机制的差异与脱靶效应 基因敲除、插入、激活与抑制
Red/ET(Red/ET重组技术) λ噬菌体Red操纵子和Rac噬菌体RecE/RecT系统介导的DNA同源重组 所需同源序列短,突变率低,无限制性内切酶位点限制和DNA大小限制;但操作复杂 细菌人工染色体长片段基因的克隆、亚克隆及快速修饰
GenomeShuffling(基因组改组
技术)		 递推式原生质体融合实现亲本基因的重组 不受种属限制,对微生物的快速改良无需清晰的遗传背景要求,在应用方面克服了“转基因生物”的限制;高通量筛选方法的建立比较复杂 激活沉默基因;获得理想的微生物表型
表2  常用的基因编辑工具
图4  环脂肽合成的路径模块优化[104]
环脂肽 底盘细胞 启动子改造 产量 参考文献
表面活性素 B.subtilis fmbR Pspac替换PsrfA 3.87 g/L [116]
B. subtilis 3A38 Pveg替换PsrfA 0.26 g/L [106]
B. subtilis THY-7 Pg3替换PsrfA 9.74 g/L [109]
B. subtilis MG13 PnasD替换PsrfA 0.696 g/L [114]
B. amyloliquefaciens GR167IDS PRsuc替换PsrfA 0.322 g/L [98]
丰原素 B. subtilis 2508 PamyQ替换Ppps 0.434 g/L [117]
B. subtilis BMG03 PrepU替换Ppps 0.507 g/L [118]
B. subtilis BBG203 Pfen替换Ppps 增加了10倍 [108]
B. subtilis BMV11 Pveg替换Ppps 0.07 g/L [119]
伊枯草菌素 B. subtilis RB14 PrepU替换Pitu 增加了3倍 [120]
B. amyloliquefaciens HZ-12 PbacA替换Pitu 0.950 g/L [48]
B. amyloliquefaciens C2LP C2up替换Pitu 0.037 g/L [107]
表3  优化环脂肽合成的启动子改造策略
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