Helmholtz International Lab for Anti-Infectives, Shandong University-Helmholtz Institute of Biotechnology, State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong 266237, PR China; Present address: Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarland University, Campus E8 1, 66123 Saarbrücken, Germany.
Helmholtz International Lab for Anti-Infectives, Shandong University-Helmholtz Institute of Biotechnology, State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong 266237, PR China.
Biotechnol Adv. 2022 Oct;59:107966. doi: 10.1016/j.biotechadv.2022.107966. Epub 2022 Apr 26.
The cryptic secondary metabolite biosynthetic gene clusters (BGCs) far outnumber currently known secondary metabolites. Heterologous production of secondary metabolite BGCs in suitable chassis facilitates yield improvement and discovery of new-to-nature compounds. The two juxtaposed conventional model microorganisms, Escherichia coli, Saccharomyces cerevisiae, have been harnessed as microbial chassis to produce a bounty of secondary metabolites with the help of certain host engineering. In last decade, engineering non-model microbes to efficiently biosynthesize secondary metabolites has received increasing attention due to their peculiar advantages in metabolic networks and/or biosynthesis. The state-of-the-art synthetic biology tools lead the way in operating genetic manipulation in non-model microorganisms for phenotypic optimization or yields improvement of desired secondary metabolites. In this review, we firstly discuss the pros and cons of several model and non-model microbial chassis, as well as the importance of developing broader non-model microorganisms as alternative programmable heterologous hosts to satisfy the desperate needs of biosynthesis study and industrial production. Then we highlight the lately advances in the synthetic biology tools and engineering strategies for optimization of non-model microbial chassis, in particular, the successful applications for efficient heterologous production of multifarious complex secondary metabolites, e.g., polyketides, nonribosomal peptides, as well as ribosomally synthesized and post-translationally modified peptides. Lastly, emphasis is on the perspectives of chassis cells development to access the ideal cell factory in the artificial intelligence-driven genome era.
隐藏的次级代谢生物合成基因簇（BGCs）远远超过目前已知的次级代谢物。在合适的底盘中异源生产次级代谢 BGCs 有助于提高产量和发现新的天然化合物。两个相邻的传统模式微生物，大肠杆菌和酿酒酵母，已经被用作微生物底盘，在某些宿主工程的帮助下，产生了大量的次级代谢物。在过去的十年中，由于其在代谢网络和/或生物合成方面的独特优势，工程非模式微生物来高效生物合成次级代谢物受到了越来越多的关注。最先进的合成生物学工具在非模式微生物中的遗传操作方面处于领先地位，以实现表型优化或所需次级代谢物产量的提高。在这篇综述中，我们首先讨论了几种模式和非模式微生物底盘的优缺点，以及开发更广泛的非模式微生物作为替代可编程异源宿主的重要性，以满足生物合成研究和工业生产的迫切需求。然后，我们重点介绍了非模式微生物底盘优化的合成生物学工具和工程策略的最新进展，特别是在各种复杂次级代谢物（如聚酮、非核糖体肽以及核糖体合成和翻译后修饰肽）的高效异源生产方面的成功应用。最后，重点介绍了底盘细胞开发的前景，以在人工智能驱动的基因组时代获得理想的细胞工厂。
