放线菌聚酮类化合物的合成生物学研究及生物制造

doi:10.16085/j.issn.1000-6613.2020-1906

摘要/Abstract

摘要：

聚酮化合物具有广泛的药用活性和极高的经济价值，但如何高效、经济、绿色、环保地合成聚酮化合物是目前急需解决的问题。随着合成生物学的发展及分子生物学技术的进步，不断有新的技术和策略被用于聚酮化合物的生物制造。本文介绍了聚酮化合物生物制造中的关键酶、前体物质及代谢途径等，分析了通过CRISPR技术及翻译后修饰代谢工程优化代谢调控网络；通过替换及优化启动子等手段改造与优化代谢途径；通过构建简单、高效的异源表达系统等策略提高聚酮化合物的生物制造效率等。在此基础上对红霉素、阿维菌素、多杀菌素的合成生物学研究的最新进展进行了总结，进而对当前聚酮化合物生物制造面临的产量及效率低下等问题和可能的解决途径，如平衡初级代谢与次级代谢，构建新型、优势底盘细胞及代谢网络的重新设计与改造等进行了展望。

关键词: 聚酮, 合成生物学, 前体供应, 代谢途径改造, 制造

Abstract:

Polyketides have wide range of medicinal activities and extremely high economic value, but how to synthesize polyketides efficiently, economically, green, and environmentally friendly remains a problem that needs to be solved urgently. With the development of synthetic biology, new technologies and strategies are constantly being used in the biomanufacturing of polyketides. This article introduces the key enzymes, precursors, and metabolic pathways in the biomanufacturing of polyketides, and analyzes utilizing the CRISPR technology and post-translational modification metabolic engineering to optimize the metabolic regulatory network, remolding and optimizing metabolic pathways by replacing and optimizing promoters, and improving the efficiency of polyketide biomanufacturing and the utilization of carbon sources by exploring strategies such as constructing simple and efficient heterologous expression systems. In addition, the latest research progresses of synthetic biology in erythromycin, abamectin, spinosyn are summarized. Finally, the problems faced by the biosynthesis of polyketides and possible solutions, such as balancing primary metabolism and secondary metabolism, constructing new and dominant chassis cells, and redesigning and remolding metabolic networks are prospected.

Key words: polyketides, synthetic biology, precursor supply, metabolic pathway modification, manufacture

中图分类号:

Q935

刘卫兵, 叶邦策. 放线菌聚酮类化合物的合成生物学研究及生物制造[J]. 化工进展, 2021, 40(3): 1226-1237.

LIU Weibing, YE Bangce. Progress of synthetic biology research and biological manufacturing of actinomycetes polyketides[J]. Chemical Industry and Engineering Progress, 2021, 40(3): 1226-1237.

图/表 8

图1 三类PKS催化的代表性反应

图2 不同微生物合成的丙二酰辅酶A衍生产物

图3 酰基辅酶A前体供应与酰基化供体对酰基辅酶A合成天然产物的功能相互作用[50]

图4 GlnR和PhoP介导的糖多孢红霉菌中初级代谢与红霉素生物合成之间的交叉调控

图5 解脂耶氏酵母TAL合成代谢途径

图6 聚酮生物合成中PKS途径与PKT途径的比较

图7 PTM-ME应用促进红霉素的高效合成

图8 ddTAG策略在阿维菌素B1a生物制造中的应用

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