放线菌聚酮类化合物生物合成体系重构研究进展  

An overview on reconstructing the biosynthetic system of actinomycetes for polyketides production

作　　者：谢皇 郑义蕾 苏依婷 阮静怡 李永泉[1,2] XIE Huang;ZHENG Yilei;SU Yiting;RUAN Jingyi;LI Yongquan(Institute of Pharmaceutical Biotechnology,Zhejiang University,Hangzhou 310058,Zhejiang,China;Zhejiang Provincial Key Laboratory for Microbial Biochemistry and Metabolic Engineering,Hangzhou 310058,Zhejiang,China)

机构地区：[1]浙江大学药物生物技术研究所,浙江杭州310058 [2]浙江省微生物生化与代谢工程重点实验室,浙江杭州310058

出　　处：《合成生物学》2024年第3期612-630,共19页Synthetic Biology Journal

基　　金：国家自然科学基金(32170057);国家重点研发计划(2019YFA09005400)。

摘　　要：放线菌因其丰富的次级代谢产物而成为候选药物发掘的宝贵资源库,其蕴含的活性化合物包含聚酮类、非核糖体肽类、氨基糖苷类、萜类等,其中聚酮类化合物占比最大。大环内酯是聚酮类化合物的典型,常常被用作抗生素、抗肿瘤剂、免疫抑制剂、抗寄生虫剂等,具有重要的生物学意义。本文立足聚酮类大环内酯的生物合成过程,提出了从基因组重塑、调控通路重组、组合代谢工程及聚酮类化合物结构的衍生与多样化等多角度,实现放线菌聚酮类生物合成体系的优化,为工业规模生产聚酮类药物及其新型衍生物提供技术支撑。通过这种多维度的方法,结合最新的合成生物学使能技术,遵循绿色、环保、高效和可持续的策略,可以更有效地优化和增强放线菌中聚酮类化合物的生产,为未来药物的开发和生产提供新的可能性。Actinomycetes,enriched with secondary metabolites,have emerged as a resource for drug discovery.These organisms predominantly harbor bioactive compounds such as polyketides,non-ribosomal peptides,aminoglycosides,and terpenes,with polyketides representing the most diverse class.Polyketides are divided into three major categories based on polyketide synthase:typeⅠ,typeⅡ,and typeⅢ,in which typeⅠpolyketides are most widely distributed and abundant,with macrocyclic lactone compounds serving as their archetypal representatives.Macrocyclic lactone compounds,frequently utilized as antibiotics,anti-cancer agents,immunosuppressants,and antiparasitic agents,hold immense biological significance.This review comments the biosynthetic process of macrolides,and strategies for biosynthesizing actinomycete polyketides are proposed,which encompass genome remodeling,regulatory pathway recombination,combinatorial metabolic engineering,and the modifications of polyketide structures.By knocking out competing gene clusters and superfluous genomic islands,augmenting the supply of precursors,and enhancing precursor supply and lipid stream processing,researchers can obtain genome minimized and optimized industrial chassis,followed with manipulations such as promoter engineering,regulatory factor engineering,overexpression of the rate-limiting enzyme genes,enhanced substrate transport and tolerance,targeted modifications of the key enzymes,rational design of polyketides,etc.Furthermore,the optimized chassis and biosynthetic gene clusters are integrated to develop robust strains for multi-omics analyses and fermentation process optimization,which can be guided by rapidly developed synthetic biology enabling technologies and artificial intelligence,to develop a high-quality,efficient polyketides biosynthesis system.These advancements can offer robust technical support for the large-scale production of polyketides pharmaceuticals and their derivatives.

关 键 词：放线菌 聚酮 菌种重构 产量 代谢工程 合成生物学 

分 类 号：Q939.97[生物学—微生物学]