Reassembly of the Biosynthetic Gene Cluster Enables High Epothilone Yield in Engineered Schlegelella brevitalea

文献类型： 外文期刊

第一作者： Yu, Yucong

作者： Yu, Yucong;Wang, Huimin;Tang, Biao;Liang, Junheng;Zhang, Lin;Zhao, Guo-ping;Ding, Xiaoming;Tang, Biao;Wang, Hongkuan;Wang, Hongkuan;Bian, Xiaoying;Li, Yue-zhong;Zhang, Youming;Zhao, Guo-ping

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关键词： Schlegelella brevitalea; biosynthetic gene cluster; epothilone; metabolic engineering; NRP/PK

期刊名称：ACS SYNTHETIC BIOLOGY （ 影响因子：5.11； 五年影响因子：5.239 ）

ISSN： 2161-5063

年卷期： 2020 年 9 卷 8 期

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收录情况： SCI

摘要： Epothilones, as a new class of microtubule-stabilizing anticancer drugs, exhibit strong bioactivity against taxane-resistant cells and show clinical activity for the treatment of advanced breast cancer. Additionally, they also show great potential for a central nervous system injury and Alzheimer's disease. However, due to the long fermentation period of the original producer and challenges of genetic engineering of nonribosomal peptide/polyketide (NRP/PK) megasynthase genes, the application of epothilones is severely limited. Here, we addressed these problems by reassembling a novel 56-kb epothilone biosynthetic gene cluster, optimizing the promoter of each gene based on RNA-seq profiling, aionyi and completing precursor synthetic pathways in engineered Schlegella epi lathv brevitalea. Furthermore, we debottlenecked the cell autolysis by mats optimizing culture conditions. Finally, the yield of epothilones in shake flasks was improved to 82 mg/L in six-day fermentation. Overall, we not only constructed epothilone overproducers for further drug development but also provided a rational strategy for high-level NRP/PK compound production.

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