Shiwen Qiu , Bowen Yang , Zilong Li , Shanshan Li , Hao Yan , Zhenguo Xin , Jingfang Liu , Xuejin Zhao , Lixin Zhang , Wensheng Xiang , Weishan Wang
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引用次数: 0
摘要
链霉菌有大量具有生物活性的次级代谢产物(SMs)。然而,设计一个异源生产这些次生代谢物的框架仍然具有挑战性。在此,我们对多功能即插即用链霉菌超级底盘进行了重新编程,并通过了解乙醇休克对委内瑞拉链霉菌生产玹霉素的固有多效性影响,建立了生产多种 SMs 的通用管道。我们初步确定并表征了一组多重靶标(afsQ1、bldD、bldA 和 miaA),这些靶标在乙醇休克时有助于 SM(贾多霉素)的产生。随后,我们开发了乙醇诱导正交扩增系统(EOAS),实现了对靶标的动态精确控制。最终,我们将这些多重目标整合到由 EOAS 控制的功能单元中,生成了一个通用的、即插即用的链霉菌超级底盘。除了获得了前所未有的金刚霉素 B 的滴度和产量,我们还证明了这种超级底盘在生产多种异源 SM 方面的潜力,包括抗生素土霉素、抗癌药物多柔比星、农用除草剂泰克多明 A 和植物生长调节剂古维菌素,所有这些在简单的矿物培养基中的产量都达到了 10 毫克/克葡萄糖。鉴于SMs的生产都需要复合培养基,而且同源物的产量通常要低得多,我们在简单矿物培养基中使用通用超级底盘和工程流水线的成果为方便异源生产SMs带来了希望。
Building a highly efficient Streptomyces super-chassis for secondary metabolite production by reprogramming naturally-evolved multifaceted shifts
Streptomyces has an extensive array of bioactive secondary metabolites (SMs). Nevertheless, devising a framework for the heterologous production of these SMs remains challenging. We here reprogrammed a versatile plug-and-play Streptomyces super-chassis and established a universal pipeline for production of diverse SMs via understanding of the inherent pleiotropic effects of ethanol shock on jadomycin production in Streptomyces venezuelae. We initially identified and characterized a set of multiplex targets (afsQ1, bldD, bldA, and miaA) that contribute to SM (jadomycin) production when subjected to ethanol shock. Subsequently, we developed an ethanol-induced orthogonal amplification system (EOAS), enabling dynamic and precise control over targets. Ultimately, we integrated these multiplex targets into functional units governed by the EOAS, generating a universal and plug-and-play Streptomyces super-chassis. In addition to achieving the unprecedented titer and yield of jadomycin B, we also evidenced the potential of this super-chassis for production of diverse heterologous SMs, including antibiotic oxytetracycline, anticancer drug doxorubicins, agricultural herbicide thaxtomin A, and plant growth regulator guvermectin, all with the yields of >10 mg/g glucose in a simple mineral medium. Given that the production of SMs all required complexed medium and the cognate yields were usually much lower, our achievement of using a universal super-chassis and engineering pipeline in a simple mineral medium is promising for convenient heterologous production of SMs.
期刊介绍:
Metabolic Engineering (MBE) is a journal that focuses on publishing original research papers on the directed modulation of metabolic pathways for metabolite overproduction or the enhancement of cellular properties. It welcomes papers that describe the engineering of native pathways and the synthesis of heterologous pathways to convert microorganisms into microbial cell factories. The journal covers experimental, computational, and modeling approaches for understanding metabolic pathways and manipulating them through genetic, media, or environmental means. Effective exploration of metabolic pathways necessitates the use of molecular biology and biochemistry methods, as well as engineering techniques for modeling and data analysis. MBE serves as a platform for interdisciplinary research in fields such as biochemistry, molecular biology, applied microbiology, cellular physiology, cellular nutrition in health and disease, and biochemical engineering. The journal publishes various types of papers, including original research papers and review papers. It is indexed and abstracted in databases such as Scopus, Embase, EMBiology, Current Contents - Life Sciences and Clinical Medicine, Science Citation Index, PubMed/Medline, CAS and Biotechnology Citation Index.