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中国科学家利用TAG提高链霉菌中多酮的效价
2019-12-10 15:01

华东理工大学张立新、中国科学院微生物研究所王为善,和中国农业科学院向文胜团队合作,利用细胞内三酰基甘油(TAG)提高链霉菌多酮的效价。2019年12月9日,《自然—生物技术》在线发表了这一成果。

研究人员应用多组学技术揭示了在初次代谢中积累的细胞内TAG在稳定期会降解。该过程可以将碳流量从细胞内TAG和细胞外底物引导到多酮的生物合成中。他们设计了一种名为“ TAG的动态降解”(ddTAG)的策略,以动员TAG池并增加多酮的生物合成。使用ddTAG,提高了天蓝色链霉菌、委内链霉菌、缘条链霉菌和阿维链霉菌中放线菌素、佳霉素B、土霉素和阿维菌素B1a的效价。ddTAG的应用在180立方米工业规模发酵中将阿维菌素B1a的效价提高了50%,达到9.31 gl−1,这是有史以来最高的效价。他们的策略可以提高药物生产中的多酮效价。

据了解,制药上重要的多酮(如阿维菌素)主要在发酵罐中链霉菌属菌种生长的稳定期以次级代谢产物的形式产生。已经证明,进入多酮生物合成的细胞内代谢物来源难以确定。

附:英文原文

Title: Harnessing the intracellular triacylglycerols for titer improvement of polyketides in Streptomyces

Author: Weishan Wang, Shanshan Li, Zilong Li, Jingyu Zhang, Keqiang Fan, Gaoyi Tan, Guomin Ai, Sin Man Lam, Guanghou Shui, Zhiheng Yang, Hongzhong Lu, Pinjiao Jin, Yihong Li, Xiangyin Chen, Xuekui Xia, Xueting Liu, H. Kathleen Dannelly, Chen Yang, Yi Yang, Siliang Zhang, Gil Alterovitz, Wensheng Xiang, Lixin Zhang

Issue&Volume: 2019-12-09

Abstract: Pharmaceutically important polyketides such as avermectin are mainly produced as secondary metabolites during the stationary phase of growth of Streptomyces species in fermenters. The source of intracellular metabolites that are funneled into polyketide biosynthesis has proven elusive. We applied multi-omics to reveal that intracellular triacylglycerols (TAGs), which accumulates in primary metabolism, are degraded during stationary phase. This process could channel carbon flux from both intracellular TAGs and extracellular substrates into polyketide biosynthesis. We devised a strategy named ‘dynamic degradation of TAG’ (ddTAG) to mobilize the TAG pool and increase polyketide biosynthesis. Using ddTAG we increased the titers of actinorhodin, jadomycin B, oxytetracycline and avermectin B1a in Streptomyces coelicolor, Streptomyces venezuelae, Streptomyces rimosus and Streptomyces avermitilis. Application of ddTAG increased the titer of avermectin B1a by 50% to 9.31 g l−1 in a 180-m3 industrial-scale fermentation, which is the highest titer ever reported. Our strategy could improve polyketide titers for pharmaceutical production.

DOI: 10.1038/s41587-019-0335-4

Source: https://www.nature.com/articles/s41587-019-0335-4

Nature Biotechnology:《自然—生物技术》,创刊于1996年。隶属于施普林格·自然出版集团,最新IF:31.864
官方网址:https://www.nature.com/nbt/
投稿链接:https://mts-nbt.nature.com/cgi-bin/main.plex


本期文章:《自然—生物技术》:Online/在线发表

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