Harnessing the intracellular triacylglycerols for titer improvement of polyketides in Streptomyces.

Nature biotechnology 2020 Jan

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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.

Citation

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. Harnessing the intracellular triacylglycerols for titer improvement of polyketides in Streptomyces. Nature biotechnology. 2020 Jan;38(1):76-83