Journal Article

Harnessing the intracellular triacylglycerols for titer improvement of polyketides in Streptomyces

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

2020

Overview

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 B 1a in Streptomyces coelicolor , Streptomyces venezuelae , Streptomyces rimosus and Streptomyces avermitilis . Application of ddTAG increased the titer of avermectin B 1a by 50% to 9.31 g l −1 in a 180-m 3 industrial-scale fermentation, which is the highest titer ever reported. Our strategy could improve polyketide titers for pharmaceutical production. Polyketide yields in Streptomyces are boosted by routing stored intracellular triacylglycerol into pathways that make industrially relevant products.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/326/252/318 / 631/326/2522 / 631/553/318 / 631/61/318 / Actinorhodin / Agriculture / Amino acids / Avermectin / Bioinformatics / Biomedical and Life Sciences / Biomedical Engineering/Biotechnology / Biomedicine / Biosynthesis / Biotechnology / Carbon - metabolism / Fermentation / Fermenters / Intracellular / Intracellular Space - metabolism / Life Sciences / Metabolic Flux Analysis / Metabolic Networks and Pathways / Metabolites / Metabolome / Oxytetracycline / Physiological aspects / Plant metabolites / Polyketides / Polyketides - metabolism / Secondary metabolites / Stationary phase / Streptomyces / Streptomyces - metabolism / Substrates / Tags / Time Factors / Triglycerides / Triglycerides - metabolism