Nature Biotechnology
Abstract
Pharmaceutically important polyketides such as avermectin are mainly produced as secondary metabolites during the stationary phase of growth ofStreptomycesspecies 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 B1ainStreptomyces coelicolor,Streptomyces venezuelae,Streptomyces rimosusandStreptomyces avermitilis. Application of ddTAG increased the titer of avermectin B1aby 50% to 9.31？g？l？1in a 180-m3industrial-scale fermentation, which is the highest titer ever reported. Our strategy could improve polyketide titers for pharmaceutical production.
| 论文编号: | DOI:10.1038/s41587-019-0335-4 |
| 论文题目: | Harnessing the Intracellular Triacylglycerols for Titer Improvement of Polyketides in Streptomyces |
| 英文论文题目: | Harnessing the Intracellular Triacylglycerols for Titer Improvement of Polyketides in Streptomyces |
| 第一作者: | 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 |
| 英文第一作者: | 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 |
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| 发表年度: | 2020-01-20 |
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| 摘要: | Pharmaceutically important polyketides such as avermectin are mainly produced as secondary metabolites during the stationary phase of growth ofStreptomycesspecies 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 B1ainStreptomyces coelicolor,Streptomyces venezuelae,Streptomyces rimosusandStreptomyces avermitilis. Application of ddTAG increased the titer of avermectin B1aby 50% to 9.31？g？l？1in a 180-m3industrial-scale fermentation, which is the highest titer ever reported. Our strategy could improve polyketide titers for pharmaceutical production. |
| 英文摘要: | Pharmaceutically important polyketides such as avermectin are mainly produced as secondary metabolites during the stationary phase of growth ofStreptomycesspecies 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 B1ainStreptomyces coelicolor,Streptomyces venezuelae,Streptomyces rimosusandStreptomyces avermitilis. Application of ddTAG increased the titer of avermectin B1aby 50% to 9.31？g？l？1in a 180-m3industrial-scale fermentation, which is the highest titer ever reported. Our strategy could improve polyketide titers for pharmaceutical production. |
| 刊物名称: | Nature Biotechnology |
| 英文刊物名称: | Nature Biotechnology |
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| 其它备注: | 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. DOI:10.1038/s41587-019-0335-4 |
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