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Nat Biotechnol. 2020 Jan;38(1):76-83. doi: 10.1038/s41587-019-0335-4. Epub 2019 Dec 9.

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

Author information

1
State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China. wangws@im.ac.cn.
2
State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China. wangws@im.ac.cn.
3
State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, China.
4
State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
5
State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China.
6
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
7
Key Biosensor Laboratory of Shandong Province, Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China.
8
Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
9
Indiana State University, Terre Haute, IN, USA.
10
CAS-Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai, China.
11
Boston Children's Hospital, Boston, MA, USA.
12
State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, China. xiangwensheng@neau.edu.cn.
13
State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China. lxzhang@ecust.edu.cn.

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.

PMID:
31819261
DOI:
10.1038/s41587-019-0335-4

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