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Heterologous expression of oxytetracycline biosynthetic gene cluster in Streptomyces venezuelae WVR2006 to improve production level and to alter fermentation process

  • Applied genetics and molecular biotechnology
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Abstract

Heterologous expression is an important strategy to activate biosynthetic gene clusters of secondary metabolites. Here, it is employed to activate and manipulate the oxytetracycline (OTC) gene cluster and to alter OTC fermentation process. To achieve these goals, a fast-growing heterologous host Streptomyces venezuelae WVR2006 was rationally selected among several potential hosts. It shows rapid and dispersed growth and intrinsic high resistance to OTC. By manipulating the expression of two cluster-situated regulators (CSR) OtcR and OtrR and precursor supply, the OTC production level was significantly increased in this heterologous host from 75 to 431 mg/l only in 48 h, a level comparable to the native producer Streptomyces rimosus M4018 in 8 days. This work shows that S. venezuelae WVR2006 is a promising chassis for the production of secondary metabolites, and the engineered heterologous OTC producer has the potential to completely alter the fermentation process of OTC production.

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Acknowledgments

The authors wish to thank Prof. Meijin Guo (East China University of Science and Technology) for providing S. rimosus M4018. This work was supported by funding from Shengxue Dacheng Pharmaceutical Co., Ltd., the National Natural Science Foundation of China (Grant Nos. 31400034 and 31570031) and the Ministry of Science and Technology of China (Grant No. 2013CB734001). Weishan Wang is an awardee of Youth Innovation Promotion Association of CAS [92016087]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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  1. State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Chaoyang District, Beijing, 100101, People’s Republic of China

    Shouliang Yin, Zilong Li, Guomin Ai, Zishang Bai, Mingxin Shi, Weishan Wang & Keqian Yang

  2. Shengxue Dacheng Pharmaceutical Co., Ltd., Shijiazhuang, 051430, Hebei, People’s Republic of China

    Xuefeng Wang, Huizhuan Wang, Xiaole Jia, Fang Yuan & Tiejun Liu

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  1. Shouliang Yin
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  2. Zilong Li
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Correspondence to Weishan Wang or Keqian Yang.

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Shouliang Yin and Zilong Li contributed equally to this work.

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Yin, S., Li, Z., Wang, X. et al. Heterologous expression of oxytetracycline biosynthetic gene cluster in Streptomyces venezuelae WVR2006 to improve production level and to alter fermentation process. Appl Microbiol Biotechnol 100, 10563–10572 (2016). https://doi.org/10.1007/s00253-016-7873-1

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