Journal
APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
Volume 100, Issue 24, Pages 10563-10572Publisher
SPRINGER
DOI: 10.1007/s00253-016-7873-1
Keywords
Oxytetracycline; Biosynthetic gene cluster; Heterologous expression; Metabolic engineering; Streptomyces venezuelae; Fermentation process
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Funding
- Shengxue Dacheng Pharmaceutical Co., Ltd.
- National Natural Science Foundation of China [31400034, 31570031]
- Ministry of Science and Technology of China [2013CB734001]
- Youth Innovation Promotion Association of CAS [92016087]
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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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