title: Heterologous expression of oxytetracycline biosynthetic gene cluster in Streptomyces venezuelae WVR2006 to improve production level and to alter fermentation process.
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.
authors.affiliation: State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Chaoyang District, Beijing, 100101, People's Republic of China.
authors.forename: Shouliang
authors.initials: S
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Chaoyang District, Beijing, 100101, People's Republic of China.
authors.forename: Zilong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Shengxue Dacheng Pharmaceutical Co., Ltd., Shijiazhuang, 051430, Hebei, People's Republic of China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wang
authors.affiliation: Shengxue Dacheng Pharmaceutical Co., Ltd., Shijiazhuang, 051430, Hebei, People's Republic of China.
authors.forename: Huizhuan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Shengxue Dacheng Pharmaceutical Co., Ltd., Shijiazhuang, 051430, Hebei, People's Republic of China.
authors.forename: Xiaole
authors.initials: X
authors.lastname: Jia
authors.affiliation: State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Chaoyang District, Beijing, 100101, People's Republic of China.
authors.forename: Guomin
authors.initials: G
authors.lastname: Ai
authors.affiliation: State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Chaoyang District, Beijing, 100101, People's Republic of China.
authors.forename: Zishang
authors.initials: Z
authors.lastname: Bai
authors.affiliation: State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Chaoyang District, Beijing, 100101, People's Republic of China.
authors.forename: Mingxin
authors.initials: M
authors.lastname: Shi
authors.affiliation: Shengxue Dacheng Pharmaceutical Co., Ltd., Shijiazhuang, 051430, Hebei, People's Republic of China.
authors.forename: Fang
authors.initials: F
authors.lastname: Yuan
authors.affiliation: Shengxue Dacheng Pharmaceutical Co., Ltd., Shijiazhuang, 051430, Hebei, People's Republic of China.
authors.forename: Tiejun
authors.initials: T
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Chaoyang District, Beijing, 100101, People's Republic of China. wangws@im.ac.cn.
authors.forename: Weishan
authors.initials: W
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Chaoyang District, Beijing, 100101, People's Republic of China. yangkq@im.ac.cn.
authors.forename: Keqian
authors.identifier: http://orcid.org/0000-0001-5203-7938
authors.initials: K
authors.lastname: Yang
mesh_terms: D000900:Anti-Bacterial Agents / Q000096:biosynthesis*; D053898:Biosynthetic Pathways / Q000235:genetics*; D003001:Cloning, Molecular; D024881:Drug Resistance, Bacterial; D005285:Fermentation; D015870:Gene Expression; D060847:Metabolic Engineering; D005810:Multigene Family; D010118:Oxytetracycline / Q000096:biosynthesis*; D013302:Streptomyces / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D010118:Oxytetracycline
keywords: Biosynthetic gene cluster; Fermentation process; Heterologous expression; Metabolic engineering; Oxytetracycline; Streptomyces venezuelae