title: FkbN and Tcs7 are pathway-specific regulators of the FK506 biosynthetic gene cluster in Streptomyces tsukubaensis L19.
abstract: FK506 (tacrolimus), which is produced by many Streptomyces strains, is clinically used as an immunosuppressive agent and for treatment of inflammatory skin diseases. Here, we identified that the FK506 biosynthetic gene cluster in an industrial FK506-producing strain Streptomyces tsukubaensis L19 is organized as eight transcription units. Two pathway-specific regulators, FkbN and Tcs7, involved in FK506 biosynthesis from S. tsukubaensis L19 were characterized in vivo and in vitro. FkbN activates the transcription of six transcription units in FK506 biosynthetic gene cluster, and Tcs7 activates the transcription of fkbN. In addition, the DNA-binding specificity of FkbN was determined. Finally, a high FK506-producing strain was constructed by overexpression of both fkbN and tcs7 in S. tsukubaensis L19, which improved FK506 production by 89 % compared to the parental strain.
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
authors.forename: Xiao-Sheng
authors.initials: XS
authors.lastname: Zhang
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
authors.forename: Hong-Dou
authors.initials: HD
authors.lastname: Luo
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Tao
authors.affiliation: School of Life Sciences, Fudan University, Shanghai, 200438, China.
authors.forename: Yue-Yue
authors.initials: YY
authors.lastname: Wang
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
authors.forename: Xin-Hang
authors.initials: XH
authors.lastname: Jiang
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China. jianghuisioc@zju.edu.cn.
authors.forename: Hui
authors.initials: H
authors.lastname: Jiang
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China. lyq@zju.edu.cn.|Zhejiang Provincial Key Laboratory for Microbial Biochemistry and Metabolism Engineering, Hangzhou, 310058, Zhejiang, China. lyq@zju.edu.cn.
authors.forename: Yong-Quan
authors.initials: YQ
authors.lastname: Li
mesh_terms: D001426:Bacterial Proteins / Q000502:physiology*; D019149:Bioreactors; D053898:Biosynthetic Pathways; D015964:Gene Expression Regulation, Bacterial; D007166:Immunosuppressive Agents / Q000378:metabolism*; D005810:Multigene Family; D013302:Streptomyces / Q000235:genetics; D016559:Tacrolimus / Q000378:metabolism*; D015534:Trans-Activators / Q000502:physiology*
chemical_list: D001426:Bacterial Proteins; D007166:Immunosuppressive Agents; D015534:Trans-Activators; D016559:Tacrolimus
keywords: Biosynthesis; FK506; Regulatory mechanism; Streptomyces tsukubaensis