Metabolic engineering of a methyltransferase for production of drug precursors demecycline and demeclocycline in Streptomyces aureofaciens  

作　　者：Weinan Yang Lingxin Kong Qing Wang Zixin Deng Delin You 

机构地区：[1]State Key Laboratory of Microbial Metabolism,Joint International Research Laboratory of Metabolic and Developmental Sciences,School of Life Sciences&Biotechnology,Shanghai Jiao Tong University,Shanghai,200030,China

出　　处：《Synthetic and Systems Biotechnology》2020年第3期121-130,共10页合成和系统生物技术（英文）

基　　金：This work was supported by grants from National Key R&D Program of China(2018YFA0900400)from the Ministry of Science and Technology;the National Natural Science Foundation of China(31630002,31770038,31700029,and 21661140002);Shanghai Pujiang Program from the Shanghai Municipal Council of Science and Technology(12PJD021);and China Postdoctoral Science Foundation(2017M620151).

摘　　要：Demecycline(DMTC)and demeclocycline(DMCTC)are C6-demethylated derivatives of tetracycline(TC)and chlortetracycline(CTC),respectively.They are precursors of minocycline and tigecycline,which showed remarkable bioactivity against TC-resistant bacteria and have been used clinically for decades.In order to biosynthesize drug precursors DMTC and DMCTC,the function of a possible C-methyltransferase encoding gene ctcK was studied systematically in the CTC high-yielding industrial strain Streptomyces aureofaciens F3.TheΔctcK mutant accumulated two new products,which were turned out to be DMTC and DMCTC.Meanwhile,timecourse analysis of the fermentation products detected the epimers of DMTC and DMCTC transformed spontaneously.Finally,an engineering strain with higher productivity of DMCTC was constructed by deleting ctcK and overexpressing ctcP of three extra copies simultaneously.Construction of these two engineering strains not only served as a successful example of synthesizing required products through metabolic engineering,but also provided original strains for following elaborate engineering to synthesize more effective tetracycline derivatives.

关 键 词：Demecycline DEMECLOCYCLINE Streptomyces aureofaciens F3 Metabolic engineering 

分 类 号：Q81[生物学—生物工程] R318[医药卫生—生物医学工程]