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

查看全文 作　　者：Weinan [1]Yang;Lingxin [1]Kong;Qing [1]Wang;Zixin [1]Deng;Delin [1]You 高影响力作者 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高影响力机构 出　　处：《Synthetic and Systems Biotechnology》索引2020年第5卷第3期,共10页高影响力期刊 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
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