Comparative functional genomics of the acarbose producers reveals potential targets for metabolic engineering  

作　　者：Huixin Xie Qinqin Zhao Xin Zhang Qianjin Kang Linquan Bai 

机构地区：[1]State Key Laboratory of Microbial Metabolism,School of Life Sciences&Biotechnology,Shanghai Jiao Tong University,Shanghai 200240,China

出　　处：《Synthetic and Systems Biotechnology》2019年第1期49-56,共8页合成和系统生物技术（英文）

基　　金：the National Natural Science Foundation of China(No.31470157,21661140002,31830104,U1703236);the Shanghai Science and Technology Committee(No.17JC1403600)。

摘　　要：Theα-glucosidase inhibitor acarbose is produced in large-scale by strains derived from Actinoplanes sp.SE50 and used widely for the treatment of type-2 diabetes.Compared with the wild-type SE50,a high-yield derivative Actinoplanes sp.SE50/110 shows 2-fold and 3–7-fold improvement of acarbose yield and acb cluster transcription,respectively.The genome of SE50 was fully sequenced and compared with that of SE50/110,and 11 SNVs and 4 InDels,affecting 8 CDSs,were identified in SE50/110.The 8 CDSs were individually inactivated in SE50.Deletions of ACWT_4325(encoding alcohol dehydrogenase)resulted in increases of acarbose yield by 25%from 1.87 to 2.34 g/L,acetyl-CoA concentration by 52.7%,and PEP concentration by 22.7%.Meanwhile,deletion of ACWT_7629(encoding elongation factor G)caused improvements of acarbose yield by 36%from 1.87 to 2.54 g/L,transcription of acb cluster,and ppGpp concentration to 2.2 folds.Combined deletions of ACWT_4325 and ACWT_7629 resulted in further improvement of acarbose to 2.83 g/L(i.e.76%of SE50/110),suggesting that the metabolic perturbation and improved transcription of acb cluster caused by these two mutations contribute substantially to the acarbose overproduction.Enforced application of similar strategies was performed to manipulate SE50/110,resulting in a further increase of acarbose titer from 3.73 to 4.21 g/L.Therefore,the comparative genomics approach combined with functional verification not only revealed the acarbose overproduction mechanisms,but also guided further engineering of its high-yield producers.

关 键 词：ACARBOSE Comparative genomics OVERPRODUCTION Regulation 

分 类 号：F42[经济管理—产业经济]