文献类型：期刊文献

英文题名：Enhancement of UDPG synthetic pathway improves ansamitocin production in Actinosynnem pretiosum

作者：Fan, Yuxiang[1];Zhao, Mengjiang[1];Wei, Liujing[1];Hu, Fengxian[1];Imanaka, Tadayuki[1];Bai, Linquan[2,3];Hua, Qiang[1,4]

机构：[1]E China Univ Sci & Technol, State Key Lab Bioreactor Engn, 130 Meilong Rd, Shanghai 200237, Peoples R China;[2]Shanghai Jiao Tong Univ, State Key Lab Microbial Metab, Shanghai 200240, Peoples R China;[3]Shanghai Jiao Tong Univ, Sch Life Sci & Biotechnol, Shanghai 200240, Peoples R China;[4]SCICBT, 130 Meilong Rd, Shanghai 200237, Peoples R China

年份：2016

卷号：100

期号：6

起止页码：2651

外文期刊名：APPLIED MICROBIOLOGY AND BIOTECHNOLOGY

收录：;EI(收录号：20154701596194);WOS:【SCI-EXPANDED(收录号:WOS:000371244300013)】；

基金：This study was funded by the National Basic Research Program of China (973 Program) (2012CB721101), National Natural Science Foundation of China (21406070), and Research Fund for the Doctoral Program of Higher Education of China (20130074110002). We are grateful to Prof. Jian-Jiang Zhong and Dr. Qianjin Kang at Shanghai Jiao Tong University, China, for their valuable advices.

语种：英文

外文关键词：Actinosynnema pretiosum; Ansamitocins; UDPG synthetic pathway; Metabolic engineering

摘要：Ansamitocin P-3 (AP-3), an amacrocyclic lactam compound, is produced by Actinosynnema pretiosum. As a group of maytansinoid antibiotics, ansamitocins have an extraordinary antitumor activity by blocking the assembly of tubulin forming into functional microtubules. The biosynthesis of ansamitocins is initialized by the formation of UDP-glucose (UDPG) which is converted from glucose-1-phosphate (G1P). In this study, we focused on the influence of enhancement of UDPG biosynthesis on the production of ansamitocins in A. pretiosum. The homologous overexpressions of phosphoglucomutase, starch phosphorylase, and UTP-G1P uridylyltransferase, respectively, could largely increase the pool sizes of G1P and UDPG and result in improved AP-3 production. The elevated intracellular glucose-6-phosphate (G6P) level provided by the enhanced glyconeogenesis had, however, no significant effects on the biosynthesis of AP-3. The G6P-G1P-UDPG pathway was therefore systematically engineered by multiple genetic modifications, and a significant increase in AP-3 production was achieved (168 mg/L of AP-3 in flask culture, 40 % higher than the control strain). We also found that the enhancement of starch assimilation pathway could also improve the assembly of AP-3 to some extent. In addition, heterologous gene overexpression from Actinosynnema mirum could result in more AP-3 biosynthesis in comparison to the corresponding homologous overexpression, suggesting an alternative and promising avenue of metabolic engineering strategy for improving AP-3 production.