文献类型：期刊文献

英文题名：Effects of modulation of pentose-phosphate pathway on biosynthesisof ansamitocins in Actinosynnema pretiosum

作者：Fan, Yuxiang[1];Hu, Fengxian[1];Wei, Liujing[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]Shanghai Collaborat Innovat Ctr Biomfg Technol, 130 Meilong Rd, Shanghai 200237, Peoples R China

年份：2016

卷号：230

起止页码：3

外文期刊名：JOURNAL OF BIOTECHNOLOGY

收录：;EI(收录号：20162102423347);WOS:【SCI-EXPANDED(收录号:WOS:000377981300002)】；

基金：This work was financially supported by the National Basic Research Program of China (973 Program) (2012CB721101), National Natural Science Foundation of China (21406070), Research Fund for the Doctoral Program of Higher Education of China (20130074110002).

语种：英文

外文关键词：Actinosynnema pretiosum; Ansamitocins; Pentose phosphate pathway; Phosphoglucomutase; Metabolic engineering

摘要：Ansamitocins, produced by Actinosynnema pretiosum, are a group of maytansinoid antibiotics that block the assembly of tubulin into functional microtubules. The precursors of ansamitocin biosynthesis are generally derived from the Embden-Meyerhof-Parnas (EMP) pathway and the tricarboxylic acid cycle. In this study, central carbon flux distributions were analyzed by C-13-based flux analysis to reveal the contribution of individual central carbon metabolism pathways. To direct more carbon flux into ansamitocin biosynthesis, pentose phosphate (PP) pathway only and the combination of PP pathway and Entner-Doudoroff (ED) pathway were weakened, respectively. Ansamitocin P-3 (AP-3) productions by both kinds of pathways weakened mutant strains were significantly enhanced in chemically defined medium. In order to draw metabolic flux to the biosynthesis of ansamitocins more efficiently, heterologous phosphoglucomutase was subsequently overexpressed based on a mutant strain with combinational regulation of PP pathway and ED pathway. More fluxes were successfully directed into the UDP-glucose synthetic pathway and the AP-3 production was further improved in this case, reaching approximately 185 mg/L in fermentation medium. It was demonstrated that eliminating the bypass pathways and favoring the precursor synthetic pathway could effectively improve ansamitocin production by A. pretiosum, suggesting a promising role of metabolic strategy in improving secondary metabolite production. (C) 2016 Elsevier B.V. All rights reserved.