The authors declare that they have no conflict of interest.
Enhanced FK506 production in Streptomyces tsukubaensis by rational feeding strategies based on comparative metabolic profiling analysis
Article first published online: 16 MAY 2013
Copyright © 2013 Wiley Periodicals, Inc.
Biotechnology and Bioengineering
Volume 110, Issue 10, pages 2717–2730, October 2013
How to Cite
Xia, M., Huang, D., Li, S., Wen, J., Jia, X. and Chen, Y. (2013), Enhanced FK506 production in Streptomyces tsukubaensis by rational feeding strategies based on comparative metabolic profiling analysis. Biotechnol. Bioeng., 110: 2717–2730. doi: 10.1002/bit.24941
Menglei Xia and Di Huang contributed equally to this work.
- Issue published online: 24 AUG 2013
- Article first published online: 16 MAY 2013
- Accepted manuscript online: 23 APR 2013 08:34AM EST
- Manuscript Accepted: 17 APR 2013
- Manuscript Revised: 22 MAR 2013
- Manuscript Received: 20 DEC 2012
- National 973 Project of China. Grant Number: 2013CB733600
- Key Program of National Natural Science Foundation of China. Grant Number: 21236005
- Program of Introducing Talents of Discipline to Universities. Grant Number: B06006
- National Natural Science Foundation of China. Grant Number: 20936002
- Streptomyces tsukubaensis;
- metabolic profiling;
- rational feeding strategies
FK506, a widely used immunosuppressant, is produced by industrial fermentation processes using various Streptomyces species. However, the low titer becomes a bottleneck for its application and industrialization. It urgently required a full understanding of the biological mechanisms for FK506 overproduction. Towards this end, comparative metabolomics approach was employed to analyze metabolite concentrations difference of Streptomyces tsukubaensis cultivated in two media with low and high productivities. Initially, 98 intracellular metabolites were identified and 13 metabolites involved in five pathways were determined to be directly correlated with FK506 biosynthesis. Then in-depth analysis elucidated how those key factors exerted influence on FK506 biosynthesis. Many previously unreported metabolites were shown to play an important role in FK506 biosynthesis and provided potential regulation points for external manipulation. Based on such key information, rationally designed feeding strategy was carried out. Results showed that the FK506 yield increased from 251 to 405 mg/L, whereas, by-products FK520 and 37,38-dihydro-FK506 decreased by 31% and 39%, respectively, compared with the values of control. To our knowledge, it is the first study to apply the comparative metabolomics method to identify key metabolites to promote the FK506 production. The strategies developed here can easily be extended to titer improvement of other important microbial natural products and process optimization. Biotechnol. Bioeng. 2013;110: 2717–2730. © 2013 Wiley Periodicals, Inc.