Document Detail

Titer improvement of iso-migrastatin in selected heterologous Streptomyces hosts and related analysis of mRNA expression by quantitative RT-PCR.
MedLine Citation:
PMID:  21132287     Owner:  NLM     Status:  MEDLINE    
iso-Migrastatin (iso-MGS) has been actively pursued recently as an outstanding candidate of antimetastasis agents. Having characterized the iso-MGS biosynthetic gene cluster from its native producer Streptomyces platensis NRRL 18993, we have recently succeeded in producing iso-MGS in five selected heterologous Streptomyces hosts, albeit the low titers failed to meet expectations and cast doubt on the utility of this novel technique for large-scale production. To further explore and capitalize on the production capacity of these hosts, a thorough investigation of these five engineered strains with three fermentation media for iso-MGS production was undertaken. Streptomyces albus J1074 and Streptomyces lividans K4-114 were found to be preferred heterologous hosts, and subsequent analysis of carbon and nitrogen sources revealed that sucrose and yeast extract were ideal for iso-MGS production. After the initial optimization, the titers of iso-MGS in all five hosts were considerably improved by 3-18-fold in the optimized R2YE medium. Furthermore, the iso-MGS titer of S. albus J1074 (pBS11001) was significantly improved to 186.7 mg/L by a hybrid medium strategy. Addition of NaHCO(3) to the latter finally afforded an optimized iso-MGS titer of 213.8 mg/L, about 5-fold higher than the originally reported system. With S. albus J1074 (pBS11001) as a model host, the expression of iso-MGS gene cluster in four different media was systematically studied via the quantitative RT-PCR technology. The resultant comparison revealed the correlation of gene expression and iso-MGS production for the first time; synchronous expression of the whole gene cluster was crucial for optimal iso-MGS production. These results reveal new insights into the iso-MGS biosynthetic machinery in heterologous hosts and provide the primary data to realize large-scale production of iso-MGS for further preclinical studies.
Dong Yang; Xiangcheng Zhu; Xueyun Wu; Zhiyang Feng; Lei Huang; Ben Shen; Zhinan Xu
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-12-04
Journal Detail:
Title:  Applied microbiology and biotechnology     Volume:  89     ISSN:  1432-0614     ISO Abbreviation:  Appl. Microbiol. Biotechnol.     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-02-24     Completed Date:  2011-05-23     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  8406612     Medline TA:  Appl Microbiol Biotechnol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  1709-19     Citation Subset:  IM    
Department of Chemical and Biological Engineering, Institute of Bioengineering, Zhejiang University, Hangzhou, Zhejiang, China.
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MeSH Terms
Antineoplastic Agents / metabolism*
Biosynthetic Pathways / genetics*
Gene Expression Profiling*
Macrolides / metabolism*
Piperidones / metabolism*
RNA, Messenger / biosynthesis*
Reverse Transcriptase Polymerase Chain Reaction
Streptomyces lividans / genetics*,  metabolism*
Grant Support
CA106150/CA/NCI NIH HHS; CA113297/CA/NCI NIH HHS; R01 CA106150/CA/NCI NIH HHS; R01 CA106150-05/CA/NCI NIH HHS; U19 CA113297/CA/NCI NIH HHS; U19 CA113297-05/CA/NCI NIH HHS
Reg. No./Substance:
0/Antineoplastic Agents; 0/Macrolides; 0/Piperidones; 0/RNA, Messenger; 0/isomigrastatin

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