Engineered production of iso-migrastatin in heterologous Streptomyces hosts.
Glutarimide-containing polyketides such as migrastatin (MGS) are well known for their ability to inhibit tumor cell migration. We have previously shown that MGS is derived from iso-migrastatin (iso-MGS) via a H(2)O-mediated ring-expansion rearrangement. A bacterial artificial chromosome (BAC) library of Streptomyces platensis NRRL18993, an iso-MGS producer, was constructed. From this library, pBS11001, a BAC clone harboring the intact iso-MGS biosynthetic gene cluster, was identified. Mobilization of pBS11001 into five heterologous Streptomyces hosts afforded recombinant strains, SB11001, SB11002, SB11003, SB11004, and SB11005, respectively. Under a standard set of media and fermentation conditions, the recombinant strains all produced the same profile of iso-MGS as that of S. platensis NRRL18993. These findings highlight the strength and flexibility of the BAC-based technology for natural product production and engineering in heterologous Streptomyces model hosts.
Feng
Zhiyang
Z
Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI 53705, USA.
Wang
Liyan
L
Rajski
Scott R
SR
Xu
Zhinan
Z
Coeffet-LeGal
Marie F
MF
Shen
Ben
B
D001483:Base Sequence; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D022202:Chromosomes, Artificial, Bacterial; D003001:Cloning, Molecular; D017931:DNA Primers; D018942:Macrolides / Q000378:metabolism*; D013058:Mass Spectrometry; D005810:Multigene Family; D010881:Piperidones / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D013302:Streptomyces / Q000235:genetics / Q000378:metabolism*
D017931:DNA Primers; D018942:Macrolides; D010881:Piperidones; C455261:isomigrastatin