Engineered production of iso-migrastatin in heterologous Streptomyces hosts

Bioorg Med Chem. 2009 Mar 15;17(6):2147-53. doi: 10.1016/j.bmc.2008.10.074. Epub 2008 Nov 5.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Base Sequence
  • Chromatography, High Pressure Liquid
  • Chromatography, Liquid
  • Chromosomes, Artificial, Bacterial
  • Cloning, Molecular
  • DNA Primers
  • Macrolides / metabolism*
  • Mass Spectrometry
  • Multigene Family
  • Piperidones / metabolism*
  • Polymerase Chain Reaction
  • Streptomyces / genetics
  • Streptomyces / metabolism*

Substances

  • DNA Primers
  • Macrolides
  • Piperidones
  • isomigrastatin