Production of novel rapamycin analogs by precursor-directed biosynthesis

Frank V. Ritacco, Edmund I. Graziani, Mia Y. Summers, T. Mark Zabriskie, Ker Yu, Valerie S. Bernan, Guy T. Carter, Michael Greenstein

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37 Scopus citations


The natural product rapamycin, produced during fermentation by Streptomyces hygroscopicus, is known for its potent antifungal, immunosuppressive, and anticancer activities. During rapamycin biosynthesis, the amino acid L-pipecolate is incorporated into the rapamycin molecule. We investigated the use of precursor-directed biosynthesis to create new rapamycin analogs by substitution of unusual L-pipecolate analogs in place of the normal amino acid. Our results suggest that the L-pipecolate analog (±)-nipecotic acid inhibits the biosynthesis of L-pipecolate, thereby limiting the availability of this molecule for rapamycin biosynthesis. We used (±)-nipecotic acid in our precursor-directed biosynthesis studies to reduce L-pipecolate availability and thereby enhance the incorporation of other pipecolate analogs into the rapamycin molecule. We describe here the use of this method for production of two new sulfur-containing rapamycin analogs, 20-thiarapamycin and 15-deoxo-19-sulfoxylrapamycin, and report measurement of their binding to FKBP12.

Original languageEnglish (US)
Pages (from-to)1971-1976
Number of pages6
JournalApplied and Environmental Microbiology
Issue number4
StatePublished - Apr 2005

ASJC Scopus subject areas

  • Biotechnology
  • Food Science
  • Applied Microbiology and Biotechnology
  • Ecology

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    Ritacco, F. V., Graziani, E. I., Summers, M. Y., Zabriskie, T. M., Yu, K., Bernan, V. S., Carter, G. T., & Greenstein, M. (2005). Production of novel rapamycin analogs by precursor-directed biosynthesis. Applied and Environmental Microbiology, 71(4), 1971-1976.