Production of novel rapamycin analogs by precursor-directed biosynthesis

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

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

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
Volume71
Issue number4
DOIs
StatePublished - Apr 2005
Externally publishedYes

Fingerprint

Sirolimus
biosynthesis
Streptomyces hygroscopicus
amino acid
immunosuppressive agents
amino acids
acids
acid
Tacrolimus Binding Protein 1A
Amino Acids
fermentation
sulfur
substitution
Streptomyces
Immunosuppressive Agents
Biological Products
Sulfur
Fermentation

ASJC Scopus subject areas

  • Biotechnology
  • Environmental Science(all)
  • Microbiology

Cite this

Ritacco, F. V., Graziani, E. I., Summers, M. Y., Zabriskie, M., Yu, K., Bernan, V. S., ... Greenstein, M. (2005). Production of novel rapamycin analogs by precursor-directed biosynthesis. Applied and Environmental Microbiology, 71(4), 1971-1976. https://doi.org/10.1128/AEM.71.4.1971-1976.2005

Production of novel rapamycin analogs by precursor-directed biosynthesis. / Ritacco, Frank V.; Graziani, Edmund I.; Summers, Mia Y.; Zabriskie, Mark; Yu, Ker; Bernan, Valerie S.; Carter, Guy T.; Greenstein, Michael.

In: Applied and Environmental Microbiology, Vol. 71, No. 4, 04.2005, p. 1971-1976.

Research output: Contribution to journalArticle

Ritacco, FV, Graziani, EI, Summers, MY, Zabriskie, M, Yu, K, Bernan, VS, Carter, GT & Greenstein, M 2005, 'Production of novel rapamycin analogs by precursor-directed biosynthesis', Applied and Environmental Microbiology, vol. 71, no. 4, pp. 1971-1976. https://doi.org/10.1128/AEM.71.4.1971-1976.2005
Ritacco, Frank V. ; Graziani, Edmund I. ; Summers, Mia Y. ; Zabriskie, Mark ; Yu, Ker ; Bernan, Valerie S. ; Carter, Guy T. ; Greenstein, Michael. / Production of novel rapamycin analogs by precursor-directed biosynthesis. In: Applied and Environmental Microbiology. 2005 ; Vol. 71, No. 4. pp. 1971-1976.
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