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Applied and Environmental Microbiology, April 2005, p. 1971-1976, Vol. 71, No. 4
0099-2240/05/$08.00+0     doi:10.1128/AEM.71.4.1971-1976.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Production of Novel Rapamycin Analogs by Precursor-Directed Biosynthesis

Frank V. Ritacco,1* Edmund I. Graziani,1 Mia Y. Summers,1 T. Mark Zabriskie,2 Ker Yu,3 Valerie S. Bernan,1 Guy T. Carter,1 and Michael Greenstein1

Natural Products,1 Oncology Research, Wyeth Research, Pearl River, New York,3 Department of Pharmaceutical Sciences, Oregon State University, Corvallis, Oregon2

Received 14 September 2004/ Accepted 9 November 2004

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.

* Corresponding author. Mailing address: Natural Products, Wyeth Research, 401 North Middletown Road, Building 205, Room 465, Pearl River, NY 10965. Phone: (845) 602-3482. Fax: (845) 602-5687. E-mail: ritaccf{at}wyeth.com.

Applied and Environmental Microbiology, April 2005, p. 1971-1976, Vol. 71, No. 4
0099-2240/05/$08.00+0     doi:10.1128/AEM.71.4.1971-1976.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.





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