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.
ASJC Scopus subject areas
- Food Science
- Applied Microbiology and Biotechnology