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Lechner, A, Wilson MC, Ban YH, Hwang JY, Yoon YJ, Moore BS.  2013.  Designed biosynthesis of 36-methyl-fk506 by polyketide precursor pathway engineering. Acs Synthetic Biology. 2:379-383.   10.1021/sb3001062   AbstractWebsite

The polyketide synthase (PKS) biosynthetic code has recently expanded to include a newly recognized group of extender unit substrates derived from alpha,beta-unsaturated acyl-CoA molecules that deliver diverse side chain chemistry to polyketide backbones. Herein we report the identification of a three-gene operon responsible for the biosynthesis of the PKS building block isobutyrylmalonyl-CoA associated with the macrolide ansalactam A from the marine bacterium Streptomyces sp. CNH189. Using a synthetic biology approach, we engineered the production of unnatural 36-methyl-FK506 in Streptomyces sp. KCTC 11604BP by incorporating the branched extender unit into FK506 biosynthesis in place of its natural C-21 allyl side chain, which has been shown to be critical for FK506's potent immunosuppressant and neurite outgrowth activities.

Miyanaga, A, Janso JE, McDonald L, He M, Liu HB, Barbieri L, Eustaquio AS, Fielding EN, Carter GT, Jensen PR, Feng XD, Leighton M, Koehn FE, Moore BS.  2011.  Discovery and Assembly-Line Biosynthesis of the Lymphostin Pyrroloquinoline Alkaloid Family of mTOR Inhibitors in Salinispora Bacteria. Journal of the American Chemical Society. 133:13311-13313.   10.1021/ja205655w   AbstractWebsite

The pyrroloquinoline alkaloid family of natural products, which includes the immunosuppressant lymphostin, has long been postulated to arise from tryptophan. We now report the molecular basis of lymphostin biosynthesis in three marine Salinispora species that maintain conserved biosynthetic gene clusters harboring a hybrid nonribosomal peptide synthetase-polyketide synthase that is central to lymphostin assembly. Through a series of experiments involving gene mutations, stable isotope profiling, and natural product discovery, we report the assembly-line biosynthesis of lymphostin and nine new analogues that exhibit potent mTOR inhibitory activity.