title: Designed biosynthesis of 36-methyl-FK506 by polyketide precursor pathway engineering.
abstract: The polyketide synthase (PKS) biosynthetic code has recently expanded to include a newly recognized group of extender unit substrates derived from α,β-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.
authors: Scripps Institution of Oceanography, University of California at San Diego, La Jolla, California 92093-0204, United States.
authors: Anna
authors: A
authors: Lechner
authors: Micheal C
authors: MC
authors: Wilson
authors: Yeon Hee
authors: YH
authors: Ban
authors: Jae-Yeon
authors: JY
authors: Hwang
authors: Yeo Joon
authors: YJ
authors: Yoon
authors: Bradley S
authors: BS
authors: Moore
mesh_terms: D001426:Bacterial Proteins / Q000502:physiology*; D015195:Drug Design; D024861:Genetic Enhancement / Q000379:methods; D008957:Models, Genetic; D009097:Multienzyme Complexes / Q000235:genetics*; D015202:Protein Engineering / Q000379:methods*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*; D013302:Streptomyces / Q000502:physiology*; D016559:Tacrolimus / Q000302:isolation & purification / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D009097:Multienzyme Complexes; D011994:Recombinant Proteins; D016559:Tacrolimus
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