Journal
ACS SYNTHETIC BIOLOGY
Volume 2, Issue 7, Pages 379-383Publisher
AMER CHEMICAL SOC
DOI: 10.1021/sb3001062
Keywords
biosynthesis; crotonyl-CoA carboxylase; FK506; immunosuppressant; polyketide synthase
Categories
Funding
- National Institutes of Health [CA127622]
- National Research Foundation of Korea [20100018430]
- Intelligent Synthetic Biology Center of Global Frontier Project
- MEST [2011-0031961]
- National Research Foundation of Korea [2011-0031961] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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.
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