Biosynthesis of the allylmalonyl-CoA extender unit for the FK506 polyketide synthase proceeds through a dedicated polyketide synthase and facilitates the mutasynthesis of analogues
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- Biosynthesis of the allylmalonyl-CoA extender unit for the FK506 polyketide synthase proceeds through a dedicated polyketide synthase and facilitates the mutasynthesis of analogues
- S Mo; D H Kim; J H Lee; J W Park; D B Basnet; Y H Ban; Y J Yoo; S Chen; S R Park; E A Choi; E Kim; Y Y Jin; S K Lee; J Y Park; Y Liu; M O Lee; K S Lee; S J Kim; Doo Il Kim; Byoung Chul Park; S G Lee; H J Kwon; J W Suh; B S Moore; S K Lim; Y J Yoon
- Bibliographic Citation
- Journal of American Chemical Society, vol. 133, no. 4, pp. 976-985
- Publication Year
- The allyl moiety of the immunosuppressive agent FK506 is structurally unique among polyketides and critical for its potent biological activity. Here, we detail the biosynthetic pathway to allylmalonyl-coenzyme A (CoA), from which the FK506 allyl group is derived, based on a comprehensive chemical, biochemical, and genetic interrogation of three FK506 gene clusters. A discrete polyketide synthase (PKS) with noncanonical domain architecture presumably in coordination with the fatty acid synthase pathway of the host catalyzes a multistep enzymatic reaction to allylmalonyl-CoA via frans-2-pentenylacyl carrier protein. Characterization of this discrete pathway facilitated the engineered biosynthesis of novel allyl group-modified FK506 analogues, 36-fluoro-FK520 and 36-methyl-FK506, the latter of which exhibits improved neurite outgrowth activity. This unique feature of FK506 biosynthesis, in which a dedicated PKS provides an atypical extender unit for the main modular PKS, illuminates a new strategy for the combinatorial biosynthesis of designer macrolide scaffolds as well as FK506 analogues.
- Amer Chem Soc
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- Critical Diseases Diagnostics Convergence Research Center > 1. Journal Articles
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