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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Title
Biosynthesis of the allylmalonyl-CoA extender unit for the FK506 polyketide synthase proceeds through a dedicated polyketide synthase and facilitates the mutasynthesis of analogues
Author(s)
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
2011
Abstract
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.
ISSN
0002-7863
Publisher
Amer Chem Soc
DOI
http://dx.doi.org/10.1021/ja108399b
Type
Article
Appears in Collections:
Critical Diseases Diagnostics Convergence Research Center > 1. Journal Articles
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