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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

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
Authors
Mo S.Kim D.H.Lee J.H.Park J.W.Basnet D.B.Ban Y.H.Yoo Y.J.Chen S.-W.Park S.R.Choi E.A.Kim E.Jin Y.-Y.Lee S.-K.Park J.Y.Liu Y.Lee M.O.Lee K.S.Kim S.J.Kim D.Park B.C.Lee S.-G.Kwon H.J.Suh J.-W.Moore B.S.Lim S.-K.Yoon Y.J.
Ewha Authors
윤여준이상기
SCOPUS Author ID
윤여준scopus; 이상기scopus
Issue Date
2011
Journal Title
Journal of the American Chemical Society
ISSN
0002-7863JCR Link
Citation
vol. 133, no. 4, pp. 976 - 985
Indexed
SCI; SCIE; SCOPUS WOS scopus
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. © 2010 American Chemical Society.
DOI
10.1021/ja108399b
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자연과학대학 > 화학·나노과학전공 > Journal papers
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