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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
- Biosynthesis of the allylmalonyl-CoA extender unit for the FK506 polyketide synthase proceeds through a dedicated polyketide synthase and facilitates the mutasynthesis of analogues
- 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
- 윤여준; 이상기
- SCOPUS Author ID
- 윤여준; 이상기
- Issue Date
- Journal Title
- Journal of the American Chemical Society
- vol. 133, no. 4, pp. 976 - 985
- SCI; SCIE; SCOPUS
- 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.
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