Biosynthesis of the allylmalonyl-CoA extender unit for the FK506 polyketide synthase proceeds through a dedicated polyketide synthase and facilitates the mutasynthesis of analogues

Sangjoon Mo, Dong Hwan Kim, Jong Hyun Lee, Je Won Park, Devi B. Basnet, Yeon Hee Ban, Young Ji Yoo, Shu Wei Chen, Sung Ryeol Park, Eun Ae Choi, Eunji Kim, Ying Yu Jin, Sung Kwon Lee, Ju Yeol Park, Yuan Liu, Mi Ok Lee, Keum Soon Lee, Sang Jun Kim, Dooil Kim, Byoung Chul ParkSang Gi Lee, Ho Jeong Kwon, Joo Won Suh, Bradley S. Moore, Si Kyu Lim, Yeo Joon Yoon

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115 Citations (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.

Original languageEnglish
Pages (from-to)976-985
Number of pages10
JournalJournal of the American Chemical Society
Volume133
Issue number4
DOIs
Publication statusPublished - 2011 Feb 2

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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    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., ... Yoon, Y. J. (2011). Biosynthesis of the allylmalonyl-CoA extender unit for the FK506 polyketide synthase proceeds through a dedicated polyketide synthase and facilitates the mutasynthesis of analogues. Journal of the American Chemical Society, 133(4), 976-985. https://doi.org/10.1021/ja108399b