earticle

영어

FK506 is the clinically important 23-membered macrocyclic immunosuppressive polyketide produced by a variety of Streptomyces species. The allyl moiety of FK506 is structurally unique amongst polyketides and critical for its potent biological activity. Here, we elucidated the detailed biosynthetic pathway of allylmalonyl-coenzyme A (CoA), from which the FK506 allyl group is derived, based on the comparison of three FK506 gene clusters, gene deletion, chemical complementation. Furthermore, the novel allyl group-modified FK506 analogs possessing improved neurite outgrowth activity were mutasynthesized. This work demonstrates the unique feature of FK506 biosynthesis in which a dedicated polyketide synthease (PKS) provides an atypical extender unit for main modular PKS, and a new tool for combinatorial biosynthesis of novel macrolide scaffolds as well as FK506 analogs.