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.
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 trans-2-pentenyl-acyl 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.
authors.affiliation: Department of Chemistry and Nano Science, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: SangJoon
authors.initials: S
authors.lastname: Mo
authors.forename: Dong Hwan
authors.initials: DH
authors.lastname: Kim
authors.forename: Jong Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: Je Won
authors.initials: JW
authors.lastname: Park
authors.forename: Devi B
authors.initials: DB
authors.lastname: Basnet
authors.forename: Yeon Hee
authors.initials: YH
authors.lastname: Ban
authors.forename: Young Ji
authors.initials: YJ
authors.lastname: Yoo
authors.forename: Shu-wei
authors.initials: SW
authors.lastname: Chen
authors.forename: Sung Ryeol
authors.initials: SR
authors.lastname: Park
authors.forename: Eun Ae
authors.initials: EA
authors.lastname: Choi
authors.forename: Eunji
authors.initials: E
authors.lastname: Kim
authors.forename: Ying-Yu
authors.initials: YY
authors.lastname: Jin
authors.forename: Sung-Kwon
authors.initials: SK
authors.lastname: Lee
authors.forename: Ju Yeol
authors.initials: JY
authors.lastname: Park
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Mi Ok
authors.initials: MO
authors.lastname: Lee
authors.forename: Keum Soon
authors.initials: KS
authors.lastname: Lee
authors.forename: Sang Jun
authors.initials: SJ
authors.lastname: Kim
authors.forename: Dooil
authors.initials: D
authors.lastname: Kim
authors.forename: Byoung Chul
authors.initials: BC
authors.lastname: Park
authors.forename: Sang-gi
authors.initials: SG
authors.lastname: Lee
authors.forename: Ho Jeong
authors.initials: HJ
authors.lastname: Kwon
authors.forename: Joo-Won
authors.initials: JW
authors.lastname: Suh
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Moore
authors.forename: Si-Kyu
authors.initials: SK
authors.lastname: Lim
authors.forename: Yeo Joon
authors.initials: YJ
authors.lastname: Yoon
mesh_terms: D008316:Malonyl Coenzyme A / Q000096:biosynthesis* / Q000737:chemistry* / Q000378:metabolism; D005810:Multigene Family; D048630:Polyketide Synthases / Q000378:metabolism*; D017384:Sequence Deletion; D013302:Streptomyces / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000378:metabolism*
chemical_list: D008316:Malonyl Coenzyme A; D048630:Polyketide Synthases; D016559:Tacrolimus