상세 정보

underline
Metadata Downloads : dc(xml) or Excel
Cited 0 time in scopus ci

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 

S MoD H KimJ H LeeJ W ParkD B BasnetY H BanY J YooS ChenS R ParkE A ChoiE KimY Y JinS K LeeJ Y ParkY LiuM O LeeK S LeeS J KimDoo Il KimByoung Chul ParkS G LeeH J KwonJ W SuhB S MooreS K LimY J Yoon

Publisher 

American Chemical Society

Issue Date 

2011

Citation 

Journal of American Chemical Society, vol. 133, no. 4, pp. 976-985

Keywords 

Allyl groupsBiological activitiesBiosynthetic pathwayCarrier proteinsCoenzyme ACombinatorial biosynthesisEngineered biosynthesisEnzymatic reactionFatty acid synthaseGene clustersImmunosuppressive agentMacrolidesMulti-stepMutasynthesisNeurite outgrowthNew strategyNoncanonical domainsPolyketide synthasesPolyketidesUnique features

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.

ISSN 

0002-7863

Link 

http://dx.doi.org/10.1021/ja108399b

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


There are no files associated with this item.
qrcode

FusionCharts.
DSpace Software Coptright(c) 2010 MIT and Hewleft-Packard  /  KRIBB-REPOSITORY ( Email:jakim@kribb.re.kr)