Source:http://linkedlifedata.com/resource/pubmed/id/21175203
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
4
|
| pubmed:dateCreated |
2011-1-27
|
| pubmed:abstractText |
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.
|
| pubmed:grant | |
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical | |
| pubmed:status |
MEDLINE
|
| pubmed:month |
Feb
|
| pubmed:issn |
1520-5126
|
| pubmed:author |
pubmed-author:BanYeon HeeYH,
pubmed-author:BasnetDevi BDB,
pubmed-author:ChenShu-weiSW,
pubmed-author:ChoiEun AeEA,
pubmed-author:JinYing-YuYY,
pubmed-author:KimDong HwanDH,
pubmed-author:KimDooilD,
pubmed-author:KimEunjiE,
pubmed-author:KimSang JunSJ,
pubmed-author:KwonHo JeongHJ,
pubmed-author:LeeJong HyunJH,
pubmed-author:LeeKeum SoonKS,
pubmed-author:LeeMi OkMO,
pubmed-author:LeeSang-giSG,
pubmed-author:LeeSung-KwonSK,
pubmed-author:LimSi-KyuSK,
pubmed-author:LiuYuanY,
pubmed-author:MoSangJoonS,
pubmed-author:MooreBradley SBS,
pubmed-author:ParkByoung ChulBC,
pubmed-author:ParkJe WonJW,
pubmed-author:ParkJu YeolJY,
pubmed-author:ParkSung RyeolSR,
pubmed-author:SuhJoo-WonJW,
pubmed-author:YooYoung JiYJ,
pubmed-author:YoonYeo JoonYJ
|
| pubmed:issnType |
Electronic
|
| pubmed:day |
2
|
| pubmed:volume |
133
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
976-85
|
| pubmed:dateRevised |
2011-10-6
|
| pubmed:meshHeading | |
| pubmed:year |
2011
|
| pubmed:articleTitle |
Biosynthesis of the allylmalonyl-CoA extender unit for the FK506 polyketide synthase proceeds through a dedicated polyketide synthase and facilitates the mutasynthesis of analogues.
|
| pubmed:affiliation |
Department of Chemistry and Nano Science, Ewha Womans University, Seoul 120-750, Republic of Korea.
|
| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
|