期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 133, 期 4, 页码 976-985出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja108399b
关键词
-
资金
- National Research Laboratory (NRL) through the National Research Foundation of Korea (NRF) [R0A-2008-000-20030-0]
- NRF [2010-0001487, 2010-0017984, 2009-0083522]
- Advanced Biomass RD Center (ABC) [ABC-2010-0029800]
- 21C Frontier Microbial Genomics and Applications Center [11-2008-16-001-00]
- Ministry of Education, Science & Technology (MEST)
- Ministry of Land, Transportation and Maritime Affairs, Republic of Korea
- National Institutes of Health [CA127622]
- National Research Foundation of Korea [11-2008-16-001-00, R0A-2008-000-20030-0] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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 ally! 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据