Designed Biosynthesis of 36-Methyl-FK506 by Polyketide Precursor Pathway Engineering

被引：23
作者：
Lechner, Anna [1 ]
Wilson, Micheal C. [1 ]
Ban, Yeon Hee [3 ]
Hwang, Jae-Yeon [3 ]
Yoon, Yeo Joon [3 ]
Moore, Bradley S. [1 ,2 ]
机构：
[1] Univ Calif San Diego, Scripps Inst Oceanog, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA
[3] Ewha Womans Univ, Dept Chem & Nano Sci, Seoul 120750, South Korea
来源：
ACS SYNTHETIC BIOLOGY | 2013年 / 2卷 / 07期
基金：
新加坡国家研究基金会; 美国国家卫生研究院;
关键词：
biosynthesis; crotonyl-CoA carboxylase; FK506; immunosuppressant; polyketide synthase; GENE-CLUSTER; FK506; FK520; ERYTHROMYCIN; ASCOMYCIN; RAPAMYCIN; ANALOGS;
D O I：
10.1021/sb3001062
中图分类号：
Q5 [生物化学];
学科分类号：
071010 ; 081704 ;
摘要：
The polyketide synthase (PKS) biosynthetic code has recently expanded to include a newly recognized group of extender unit substrates derived from alpha,beta-unsaturated acyl-CoA molecules that deliver diverse side chain chemistry to polyketide backbones. Herein we report the identification of a three-gene operon responsible for the biosynthesis of the PKS building block isobutyrylmalonyl-CoA associated with the macrolide ansalactam A from the marine bacterium Streptomyces sp. CNH189. Using a synthetic biology approach, we engineered the production of unnatural 36-methyl-FK506 in Streptomyces sp. KCTC 11604BP by incorporating the branched extender unit into FK506 biosynthesis in place of its natural C-21 allyl side chain, which has been shown to be critical for FK506's potent immunosuppressant and neurite outgrowth activities.
引用
收藏
页码：379 / 383
页数：5
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