Biosynthesis of the Allylmalonyl-CoA Extender Unit for the FK506 Polyketide Synthase Proceeds through a Dedicated Polyketide Synthase and Facilitates the Mutasynthesis of Analogues

被引：136

作者：

Mo, SangJoon ^{[2
]}

Kim, Dong Hwan ^{[1
,3
]}

Lee, Jong Hyun ^{[2
]}

Park, Je Won ^{[2
]}

Basnet, Devi B. ^{[2
]}

Ban, Yeon Hee ^{[2
]}

Yoo, Young Ji ^{[2
]}

Chen, Shu-wei ^{[2
]}

Park, Sung Ryeol ^{[2
]}

Choi, Eun Ae ^{[2
]}

Kim, Eunji ^{[2
]}

Jin, Ying-Yu ^{[4
]}

Lee, Sung-Kwon ^{[4
]}

Park, Ju Yeol ^{[5
]}

Liu, Yuan ^{[6
,7
]}

Lee, Mi Ok ^{[1
]}

Lee, Keum Soon ^{[1
]}

Kim, Sang Jun ^{[1
]}

Kim, Dooil ^{[8
]}

Park, Byoung Chul ^{[8
]}

Lee, Sang-gi ^{[2
]}

Kwon, Ho Jeong ^{[5
]}

Suh, Joo-Won ^{[4
]}

Moore, Bradley S. ^{[6
,7
]}

Lim, Si-Kyu ^{[1
]}

Yoon, Yeo Joon ^{[2
]}

机构：

[1] GenoTech Corp, Taejon 305343, South Korea

[2] Ewha Womans Univ, Dept Chem & Nano Sci, Seoul 120750, South Korea

[3] Chungnam Natl Univ, Dept Microbiol & Mol Biol, Taejon 305764, South Korea

[4] Myongji Univ, Div Biosci & Bioinformat, Gyeonggi 449728, South Korea

[5] Yonsei Univ, Translat Res Ctr Prot Funct Control, Dept Biotechnol, Seoul 120746, South Korea

[6] Univ Calif San Diego, Scripps Inst Oceanog, La Jolla, CA 92093 USA

[7] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA

[8] Korea Res Inst Biosci & Biotechnol, Taejon 305600, South Korea

来源：

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | 2011年 / 133卷 / 04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：

GENE-CLUSTER; IMMUNOSUPPRESSANT FK506; MASS SPECTROMETRY; STREPTOMYCES; FK-506; FK520; TRANSFERASE; RAPAMYCIN; COENZYME; PATHWAY;

D O I：

10.1021/ja108399b

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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.

引用

页码：976 / 985

页数：10

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