Multiple genetic modifications of the erythromycin polyketide synthase to produce a library of novel "unnatural" natural products

被引：371

作者：

McDaniel, R ^{[1
]}

Thamchaipenet, A ^{[1
]}

Gustafsson, C ^{[1
]}

Fu, H ^{[1
]}

Betlach, M ^{[1
]}

Ashley, G ^{[1
]}

机构：

[1] KOSAN Biosci Inc, Burlingame, CA 94010 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 1999年 / 96卷 / 05期

关键词：

D O I：

10.1073/pnas.96.5.1846

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The structures of complex polyketide natural products, such as erythromycin, are programmed by multifunctional polyketide synhases (PKSs) that contain modular arrangements of functional domains. The colinearity between the activities of modular PKS domains and structure of the polyketide product portends the generation of novel organic compounds-"unnatural" natural products-by genetic manipulation. We have engineered the erythromycin polyketide synthase genes to effect combinatorial alterations of catalytic activities in the biosynthetic pathway, generating a library of >50 macrolides that would be impractical to produce by chemical methods. The library includes examples of analogs with one, two, and three altered carbon centers of the polyketide products. The manipulation of multiple biosynthetic steps in a PKS is an important milestone toward the goal of producing large libraries of unnatural natural products for biological and pharmaceutical applications.

引用

页码：1846 / 1851

页数：6

共 31 条

[1] A functional chimeric modular polyketide synthase generated via domain replacement [J].