Structural and functional analysis of two di-domain aromatase/cyclases from type II polyketide synthases

被引：25

作者：

Caldara-Festin, Grace ^{[1
,2
,3
]}

Jackson, David R. ^{[1
,2
,3
]}

Barajas, Jesus F. ^{[1
,2
,3
]}

Valentic, Timothy R. ^{[1
,2
,3
]}

Patel, Avinash B. ^{[1
,2
,3
]}

Aguilar, Stephanie ^{[1
,2
,3
]}

Nguyen, MyChi ^{[1
,2
,3
]}

Vo, Michael ^{[1
,2
,3
]}

Khanna, Avinash ^{[1
,2
,3
]}

Sasaki, Eita ^{[4
,5
]}

Liu, Hung-wen ^{[4
,5
]}

Tsai, Shiou-Chuan ^{[1
,2
,3
]}

机构：

[1] Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA

[2] Univ Calif Irvine, Dept Chem, Irvine, CA 92697 USA

[3] Univ Calif Irvine, Dept Pharmaceut Sci, Irvine, CA 92697 USA

[4] Univ Texas Austin, Coll Pharm, Div Med Chem, Austin, TX 78712 USA

[5] Univ Texas Austin, Dept Chem, Austin, TX 78712 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2015年 / 112卷 / 50期

关键词：

polyketide biosynthesis; structural biology; aromatase/cyclase; BIOSYNTHETIC GENE-CLUSTER; ENGINEERED BIOSYNTHESIS; HETEROLOGOUS EXPRESSION; AROMATIC POLYKETIDES; ACTINORHODIN BIOSYNTHESIS; CRYSTAL-STRUCTURE; STEFFIMYCIN; SPECIFICITY; CLONING; INSIGHTS;

D O I：

10.1073/pnas.1512976112

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：

Aromatic polyketides make up a large class of natural products with diverse bioactivity. During biosynthesis, linear poly-beta-ketone intermediates are regiospecifically cyclized, yielding molecules with defined cyclization patterns that are crucial for polyketide bioactivity. The aromatase/cyclases (ARO/CYCs) are responsible for regiospecific cyclization of bacterial polyketides. The two most common cyclization patterns are C7-C12 and C9-C14 cyclizations. We have previously characterized three monodomain ARO/CYCs: ZhuI, TcmN, and WhiE. The last remaining uncharacterized class of ARO/CYCs is the di-domain ARO/CYCs, which catalyze C7-C12 cyclization and/or aromatization. Di-domain ARO/CYCs can further be separated into two subclasses: "nonreducing" ARO/CYCs, which act on nonreduced poly-beta-ketones, and "reducing" ARO/CYCs, which act on cyclized C9 reduced poly-beta-ketones. For years, the functional role of each domain in cyclization and aromatization for di-domain ARO/CYCs has remained a mystery. Here we present what is to our knowledge the first structural and functional analysis, along with an in-depth comparison, of the nonreducing (StfQ) and reducing (BexL) di-domain ARO/CYCs. This work completes the structural and functional characterization of mono-and di-domain ARO/CYCs in bacterial type II polyketide synthases and lays the groundwork for engineered biosynthesis of new bioactive polyketides.

引用

页码：E6844 / E6851

页数：8

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