Crystal structure and biochemical studies of the trans-acting polyketide enoyl reductase LovC from lovastatin biosynthesis

被引：66

作者：

Ames, Brian D. ^{[2
,3
,4
]}

Chi Nguyen ^{[2
,3
,4
]}

Bruegger, Joel ^{[2
,3
,4
]}

Smith, Peter ^{[2
,3
,4
]}

Xu, Wei ^{[1
]}

Ma, Suzanne ^{[1
]}

Wong, Emily ^{[2
,3
,4
]}

Wong, Steven ^{[2
,3
,4
]}

Xie, Xinkai ^{[1
]}

Li, Jesse W. -H. ^{[5
]}

Vederas, John C. ^{[5
]}

Tang, Yi ^{[1
]}

Tsai, Shiou-Chuan ^{[2
,3
,4
]}

机构：

[1] Univ Calif Los Angeles, Dept Chem & Biomol Engn, Los Angeles, CA 90095 USA

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

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

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

[5] Univ Alberta, Dept Chem, Edmonton, AB T6G 2G2, Canada

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2012年 / 109卷 / 28期

关键词：

FATTY-ACID SYNTHASE; ESCHERICHIA-COLI; GENE-CLUSTER; QUINONE OXIDOREDUCTASE; THIOESTER REDUCTASE; ACP REDUCTASE; STEREOCHEMISTRY; MECHANISM; DEHYDROGENASE; INTERCONVERSION;

D O I：

10.1073/pnas.1113029109

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：

Lovastatin is an important statin prescribed for the treatment and prevention of cardiovascular diseases. Biosynthesis of lovastatin uses an iterative type I polyketide synthase (PKS). LovC is a transacting enoyl reductase (ER) that specifically reduces three out of eight possible polyketide intermediates during lovastatin biosynthesis. Such trans-acting ERs have been reported across a variety of other fungal PKS enzymes as a strategy in nature to diversify polyketides. How LovC achieves such specificity is unknown. The 1.9-angstrom structure of LovC reveals that LovC possesses a medium-chain dehydrogenase/reductase (MDR) fold with a unique monomeric assembly. Two LovC cocrystal structures and enzymological studies help elucidate the molecular basis of LovC specificity, define stereochemistry, and identify active-site residues. Sequence alignment indicates a general applicability to trans-acting ERs of fungal PKSs, as well as their potential application to directing biosynthesis.

引用

页码：11144 / 11149

页数：6

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