An aldol switch discovered in stilbene synthases mediates cyclization specificity of type III polyketide synthases

被引:222
作者
Austin, MB
Bowman, ME
Ferrer, JL
Schröder, J
Noel, JP
机构
[1] Salk Inst Biol Studies, Struct Biol Lab, La Jolla, CA 92037 USA
[2] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92037 USA
[3] IBS JP Ebel, F-38027 Grenoble 1, France
[4] Univ Freiburg, Inst Biol 2 Biochem Pflanzen, D-79104 Freiburg, Germany
来源
CHEMISTRY & BIOLOGY | 2004年 / 11卷 / 09期
基金
美国国家卫生研究院; 美国国家科学基金会;
关键词
D O I
10.1016/j.chembiol.2004.05.024
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Stilbene synthase (STS) and chalcone synthase (CHS) each catalyze the formation of a tetraketide intermediate from a CoA-tethered phenylpropanoid starter and three molecules of malonyl-CoA, but use different cyclization mechanisms to produce distinct chemical scaffolds for a variety of plant natural products. Here we present the first STS crystal structure and identify, by mutagenic conversion of alfalfa CHS into a functional stilbene synthase, the structural basis for the evolution of STS cyclization specificity in type III polyketide synthase (PKS) enzymes. Additional mutagenesis and enzymatic characterization confirms that electronic effects rather than steric factors balance competing cyclization specificities in CHS and STS. Finally, we discuss the problematic in vitro reconstitution of plant stilbenecarboxylate pathways, using insights from existing biomimetic polyketide cyclization studies to generate a novel mechanistic hypothesis to explain stilbenecarboxylate biosynthesis.
引用
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页码:1179 / 1194
页数:16
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