Enzyme-Dependent [4 + 2] Cycloaddition Depends on Lid-like Interaction of the N-Terminal Sequence with the Catalytic Core in PyrI4
Enzyme-Dependent [4 + 2] Cycloaddition Depends on Lid-like Interaction of the N-Terminal Sequence with the Catalytic Core in PyrI4
复制标题
酶依赖性 [4 2] 环加成取决于 PyrI4 中 N 末端序列与催化核心的类似盖子的相互作用
DOI：
10.1016/j.chembiol.2016.01.005
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发表时间：
2016
影响因子：
8.6
通讯作者：
Wen Liu
中科院分区：
文献类型：
--
作者：
Qingfei Zheng;Yujiao Guo;Linlin Yang;Zhixiong Zhao;Zhuhua Wu;Hua Zhang;Jianping Liu;Xiaofang Cheng;Jiequn Wu;Huaiyu Yang;Hualiang Jiang;Lifeng Pan;Wen Liu
Diels-Alder [4 + 2]环加成反应是合成六元大分子的最有效的有机合成方法之一，已有近世纪的历史。然而，酶是否以及如何催化这种类型的反应仍然不完全清楚。在这里，我们专注于PyrI 4，一种在吡咯吲哚霉素的生物合成途径中发现的酶，在该途径中，它通过酶依赖性的选择性[4 + 2]环加成反应催化螺环缀合物的形成。我们报告的晶体结构的PyrI 4单独和复杂的与它的产品。这些结构的比较分析，结合生物化学分析，使我们提出了一个独特的捕获机制，其中的盖状行动的N-末端尾部施加构象约束的β桶催化核心，这增强了邻近和极化效应的反应性基团（1，3-二烯和烯烃），以驱动环化的区域和立体特异性的方式。这项工作代表了一个重要的一步，更广泛的应用酶催化的[4 + 2]环化的合成目的。
The Diels-Alder [4 + 2] cycloaddition reaction is one of the most powerful and elegant organic synthesis methods for forming 6-membered molecules and has been known for nearly a century. However, whether and how enzymes catalyze this type of reaction is still not completely clear. Here we focus on PyrI4, an enzyme found in the biosynthetic pathway of pyrroindomycins where it catalyzes the formation of a spiro-conjugate via an enzyme-dependentexo-selective [4 + 2] cycloaddition reaction. We report the crystal structures of PyrI4 alone and in complex with its product. Comparative analysis of these structures, combined with biochemical analysis, lead us to propose a unique trapping mechanism whereby the lid-like action of the N-terminal tail imposes conformational constraints on the β barrel catalytic core, which enhances the proximity and polarization effects of reactive groups (1,3-diene and alkene) to drive cyclization in a regio- and stereo-specific manner. This work represents an important step toward the wider application of enzyme-catalyzed [4 + 2] cyclization for synthetic purposes.