An Enzymatic [4+2] Cyclization Cascade Creates the Pentacyclic Core of Pyrroindomycins
An Enzymatic [4+2] Cyclization Cascade Creates the Pentacyclic Core of Pyrroindomycins
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酶促 [4 2] 环化级联创建吡咯吲哚霉素的五环核心
DOI：
10.1038/nchembio.1769
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发表时间：
2015
影响因子：
14.8
通讯作者：
Wen Liu
中科院分区：
文献类型：
--
作者：
Zhenhua Tian;Peng Sun;Yan Yan;Zhuhua Wu;Qingfei Zheng;Shuaixiang Zhou;Hua Zhang;Futao Yu;Xinying Jia;D;an Chen;Attila M;i;Tibor Kurtan;Wen Liu
[4+2]环加成反应仍然是合成和天然产物化学中最耐人寻味的转化之一。然而，在自然界中，已知的具有这种活性的酶非常少。在此，我们报告了一种前所未有的酶促[4+2]环化级联反应，它在吡咯菌素的生物合成中起着核心作用，吡咯菌素是五环螺四酸酯的天然产物。从含有两对1，3-二烯和烯基的线性中间体开始，专用的环化酶PyrE3和PyrI4协同作用，催化二烷基十氢林体系中两个环己烯的形成和分子的四螺环共轭。这两个环化反应完全依赖于酶，并且以区域和立体选择性的方式进行，以建立对映体纯的五环核心。对相关的螺四磷酸途径的分析证实，同系物在功能上是可交换的，建立了这些发现的普遍性，并解释了大自然如何用类似的刚性支架创造不同的活性分子。
The [4+2] cycloaddition remains one of the most intriguing transformations in synthetic and natural products chemistry. In nature, however, there are remarkably few enzymes known to have this activity. We herein report an unprecedented enzymatic [4+2] cyclization cascade that has a central role in the biosynthesis of pyrroindomycins, which are pentacyclic spirotetramate natural products. Beginning with a linear intermediate that contains two pairs of 1,3-diene and alkene groups, the dedicated cyclases PyrE3 and PyrI4 act in tandem to catalyze the formation of two cyclohexene rings in the dialkyldecalin system and the tetramate spiro-conjugate of the molecules. The two cyclizations are completely enzyme dependent and proceed in a regio- and stereoselective manner to establish the enantiomerically pure pentacyclic core. Analysis of a related spirotetronate pathway confirms that homologs are functionally exchangeable, establishing the generality of these findings and explaining how nature creates diverse active molecules with similar rigid scaffolds.