An ongoing challenge in chemical research is to design catalysts that select the outcomes of the reactions of complex molecules. Chemists rely on organocatalysts or transition metal catalysts to control stereoselectivity, regioselectivity and periselectivity (selectivity among possible pericyclic reactions). Nature achieves these types of selectivity with a variety of enzymes such as the recently discovered pericyclases-a family of enzymes that catalyse pericyclic reactions1. Most characterized enzymatic pericyclic reactions have been cycloadditions, and it has been difficult to rationalize how the observed selectivities are achieved2-13. Here we report the discovery of two homologous groups of pericyclases that catalyse distinct reactions: one group catalyses an Alder-ene reaction that was, to our knowledge, previously unknown in biology; the second catalyses a stereoselective hetero-Diels-Alder reaction. Guided by computational studies, we have rationalized the observed differences in reactivities and designed mutant enzymes that reverse periselectivities from Alder-ene to hetero-Diels-Alder and vice versa. A combination of in vitro biochemical characterizations, computational studies, enzyme co-crystal structures, and mutational studies illustrate how high regioselectivity and periselectivity are achieved in nearly identical active sites.

中文翻译：

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酶促阿尔德烯反应

化学研究中的一个持续挑战是设计选择复杂分子反应结果的催化剂。化学家依靠有机催化剂或过渡金属催化剂来控制立体选择性、区域选择性和周选择性（可能的周环反应之间的选择性）。大自然通过多种酶实现这些类型的选择性，例如最近发现的周环酶——催化周环反应的酶家族1。最具特征的酶促周环反应是环加成反应，很难解释观察到的选择性是如何实现的 2-13。在这里，我们报告了两个同源的周环化酶组的发现，它们催化不同的反应：一组催化 Alder-ene 反应，据我们所知，这在生物学中是以前未知的；第二个催化立体选择性的杂-Diels-Alder反应。在计算研究的指导下，我们对观察到的反应性差异进行了合理化，并设计了突变酶，这些酶可以逆转从 Alder-ene 到异质 Diels-Alder 的周选择性，反之亦然。体外生化表征、计算研究、酶共晶结构和突变研究的组合说明了如何在几乎相同的活性位点上实现高区域选择性和周选择性。