The paraherquamides are potent anthelmintic natural products with complex heptacyclic scaffolds. One key feature of these molecules is the spiro-oxindole moiety that lends a strained three-dimensional architecture to these structures. The flavin monooxygenase PhqK was found to catalyze spirocycle formation through two parallel pathways in the biosynthesis of paraherquamides A and G. Two new paraherquamides (K and L) were isolated from a ΔphqK strain of Penicillium simplicissimum, and subsequent enzymatic reactions with these compounds generated two additional metabolites paraherquamides M and N. Crystal structures of PhqK in complex with various substrates provided a foundation for mechanistic analyses and computational studies. While it is evident that PhqK can react with various substrates, reaction kinetics and molecular dynamics simulations indicated that the dioxepin-containing paraherquamide L was the favored substrate. Through this effort, we have elucidated a key step in the biosynthesis of the paraherquamides, and provided a rationale for the selective spirocyclization of these powerful anthelmintic agents.

中文翻译：

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paraherquamide 生物合成途径中螺环形成的分子基础

paraherquamides 是具有复杂七环支架的有效驱虫天然产品。这些分子的一个关键特征是螺-羟吲哚部分，它为这些结构提供了一种应变的三维结构。黄素单加氧酶 PhqK 被发现通过平行链霉菌 A 和 G 生物合成中的两条平行途径催化螺环的形成。从简单青霉的 ΔphqK 菌株中分离出两种新的平行链甲酰胺（K 和 L），随后与这些化合物的酶促反应产生了两种其他代谢物 paraherquamides M 和 N。PhqK 与各种底物复合的晶体结构为机械分​​析和计算研究提供了基础。虽然很明显 PhqK 可以与各种底物反应，反应动力学和分子动力学模拟表明，含二恶英的 paraherquamide L 是首选底物。通过这一努力，我们阐明了paraherquamides 生物合成的关键步骤，并为这些强大的驱虫剂的选择性螺环化提供了基本原理。