The Role of Cytochrome P450 AbyV in the Final Stages of Abyssomicin C Biosynthesis
The Role of Cytochrome P450 AbyV in the Final Stages of Abyssomicin C Biosynthesis
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细胞色素 P450 AbyV 在 Abyssomicin C 生物合成最后阶段的作用
DOI：
10.1002/ange.202213053
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发表时间：
2022
影响因子：
--
通讯作者：
Devine A
中科院分区：
文献类型：
--
作者：
Devine A
Abyssomicin C及其阻转异构体是细菌叶酸代谢的有效抑制剂。 它们具有复杂的多环结构，并且它们的生物合成已被证明涉及几种不寻常的酶促转化。使用合成和体外试验的组合，我们揭示了AbyV，一种来自abygene簇的细胞色素P450酶，催化了一个关键的后期环氧化反应，该反应是安装abyssomicin C的特征醚桥核心所需的。 已经确定了AbyV的X射线晶体结构，结合分子动力学模拟为我们的功能数据提供了结构框架。这项工作证明了选择性碳13标记与NMR光谱相结合的力量，作为一种灵敏的工具，可以在体外询问酶催化反应，而无需纯化。
Abyssomicin C and its atropisomer are potent inhibitors of bacterial folate metabolism. They possess complex polycyclic structures, and their biosynthesis has been shown to involve several unusual enzymatic transformations. Using a combination of synthesis and in vitro assays we reveal that AbyV, a cytochrome P450 enzyme from theabygene cluster, catalyses a key late‐stage epoxidation required for the installation of the characteristic ether‐bridged core of abyssomicin C. The X‐ray crystal structure of AbyV has been determined, which in combination with molecular dynamics simulations provides a structural framework for our functional data. This work demonstrates the power of combining selective carbon‐13 labelling with NMR spectroscopy as a sensitive tool to interrogate enzyme‐catalysed reactions in vitro with no need for purification.