Hua Xia, Wang Yuan-Fei, Jin Xiao, Yu Hong-Yin, Wang Hui-Hui, Chen Yong-Zheng, Wan Nan-Wei
School of Pharmacy, Zunyi Medical University, Zunyi, 563000, China.
Nat Commun. 2025 Jan 30;16(1):1170. doi: 10.1038/s41467-025-56463-z.
Although biocatalysis offers complementary or alternative approaches to traditional synthetic methods, the limited range of available enzymatic reactions currently poses challenges in synthesizing a diverse array of desired compounds. Consequently, there is a significant demand for developing novel biocatalytic processes to enable reactions that were previously unattainable. Herein, we report the discovery and subsequent protein engineering of a unique halohydrin dehalogenase to develop a biocatalytic platform for enantioselective formation and ring-opening of oxetanes. This biocatalytic platform, exhibiting high efficiency, excellent enantioselectivity, and broad scopes, facilitates the preparative-scale synthesis of chiral oxetanes and a variety of chiral γ-substituted alcohols. Additionally, both the enantioselective oxetane formation and ring-opening processes are proven scalable for large-scale transformations at high substrate concentrations, and can be integrated efficiently in a one-pot, one-catalyst cascade system. This work expands the enzymatic toolbox for non-natural reactions and will promote further exploration of the catalytic repertoire of halohydrin dehalogenases in synthetic and pharmaceutical chemistry.
尽管生物催化为传统合成方法提供了互补或替代方法，但目前可用酶促反应的范围有限，这在合成各种所需化合物时带来了挑战。因此，迫切需要开发新型生物催化过程，以实现以前无法实现的反应。在此，我们报告了一种独特的卤代醇脱卤酶的发现及后续蛋白质工程改造，以开发一个用于对映选择性形成和开环氧杂环丁烷的生物催化平台。这个生物催化平台具有高效率、优异的对映选择性和广泛的适用范围，有助于手性氧杂环丁烷和各种手性γ-取代醇的制备规模合成。此外，对映选择性氧杂环丁烷的形成和开环过程在高底物浓度下进行大规模转化时都被证明是可扩展的，并且可以有效地集成到一锅、一催化剂的级联系统中。这项工作扩展了用于非天然反应的酶工具箱，并将促进在合成化学和药物化学中进一步探索卤代醇脱卤酶的催化功能。
