近日，美国加州大学圣芭芭拉分校Yang, Yang团队报道了立体选择性合成非天然脯氨酸的吡哆醛自由基碳糖酶和亚胺还原酶光催化级联。该项研究成果发表在2025年9月25日出版的《自然-化学》杂志上。

协同光生物催化是实现分子间立体选择性自由基反应的一种重要策略，这种反应在生物学和化学中都是未知的。环非正则氨基酸的非对映选择性和非对映选择性合成仍然是对现有方法的挑战。

研究组报告了一个多酶光生物催化级联立体选择性制备多取代非天然脯氨酸。他们设计了一类尚未开发的吡哆醛5 '' -磷酸醛缩酶，作为新的天然自由基碳糖酶，催化天冬氨酸的脱羧C-C偶联，提供含亚胺的氮杂环非规范氨基酸。元基因组亚胺还原酶的高通量筛选导致了环亚胺非对映选择性生物催化还原和动态动力学不对称转化的发展，提供了光学纯的非天然脯氨酸，这些脯氨酸具有2,5-反立体化学，具有多达三个立体中心。除了其合成用途外，研究组还利用开壳酶胺催化建立了一种新的自由基吡哆醛酶学模式，为开发新的自由基反应开辟了途径。

附：英文原文

Title: A pyridoxal radical carboligase and imine reductase photobiocatalytic cascade for stereoselective synthesis of unnatural prolines

Author: Zhang, Chen, Zhou, Jun, Mai, Binh Khanh, Qin, Zijun, Finnigan, James, Gittings, Samantha, Liu, Peng, Yang, Yang

Issue&Volume: 2025-09-25

Abstract: Cooperative photobiocatalysis is a useful strategy for achieving stereoselective intermolecular radical reactions that are not known in either biology or chemistry. The diastereoselective and enantioselective synthesis of cyclic non-canonical amino acids remains challenging using established methods. Here we report a multienzyme photobiocatalytic cascade to stereoselectively prepare polysubstituted unnatural prolines. We engineered an underexploited class of pyridoxal 5′-phosphate aldolases as new-to-nature radical carboligases to catalyse the decarboxylative C–C coupling of aspartic acid, furnishing imine-containing azacyclic non-canonical amino acids. High-throughput screening of metagenomic imine reductases led to the development of diastereoselective biocatalytic reduction and dynamic kinetic asymmetric transformation of cyclic imines, providing optically pure unnatural prolines featuring an elusive 2,5-anti stereochemistry with up to three stereocentres. Beyond its synthetic utility, this study established a new mode of radical pyridoxal enzymology by leveraging open-shell enamine catalysis, opening up avenues for developing new free radical reactions.

DOI: 10.1038/s41557-025-01937-2

Source: https://www.nature.com/articles/s41557-025-01937-2