近日，瑞士巴塞尔大学Ward, Thomas R.团队实现了重新利用血液蛋白进行不对称金属催化的氢原子转移。这一研究成果发表在2025年7月30日出版的《自然》杂志上。

过渡金属氢化物已广泛应用于催化羰基、烯烃和炔烃等不饱和基团的加氢功能化。金属氢化物氢原子转移（MHAT）作为非活化烯烃自由基加氢功能化的一种很有前途的策略，弥补了金属氢化物键的异裂作用，使复合物分子在后期多样化。然而，由于前手性有机自由基与对映不纯催化剂之间的弱相互作用，不对称MHAT6仍然具有挑战性。

研究组发现细胞色素P450酶（CYPs）可以被重新利用来催化不对称的MHAT反应，这是一种新的自然反应。P450BM3的定向进化产生了一个三重突变体，该突变体催化非活化烯烃的MHAT自由基环化，在有氧全细胞条件下产生多种环化合物，包括吡啶和哌啶，其对构象比高达98:2。

除了缺电子的烯烃，其他的自由基受体——包括腙、肟和腈——也被重新利用的P450BM3转化为富集对映体的环化产物。机理研究支持MHAT机制是由一种瞬态的铁(III) -氢化物的均溶解理进行的。从CYP119开始，定向进化提供了立体互补的MHATase，突出了重新利用CYPs进行MHAT生物催化的潜力。该研究突出了将均溶金属氢化物反应性整合到金属酶中的前景，扩大了不对称自由基生物催化的范围。

附：英文原文

Title: Repurposing haemoproteins for asymmetric metal-catalysed H atom transfer

Author: Zhang, Xiang, Chen, Dongping, lvarez, Mara, Ward, Thomas R.

Issue&Volume: 2025-07-30

Abstract: Transition metal–hydrides have been widely exploited in catalysis for the hydrofunctionalization of unsaturated moieties, including carbonyls, alkenes and alkynes1. To complement heterolytic metal–hydride bond cleavage, metal–hydride hydrogen atom transfer (MHAT) has recently gained attention, as a promising strategy for radical hydrofunctionalization of unactivated alkenes2, thus enabling late-stage diversification of complex molecules3,4. However, owing to the weak interactions between the prochiral organic radical and the enantiopure catalyst5, asymmetric MHAT6 remains challenging. Here we show that cytochrome P450 enzymes (CYPs) can be repurposed to catalyse asymmetric MHAT, a new-to-nature reaction. Directed evolution of P450BM3 yielded a triple mutant that catalyses MHAT radical cyclization of unactivated alkenes, producing diverse cyclic compounds—including pyrrolidines and piperidines—with up to 98:2 enantiomeric ratio under aerobic whole-cell conditions. Apart from electron-deficient alkenes, alternative radical acceptors—including hydrazones, oximes and nitriles—were converted by repurposed P450BM3 to enantioenriched cyclization products. Mechanistic investigations support an MHAT mechanism proceeding by homolytic cleavage of a fleeting iron(III)–hydride species2,6. Starting from CYP119, directed evolution afforded a stereocomplementary MHATase, highlighting the potential of repurposed CYPs for MHAT biocatalysis. Our study highlights the prospect of integrating homolytic metal–hydride reactivity into metalloenzymes, thus expanding the scope of asymmetric radical biocatalysis.

DOI: 10.1038/s41586-025-09308-0

Source: https://www.nature.com/articles/s41586-025-09308-0