基于金属配位挖掘的靶向酶发现
近日，美国普林斯顿大学Chang, Michelle C. Y.团报报道了基于金属配位挖掘的靶向酶发现。该项研究成果发表在2026年7月1日出版的《自然》杂志上。
基因组测序和蛋白质结构预测领域近期的革命性进展，为理解、预测和设计酶功能开辟了新前沿。其中，新酶的发现与功能注释是这些工作的核心，它对于阐明基因型与表型之间的联系以及开发工业用生物催化剂至关重要。然而，准确预测酶功能仍是一大挑战，而新酶的发现往往依赖于偶然性。
研究组提出一种金属配位指导策略，该策略利用原子水平的机理原则，在蛋白质结构数据库中挖掘目标金属酶。研究组将该框架应用于AlphaFold2蛋白质结构数据库，以鉴定依赖于FeII/α-酮戊二酸的自由基卤化酶家族的新成员——这类酶能够选择性地功能化未活化的C(sp³)-H键，这是药物和其他高价值化合物生产中的关键转化步骤。这些自由基卤化酶在庞大而多样的Cupin超家族中属于低丰度类别。由于序列保守性低，在羟化酶、去饱和酶和差向异构酶等相关家族成员的复杂背景下，它们尤其难以被发现。
该金属配位挖掘方法以极低的计算成本，揭示出数个此前未知的自由基卤化酶家族，它们分布在不同系统发育空间中。研究组对两种新型自由基卤化酶——AspX和BtnX——的实验表征验证了预测。值得注意的是，BtnX展现出在自由基卤化酶中前所未有的底物混杂性，这为广泛的生物催化应用开辟了道路。
附：英文原文
Title: Targeted enzyme discovery using metal-coordination mining
Author: Kipouros, Ioannis, Chang, Michelle C. Y.
Issue&Volume: 2026-07-01
Abstract: The recent revolution in genome sequencing and protein structure prediction has opened new frontiers in understanding, predicting and designing enzyme function1,2. Central to these efforts is the discovery and functional annotation of novel enzymes, which is essential for elucidating the connection between genotype and phenotype and for developing biocatalysts for industrial applications. However, accurately predicting enzymatic function remains a major challenge, and the discovery of new enzymes often relies on serendipity. Here we present a metal-coordination-guided strategy that uses atomic-level mechanistic principles to mine protein structure databases for the targeted discovery of metalloenzymes. We apply this framework to the AlphaFold2 Protein Structure Database to identify new members of the FeII/α-ketoglutarate-dependent halogenase family, which selectively functionalize unactivated C(sp3)-H-bonds, a crucial transformation in the production of pharmaceuticals and other high-value compounds3,4. These radical halogenases constitute a low-abundance class within the large and diverse cupin superfamily5. Owing to low sequence conservation, they have been especially challenging to find against the complex background of related family members, such as hydroxylases, desaturases and epimerases. Our metal-coordination mining methodology reveals several previously unrecognized radical halogenase families spanning diverse phylogenetic space, at minimal computational cost. Our predictions are validated by the experimental characterization of two new radical halogenases, AspX and BtnX. Notably, BtnX shows a substrate promiscuity that is unprecedented in radical halogenases, opening the way for a broad range of biocatalytic applications.
DOI: 10.1038/s41586-026-10716-z
Source: https://www.nature.com/articles/s41586-026-10716-z
期刊信息
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html