近日，美国哈佛大学Emily P. Balskus团队报道了重氮代谢物的化学捕获揭示了生物合成腙氧化。该项研究成果发表在2026年2月4日出版的《自然》杂志上。

具有化学反应活性的微生物天然产物凭借其公认的抗癌、抗菌和抗氧化活性，已推动药物研发取得重要进展。然而，高活性代谢物的发现尤为困难，因为它们往往难以适应传统的生物活性导向分离流程。含重氮基团的天然产物作为高活性微生物代谢物的一个重要分支，既展现出显著的生物活性，又能实现高效的生物合成转化；但由于重氮基团对光、热、弱酸及机械冲击的不稳定性，其高效发现与应用长期受到制约。

研究组开发了一种基于反应性的筛选方法，通过质谱技术捕获含重氮基团代谢物以促进其发现。该技术流程从人类肺病原体Nocardia ninae中鉴定出两种新型含重氮天然产物：4-重氮-3-氧代丁酸（1）与重氮丙酮（2）。生物合成机制研究揭示了一种独特的重氮形成酶促逻辑，涉及金属酶Dob3催化的腙氧化反应；该酶的生化特性表征显示其在生物催化领域具有广阔的应用前景。总体而言，该研究彰显了反应性导向策略在发现高活性代谢物及发掘独特酶促转化反应方面的重要价值。

附：英文原文

Title: Chemical capture of diazo metabolites reveals biosynthetic hydrazone oxidation

Author: Pfeifer, Katarina, Van Cura, Devon, Wu, Kelvin J. Y., Balskus, Emily P.

Issue&Volume: 2026-02-04

Abstract: Chemically reactive microbial natural products have enabled therapeutic development1 via their well-established anticancer, antibiotic and antioxidant activities. However, discovery of reactive metabolites is particularly challenging because they may not tolerate traditional bioactivity-guided isolation workflows2. Diazo-containing natural products are a subset of highly reactive microbial metabolites that display potent bioactivity3 and enable powerful biosynthetic transformations4,5; however, instability of the diazo group to light6, heat7, mild acid8 and mechanical shock9 has precluded their efficient discovery and application. Here we develop a reactivity-based screening approach to capture diazo-containing metabolites and facilitate their discovery by mass spectrometry. This workflow revealed two novel diazo-containing natural products, 4-diazo-3-oxobutanoic acid (1) and diazoacetone (2), from the human lung pathogen Nocardia ninae. Biosynthetic investigations revealed a distinct enzymatic logic for diazo formation involving hydrazone oxidation catalysed by the metalloenzyme Dob3, and its biochemical characterization suggests promising future applications in biocatalysis. Overall, our work highlights the power of reactivity-guided strategies for identifying reactive metabolites and facilitating the discovery of unique enzymatic transformations.

DOI: 10.1038/s41586-025-10079-x

Source: https://www.nature.com/articles/s41586-025-10079-x