近日，美国芝加哥大学何川团队实现了小分子催化脱氨基助力RNA中N⁶甲基腺苷的转录组范围分析。该研究于2025年4月17日发表在《自然-化学》杂志上。

脱氨反应在基础有机化学和生物化学中都很重要。传统的化学脱氨方法依赖于芳基重氮盐在恶劣酸性条件下的主题，这限制了大多数生物底物的应用范围。

研究组提出了一种在DNA和RNA生物大分子可以耐受的温和条件下进行N-亚硝化脱胺的策略。羰基有机催化剂与Lewis酸催化剂的协同催化作用有利于伯胺形成碳-硝基中间体，该中间体重排为N-亚硝胺，在温和条件下导致未取代的典型DNA/RNA碱基的选择性脱胺。

研究组利用这种方法将腺嘌呤脱胺分解为次黄嘌呤，通过逆转录酶或DNA聚合酶解读为鸟嘌呤，而N⁶-甲基腺苷位点抵抗脱胺作用，仍然被鉴定为腺嘌呤。这种反应性使一种化学上温和、低输入的检测方法能够在碱基分辨率上测序腺苷甲基化，称为化学协同催化辅助N⁶ -甲基腺苷测序。

附：英文原文

Title: Small-molecule-catalysed deamination enables transcriptome-wide profiling of N6-methyladenosine in RNA

Author: Wang, Pingluan, Ye, Chang, Zhao, Michelle, Jiang, Bochen, He, Chuan

Issue&Volume: 2025-04-17

Abstract: The deamination reaction is important to both fundamental organic chemistry and biochemistry. Traditional chemical methods of deamination rely on the use of aryldiazonium salts under harsh acidic conditions, which limits the application scope for most biological substrates. Here we present an N-nitrosation strategy for deamination under mild conditions that DNA and RNA biological macromolecules can tolerate. Cooperative catalysis combining a carbonyl organocatalyst with a Lewis acid catalyst facilitates the formation of a carbon–nitro intermediate from a primary amine, which, on rearrangement into N-nitrosamine, leads to the selective deamination of unsubstituted canonical DNA/RNA bases under mild conditions. We used this approach to deaminate adenine into hypoxanthine, read as guanine by reverse transcriptases or DNA polymerases, while N6-methyladenosine sites resist deamination and remain identified as adenine. This reactivity enables a chemically mild, low-input detection method for sequencing of adenosine methylation at base resolution, named chemical cooperative catalysis-assisted N6-methyladenosine sequencing.

DOI: 10.1038/s41557-025-01801-3

Source: https://www.nature.com/articles/s41557-025-01801-3