John Tobias, Pires Elisabete, Hester Svenja S, Salah Eidarus, Hopkinson Richard J, Schofield Christopher J
Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK.
Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford, UK.
Commun Chem. 2023 Jan 13;6(1):12. doi: 10.1038/s42004-022-00801-5.
Formaldehyde (HCHO) is a potent electrophile that is toxic above threshold levels, but which is also produced in the nuclei of eukaryotic cells by demethylases. We report studies with the four canonical human histones revealing that histone H2B reacts with HCHO, including as generated by a histone demethylase, to give a stable product. NMR studies show that HCHO reacts with the N-terminal proline and associated amide of H2B to give a 5,5-bicyclic aminal that is relatively stable to competition with HCHO scavengers. While the roles of histone modification by this reaction require further investigation, we demonstrated the potential of N-terminal aminal formation to modulate protein function by conducting biochemical and cellular studies on the effects of HCHO on catalysis by 4-oxalocrotonate tautomerase, which employs a nucleophilic N-terminal proline. The results suggest that reactions of N-terminal residues with HCHO and other aldehydes have potential to alter protein function.
甲醛（HCHO）是一种强效亲电试剂，在阈值以上具有毒性，但在真核细胞的细胞核中也由去甲基酶产生。我们报告了对四种典型人类组蛋白的研究，结果表明组蛋白H2B与HCHO发生反应，包括由组蛋白去甲基酶产生的HCHO，生成一种稳定的产物。核磁共振研究表明，HCHO与H2B的N端脯氨酸及相关酰胺反应，生成一种对HCHO清除剂竞争相对稳定的5,5-双环缩醛胺。虽然该反应对组蛋白修饰的作用有待进一步研究，但我们通过对HCHO对4-氧代巴豆酸互变异构酶催化作用的影响进行生化和细胞研究，证明了N端缩醛胺形成对调节蛋白质功能的潜力，4-氧代巴豆酸互变异构酶利用亲核性的N端脯氨酸。结果表明，N端残基与HCHO和其他醛类的反应有可能改变蛋白质功能。
