Visnes Torkild, Zhou Kaixin, Kemas Aurino M, Campopiano Dominic, Lauschke Volker M, Michel Maurice
Department of Biotechnology and Nanomedicine, SINTEF, N-7465, Trondheim, Norway.
School of Chemistry, University of Edinburgh, Edinburgh, EH9 3FJ, UK.
Chembiochem. 2025 Jun 3;26(11):e202500220. doi: 10.1002/cbic.202500220. Epub 2025 May 26.
In this perspective the character of aldehyde functional groups is outlined as central intermediates in DNA repair. As highly reactive entities, aldehydes exist in limited quantities and in contextualized scenarios only and are commonly masked as a Schiff base. Recent advances reveal that principles of organic chemistry can modulate the enzymatic cleavage of Schiff bases, a process termed chemical switching. This approach not only enhances the production of canonical DNA repair products, bolstering cellular function, but also generates novel reaction intermediates, potentially rewiring cellular pathways. However, such rewiring could increase the complexity and toxicity of DNA repair intermediates, influencing therapeutic outcomes. To shape novel classes of therapeutics, an exploitation of these fine-tuned reaction principles requires expertise of enzymologists and scientists skilled in bio- and organocatalysis. Here, the current state of the art is outlined in chemically switching enzymatic function in cells with focus on DNA repair, highlighting challenges of this new type of protein modulation and discussing possible solutions. This paints a picture of the chemical switching concept as an emerging playing field with exciting translational prospects.
从这个角度来看，醛官能团的特性被概述为DNA修复中的核心中间体。作为高反应性实体，醛仅以有限的量存在于特定的情境中，并且通常以席夫碱的形式被掩盖。最近的进展表明，有机化学原理可以调节席夫碱的酶促裂解，这一过程被称为化学转换。这种方法不仅能提高标准DNA修复产物的产量，增强细胞功能，还能产生新的反应中间体，可能会重新连接细胞通路。然而，这种重新连接可能会增加DNA修复中间体的复杂性和毒性，从而影响治疗效果。为了开发新型治疗方法，利用这些微调的反应原理需要酶学家以及生物催化和有机催化领域的科学家的专业知识。在此，概述了通过化学转换细胞中酶功能（重点是DNA修复）的当前技术水平，突出了这种新型蛋白质调节的挑战并讨论了可能的解决方案。这描绘了化学转换概念作为一个具有令人兴奋的转化前景的新兴领域的图景。
