Chemical Switching: A Concept Inspired by Strategies from Biocatalysis and Organocatalysis.

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.