Light responsive hydrogen selenide (H ₂ Se)/hydrogen diselenide (H ₂ Se ₂ ) donors: applied for protein <i>S</i> -selenylation on PRDX6

Hydrogen selenide (H₂Se) is an important metabolite in selenium biochemistry and plays a crucial role in redox biology. While its significance has become increasingly recognized, research on H₂Se is challenging due to its instability and high reactivity. Suitable compounds (aka donors) that can selectively produce H₂Se in biological systems would facilitate this research field. In this work, we explored photo-triggered H₂Se donors by utilizing two structural templates: 2-nitrobenzyl selenides and 2-methoxy-6-naphthacyl selenides. The photoreactions of these compounds under light were studied. 2-Nitrobenzyl selenides were found to release H₂Se (and its oxidized form H₂Se₂) slowly under UV light, but the released H₂Se/H₂Se₂ could further react with the photoproduct and be consumed. On the other hand, naphthacyl selenides could undergo clean and fast reactions to produce H₂Se/H₂Se₂, as well as a stable and fluorescent photoproduct. This self-monitoring and quick releasing ability make naphthacyl selenides ‛smart donors' for biological applications. Importantly, this donor was found to induce protein <i>S</i>-selenylation (CysS-SeH) on Cys47 and Cys91 in both recombinant peroxiredoxin-6 (PRDX6) and PRDX6-overexpressing HEK293T cells. This photo-triggered donor system may serve as a new strategy to control selenium-based protein post-translational modifications for mechanistic studies into selenium metabolic pathways and ferroptosis.