A Crystalline and Thermally Stable Selenocysteine Selenenic Acid

Despite more than half a century of research on selenoproteins, the central catalytic intermediate, selenocysteine selenenic acid (Sec-SeOH), has remained experimentally elusive. Its isolation has long been impeded by its presumed instability and propensity for thermal deselenation. Here, we report the first isolable Sec-SeOH at ambient temperature. This relies on a bioinspired design of a selenopeptide sequence encapsulated within a protective cradle, together with an oxidant-free route from the corresponding selenenyl iodides (Sec-SeI), enabling x-ray structural analysis and chemical characterization. The isolated Sec-SeOH shows unexpected resistance to β-elimination to dehydroalanine (DHA). Oxidation experiments combined with theoretical calculations demonstrate that conversion to DHA proceeds preferentially via overoxidation to the seleninic acid (Sec-SeO₂H), for which β-elimination is substantially more favorable. Reactivity profiling further highlights the pronounced electrophilicity of Sec-SeOH toward biologically and pharmacologically relevant nucleophiles. These findings redefine the stability-reactivity landscape of Sec-SeOH and provide a foundation for strategies aimed at preventing selenoprotein inactivation. Beyond defining an isolable Sec-SeOH model, the work provides a molecular-level rationale for how selenoproteins can combine high selenium-centered reactivity with resistance to irreversible oxidative self-inactivation.