A Crystalline and Thermally Stable Selenocysteine Selenenic Acid

Abstract

ABSTRACT 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–SeO 2 H), 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.