増田 涼介

Abstract The catalytic selenium redox chemistry of iodothyronine deiodinases (DIOs) has remained largely speculative because the proposed oxidized selenium intermediates have never been connected through direct chemical transformations. Herein, we examine the chemical feasibility of the proposed DIO selenium redox cycle using isolable DIO-inspired selenopeptide models encapsulated within molecular-cradle frameworks. The reaction of a cradled selenocysteine selenol (Sec−SeH) with a thyroxine derivative produced the corresponding selenocysteine selenenyl iodide (Sec−SeI) together with the outer-ring-deiodinated product, providing the first direct chemical demonstration of the proposed initial oxidation step in a selenocysteine-containing system. Isolated Sec−SeI underwent trapping by cysteine thiols to form selenenyl sulfides, hydrolysis to selenenic acid (Sec−SeOH), including the DIO1-inspired species reported here for the first time, and reductive conversion back to Sec−SeH through the selenenyl sulfide. These reactions establish the chemical competence of several key selenium transformations proposed for the DIO catalytic cycle. Propylthiouracil (PTU) rapidly trapped Sec−SeI under basic conditions, whereas the corresponding selenenyl sulfides were unreactive, indicating that oxidized selenium species preceding Se−S resolution are more plausible PTU targets than the resolved selenenyl sulfides. These findings provide a molecular-level experimental framework for evaluating the proposed elementary steps in DIO catalysis and inhibition.