Highly Electrophilic Intermediates in the Bypass Mechanism of Glutathione Peroxidase: Synthesis, Reactivity, and Structures of Selenocysteine‐Derived Cyclic Selenenyl Amides

Abstract

Selenocysteine (Sec)‐derived cyclic selenenyl amides, formed by the intramolecular cyclization of Sec selenenic acids (Sec–SeOHs), have been postulated to function as protective forms in the bypass mechanism of glutathione peroxidase (GPx). However, their chemical properties have not been experimentally elucidated in proteins or small‐molecule systems. Recently, we reported the first nuclear magnetic resonance observation of Sec–SeOHs and their cyclization to the corresponding cyclic selenenyl amides using selenopeptide model systems incorporated in a molecular cradle. Herein, we elucidate the structures and reactivities of Sec‐derived cyclic selenenyl amides. The crystal structures and reactions toward a cysteine thiol or a 1,3‐diketone‐type chemical probe indicated the highly electrophilic character of cyclic selenenyl amides. This suggests that they can serve not only as protective forms to suppress the inactivation of Sec–SeOHs in GPx but also as highly electrophilic intermediates in the reactions of selenoproteins.

Demonstration of the Formation of a Selenocysteine Selenenic Acid through Hydrolysis of a Selenocysteine Selenenyl Iodide Utilizing a Protective Molecular Cradle

“…2.3 × 1.7 nm). Similar to the Sec-SeIs we previously reported [40][41][42][43][44], Sec-SeI 4 exhibited high thermal stability, with a melting point of above 250 • C. Sec-SeI 4 is also stable in air and can be manipulated as a compound having "shelf-stability". In the catalytic mechanism of Dio, the formation of a Sec-SeI intermediate during the deiodination of iodothyronine substrates in the first half-reaction has been widely accepted (Scheme 2).…”

“…In smallmolecule systems, selenenic acids undergo facile self-condensation to selenoseleninates [36], and selenenyl iodides readily disproportionate to diselenides and iodine [37,38]. As a chemical tool to stabilize such reactive species, we have developed a large molecular cradle capable of accommodating a reactive amino acid residue (Figure 1) [39][40][41][42][43]. By using the molecular cradle as an N-terminal protecting group (henceforth denoted as "Bpsc"), we recently succeeded in the first spectroscopic observation of Sec-SeOHs.…”

“…Sec-SeOH 2 derived from a selenocysteine methyl ester was generated by the oxidation of Sec-SeH 1 with H 2 O 2 in the presence of NaOH at −65 • C in high yield (Scheme 1) [40]. Although 2 was found to be stable at −20 • C, it underwent thermal deselenation to form the corresponding dehydroalanine 3 upon warming to 15 • C. We also achieved the synthesis and isolation of Sec-SeIs utilizing the molecular cradle [40][41][42][43][44], which were found to have high thermal stability in contrast to Sec-SeOHs. Recently, it has been postulated that the conversion of a Sec-SeI to a Sec-SeOH is potentially involved in the Dio catalytic mechanism (Scheme 2) [27,33].…”

Glutathione Peroxidase-like Antioxidant Activity of 1,3-Benzoselenazoles: Synthesis and In Silico Molecular Docking Studies as Pancreatic Lipase Inhibitors

“…Excess of ROS was ameliorated by some natural enzymatic preventive antioxidants such as catalases, superoxide dismutase, and the GPx-enzymes in biological systems . A variety of organoselenium compounds as antioxidants have been developed to mimic the action of the GPx-enzymes. , In this regard, the first synthetic heterocyclic organoselenium compound as ebselen (2-phenyl-1,2-benzoisoselenazol-3-[2 H ] one, 1 ) with the Se–N bond in a five-membered ring was discovered as the GPx-mimic (Figure ). …”