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Selenocysteine selenenic acids (Sec–SeOHs) and selenocysteine selenenyl iodides (Sec–SeIs) have long been recognized as crucial intermediates in the catalytic cycle of glutathione peroxidase (GPx) and iodothyronine deiodinase (Dio), respectively. However, the observation of these reactive species remained elusive until our recent study, where we successfully stabilized Sec–SeOHs and Sec–SeIs using a protective molecular cradle. Here, we report the first demonstration of the chemical transformation from a Sec–SeI to a Sec–SeOH through alkaline hydrolysis. A stable Sec–SeI derived from a selenocysteine methyl ester was synthesized using the protective cradle, and its structure was determined by crystallographic analysis. The alkaline hydrolysis of the Sec–SeI at −50 °C yielded the corresponding Sec–SeOH in an 89% NMR yield, the formation of which was further confirmed by its reaction with dimedone. The facile and nearly quantitative conversion of the Sec–SeI to the Sec–SeOH not only validates the potential involvement of this process in the catalytic mechanism of Dio, but also highlights its utility as a method for producing a Sec–SeOH. [ABSTRACT FROM AUTHOR]

Selenocysteine selenenic acids (Sec–SeOHs) and selenocysteine selenenyl iodides (Sec–SeIs) have long been recognized as crucial intermediates in the catalytic cycle of glutathione peroxidase (GPx) and iodothyronine deiodinase (Dio), respectively. However, the observation of these reactive species remained elusive until our recent study, where we successfully stabilized Sec–SeOHs and Sec–SeIs using a protective molecular cradle. Here, we report the first demonstration of the chemical transformation from a Sec–SeI to a Sec–SeOH through alkaline hydrolysis. A stable Sec–SeI derived from a selenocysteine methyl ester was synthesized using the protective cradle, and its structure was determined by crystallographic analysis. The alkaline hydrolysis of the Sec–SeI at −50 °C yielded the corresponding Sec–SeOH in an 89% NMR yield, the formation of which was further confirmed by its reaction with dimedone. The facile and nearly quantitative conversion of the Sec–SeI to the Sec–SeOH not only validates the potential involvement of this process in the catalytic mechanism of Dio, but also highlights its utility as a method for producing a Sec–SeOH.

A primary-alkyl-substituted selenenyl iodide was successfully synthesized through oxidative iodination of a selenol with N-iodosuccinimide by taking advantage of a cavity-shaped steric protection group. The selenenyl iodide exhibited high thermal stability and remained unchanged upon heating at 100 °C for 3 h in [D8]toluene. The selenenyl iodide was reduced to the corresponding selenol by treatment with dithiothreitol. Hydrolysis of the selenenyl iodide under alkaline conditions afforded the corresponding selenenic acid almost quantitatively, corroborating the chemical validity of the recent proposal that hydrolysis of a selenenyl iodide to a selenenic acid is potentially involved in the catalytic mechanism of an iodothyronine deiodinase.

Iodothyronine deiodinases (Dios) are involved in the regioselective removal of iodine from thyroid hormones (THs). Deiodination is essential to maintain TH homeostasis, and disruption can have detrimental effects. Halogen bonding (XB) to the selenium of the selenocysteine (Sec) residue in the Dio active site has been proposed to contribute to the mechanism for iodine removal. Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) are known disruptors of various pathways of the endocrine system. Experimental evidence shows PBDEs and their hydroxylated metabolites (OH-BDEs) can inhibit Dio, while data regarding PCB inhibition are limited. These xenobiotics could inhibit Dio activity by competitively binding to the active site Sec through XB to prevent deiodination. XB interactions calculated using density functional theory (DFT) of THs, PBDEs, and PCBs to a methyl selenolate (MeSe−) arrange XB strengths in the order THs > PBDEs > PCBs in agreement with known XB trends. THs have the lowest energy C−X*-type unoccupied orbitals and overlap with the Se lp donor leads to high donor-acceptor energies and the greatest activation of the C−X bond. The higher energy C−Br* and C−Cl* orbitals similarly result in weaker donor-acceptor complexes and less activation of the C−X bond. Comparison of the I···Se interactions for the TH group suggest that a threshold XB strength may be required for dehalogenation. Only highly brominated PBDEs have binding energies in the same range as THs, suggesting that these compounds may inhibit Dio and undergo debromination. While these small models provide insight on the I···Se XB interaction itself, interactions with other active site residues are governed by regioselective preferences observed in Dios.

Iodothyronine deiodinases (Dios) are involved in the regioselective removal of iodine from thyroid hormones (THs). Deiodination is essential to maintain TH homeostasis, and disruption can have detrimental effects. Halogen bonding (XB) to the selenium of the selenocysteine (Sec) residue in the Dio active site has been proposed to contribute to the mechanism for iodine removal. Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) are known disruptors of various pathways of the endocrine system. Experimental evidence shows PBDEs and their hydroxylated metabolites (OH-BDEs) can inhibit Dio, while data regarding PCB inhibition are limited. These xenobiotics could inhibit Dio activity by competitively binding to the active site Sec through XB to prevent deiodination. XB interactions calculated using density functional theory (DFT) of THs, PBDEs, and PCBs to a methyl selenolate (MeSe−) arrange XB strengths in the order THs > PBDEs > PCBs in agreement with known XB trends. THs have the lowest energy C–X*-type unoccupied orbitals and overlap with the Se lp donor leads to high donor-acceptor energies and the greatest activation of the C–X bond. The higher energy C–Br* and C–Cl* orbitals similarly result in weaker donor-acceptor complexes and less activation of the C–X bond. Comparison of the I···Se interactions for the TH group suggest that a threshold XB strength may be required for dehalogenation. Only highly brominated PBDEs have binding energies in the same range as THs, suggesting that these compounds may inhibit Dio and undergo debromination. While these small models provide insight on the I···Se XB interaction itself, interactions with other active site residues are governed by regioselective preferences observed in Dios. [ABSTRACT FROM AUTHOR]