A Halogen Bonding Perspective on Iodothyronine Deiodinase Activity

Abstract

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.

Thyroxine binding to type III iodothyronine deiodinase

“…The selenenyl iodide (-SeI) intermediate reacts with an internal resolving Cys to a selenosulfide and Dio is regenerated through reduction by dithiothreitol in vitro or an endogenous thiol cofactor 23 . Endocrine disrupting halogenated aromatic compounds such as polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) could inhibit Dio by forming a X⋯Se complex that blocks TH access to Sec 24 – 26 . Although XB interactions differ in strength for inner and outer-ring iodines when calculated by density functional theory (DFT) 24 , 27 , the regioselectivity of deiodination (IRD vs ORD) must be controlled by interactions between the substrate and active site residues 24 .…”

Functionalized Selenium Nanoparticles Synergizes With Metformin to Treat Breast Cancer Cells Through Regulation of Selenoproteins

“…To determine whether the regulation of selenoproteins was influenced by SeNPs or by the increase in intracellular ROS levels after combined drug treatment, we measured the mRNA expression levels of several selenoenzymes related to the regulation of redox balance. Deiodinase (Dio) is a selenium-dependent enzyme that catalyzes the transformation of thyroid hormone from T4 to T3 ( Marsan and Bayse, 2020 ). The levels of thyroid hormones affect the synthesis of selenoproteins in tissues throughout the body, and Dio indirectly affects the immune response.…”

Halogen Bonding Interactions of Haloaromatic Endocrine Disruptors and the Potential for Inhibition of Iodothyronine Deiodinases

“…Just as Dio reacts regioselectively with THs, PHAHs may be most effective against Dios with similar substitutions [35] . Where Dio1 deiodinates at either site and may be inhibited by a wide range of PHAHs, Dio2 activates T4 to T3 by removing an outer‐ring iodine, which is meta to the ether linkage to the inner ring.…”