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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.
Highlights
Thyroid hormones (THs) are essential biomolecules involved in many biochemical processes, in early developmental stages [1,2,3,4,5]
PBDEsRecent could nucleophilicity relative to Cys, which isthe enhanced by deprotonation at physiological inhibit activity blocking active site through an X⋅⋅⋅Se like halogen (XB)could interaction studies Dio by our groupby explored thethe possibility that organohalogens
X···Se halogen bonding (XB) is observed in X-ray structures of thyroid hormones (THs) binding proteins, such as TTR and TBG, primarily is observed
Summary
Thyroid hormones (THs) are essential biomolecules involved in many biochemical processes, in early developmental stages [1,2,3,4,5]. Dio activity may neurodegenerative effects studies have shown that inhibition of. PCBs, like PBDEs, are industrial flame retardants with high chemical stability (Figure 2b) [42,43]. PBDEs, areformulations industrial flame retardants with chemical stability (Figure 2b) [42,43] Production of These some PCB formulations were banned in two the 1970s, but they still contaminate urban areas [44,45,46,47]. Dio which display high activity a combination of halogen and chalcogen bonding [72]. PBDEsRecent could nucleophilicity relative to Cys, which isthe enhanced by deprotonation at physiological inhibit activity blocking active site through an X⋅⋅⋅Se like halogen (XB)could interaction studies Dio by our groupby explored thethe possibility that organohalogens.
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