A Halogen Bonding Perspective on Iodothyronine Deiodinase Activity

Area of Science:

• Biochemistry
• Endocrinology
• Environmental Science

Background:

• Iodothyronine deiodinases (Dios) regulate thyroid hormone (TH) homeostasis through iodine removal.
• Halogen bonding (XB) to selenocysteine (Sec) in the Dio active site is hypothesized to facilitate deiodination.
• Environmental contaminants like polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) can disrupt endocrine pathways.

Purpose of the Study:

• To investigate the role of halogen bonding in the inhibitory mechanisms of PBDEs and PCBs on iodothyronine deiodinases.
• To compare the halogen bonding strengths of THs, PBDEs, and PCBs with the Dio active site.
• To assess the potential for xenobiotic debromination by Dios.

Main Methods:

• Density functional theory (DFT) calculations were used to model halogen bonding interactions.
• Calculations focused on interactions between methyl selenolate (a model for the Sec residue) and THs, PBDEs, and PCBs.
• XB strengths and donor-acceptor energies were analyzed.

Main Results:

• Halogen bonding strengths followed the order: THs > PBDEs > PCBs.
• THs exhibited strong interactions, activating the carbon-iodine bond for deiodination.
• Highly brominated PBDEs showed binding energies comparable to THs, suggesting potential inhibition and debromination.

Conclusions:

• Halogen bonding plays a crucial role in the mechanism of iodothyronine deiodinases.
• Certain PBDEs may inhibit Dio activity through competitive binding and undergo debromination.
• Further research is needed to understand interactions with other active site residues and regioselectivity.