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.

Keywords: endocrine disruption; halogen bonding; iodothyronine deiodinase; polybrominated diphenyl ethers (PBDEs); polychlorinated biphenyls (PCBs); thyroid hormones (THs); xenobiotics.

Figure 1

Mechanistic pathways of deiodination by each deiodinase with thyroid hormone (TH) substrates. Dio is regioselective for outer-ring or inner-ring deiodination (ORD and IRD, respectively).

Figure 2

Examples of (a) polybrominated diphenyl ethers (PBDEs)—BDE-47 and 3-HO-BDE-47; (b) polychlorinated biphenyls (PCBs)—PCB-77 and triclosan.

Figure 3

Proposed halogen bonding-based mechanism for deiodination by Dio adapted from reference [71]. The identities of B and their protonation states have not been determined.

Figure 4

XB as described by the molecular orbital (MO) model showing the interaction between a lone pair of a donor and the R–X antibonding orbital, alongside the corresponding average stabilization of the Se donor lone pair by THs, PBDEs, and PCBs as determined by Natural Bond Orbital (NBO) ΔE_D→A analysis. Units are kcal mol⁻¹. Adapted from reference [66].

Figure 5

Comparison of lowest unoccupied molecular orbital (LUMO) energies with respect to ΔE_ZPE and select LUMOs of the inner and outer rings of T₄ and T₃. Adapted from reference [28].

Figure 6

Sample structures of PBDEs and the hydroxylated metabolites of BDE-47.

Figure 7

Density functional theory (DFT) optimized structures of XB complexes at the ortho and para positions of hydroxylated BDE-47 metabolites. Distances are in Angstroms.

Figure 8

Structures of the active site of the crystal structure of Dio3 (PDB = 4TR4) with Sec170 and the residues of the His202-Arg275 clamp proposed by Schweizer et al. indicated [7].

Figure 9

Comparison of XB interactions of THs, PBDEs, and PCBs. The red line indicates a proposed energy threshold needed for dehalogenation, based upon the interaction energy for 3-T₁.

Figure 10

Comparison of donor-acceptor energies (ΔE_D→A) to the activation of the C–Cl bond (Δd(C–Cl)) by XB position.

Figure 11

Comparison of donor-acceptor energies (ΔE_D→A) to percent contribution of X (%X) by XB position.