Modeling Type‐1 Iodothyronine Deiodinase with Peptide‐Based Aliphatic Diselenides: Potential Role of Highly Conserved His and Cys Residues as a General Acid Catalyst

Abstract

Type‐1 iodothyronine deiodinase (ID‐1) catalyzes the reductive elimination of 5’‐I and 5‐I on the phenolic and tyrosyl rings of thyroxine (T4), respectively. Chemically verifying whether I atoms with different chemical properties undergo deiodination through a common mechanism is challenging. Herein, we report the modeling of ID‐1 using aliphatic diselenide (Se‐Se) and selenenylsulfide (Se‐S) compounds. Mechanistic investigations of deiodination using the ID‐1‐like reagents suggested that the 5’‐I and 5‐I deiodinations proceed via the same mechanism through an unstable intermediate containing a Se⋅⋅⋅I halogen bond between a selenolate anion, reductively produced from Se‐Se (or Se‐S) in the compound, and an I atom in T4. Moreover, imidazolium and thiol groups, which may act as general acid catalysts, promoted the heterolytic cleavage of the C‐I bond in the Se⋅⋅⋅I intermediate, which is the rate‐determining step, by donating a proton to the C atom.

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

“…In our proposed mechanism, an initially formed XB intermediate is stabilized by the protein to convert the non‐bonding interaction to a nucleophilic attack at the aromatic iodine. Subsequent experimental studies and computational models have provided strong support for this initial hypothesis [7–11] . Additionally, hydrogen shuttle pathways to facilitate deiodination via this mechanism were identified in the crystal structure of the Dio3 monomer [12] .…”

“…Subsequent experimental studies and computational models have provided strong support for this initial hypothesis. [7][8][9][10][11] Additionally, hydrogen shuttle pathways to facilitate deiodination via this mechanism were identified in the crystal structure of the Dio3 monomer. [12] Although less abundant than other chalcogens and halogens, selenium and iodine are incorporated into the TH signaling pathways due to the high nucleophilicity of selenium and the low electronegativity of iodine, both properties that contribute to strong XB.…”

Demonstration of the Formation of a Selenocysteine Selenenic Acid through Hydrolysis of a Selenocysteine Selenenyl Iodide Utilizing a Protective Molecular Cradle

“…Selenocysteine selenenyl iodides (Sec-SeIs) have also garnered increasing attention as important intermediates of iodothyronine deiodinase (Dio). The Dio family controls the concentration of the active thyroid hormone (3,3 ,5-triiodothyronine) through the reductive elimination of iodide from iodothyronines by Sec-SeHs in the catalytic sites, presumably leading to the formation of Sec-SeI intermediates [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35].…”