title: Regioselective deiodination of thyroxine by iodothyronine deiodinase mimics: an unusual mechanistic pathway involving cooperative chalcogen and halogen bonding.
abstract: Iodothyronine deiodinases (IDs) are mammalian selenoenzymes that catalyze the conversion of thyroxine (T4) to 3,5,3'-triiodothyronine (T3) and 3,3',5'-triiodothyronine (rT3) by the outer- and inner-ring deiodination pathways, respectively. These enzymes also catalyze further deiodination of T3 and rT3 to produce a variety of di- and monoiodo derivatives. In this paper, the deiodinase activity of a series of peri-substituted naphthalenes having different amino groups is described. These compounds remove iodine selectively from the inner-ring of T4 and T3 to produce rT3 and 3,3'-diiodothyronine (3,3'-T2), respectively. The naphthyl-based compounds having two selenols in the peri-positions exhibit much higher deiodinase activity than those having two thiols or a thiol-selenol pair. Mechanistic investigations reveal that the formation of a halogen bond between the iodine and chalcogen (S or Se) and the peri-interaction between two chalcogen atoms (chalcogen bond) are important for the deiodination reactions. Although the formation of a halogen bond leads to elongation of the C-I bond, the chalcogen bond facilitates the transfer of more electron density to the C-I σ* orbitals, leading to a complete cleavage of the C-I bond. The higher activity of amino-substituted selenium compounds can be ascribed to the deprotonation of thiol/selenol moiety by the amino group, which not only increases the strength of halogen bond but also facilitates the chalcogen-chalcogen interactions.
authors.affiliation: Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore 560 012, India.
authors.forename: Debasish
authors.initials: D
authors.lastname: Manna
authors.forename: Govindasamy
authors.initials: G
authors.lastname: Mugesh
mesh_terms: D055162:Biocatalysis; D018011:Chalcogens / Q000737:chemistry / Q000378:metabolism*; D006219:Halogens / Q000737:chemistry / Q000378:metabolism*; D007453:Iodide Peroxidase / Q000737:chemistry / Q000378:metabolism*; D015394:Molecular Structure; D013237:Stereoisomerism; D013974:Thyroxine / Q000737:chemistry / Q000378:metabolism*; D014284:Triiodothyronine / Q000737:chemistry / Q000378:metabolism*
chemical_list: D018011:Chalcogens; D006219:Halogens; D014284:Triiodothyronine; D007453:Iodide Peroxidase; D013974:Thyroxine