title: Halogen bonding controls the regioselectivity of the deiodination of thyroid hormones and their sulfate analogues.
abstract: The type 1 iodothyronine deiodinase (1D-1) in liver and kidney converts the L-thyroxine (T4), a prohormone, by outer-ring (5') deiodination to biologically active 3,3',5-triiodothyronine (T3) or by inner-ring (5) deiodination to inactive 3,3',5'-triiodothronine (rT3). Sulfate conjugation is an important step in the irreversible inactivation of thyroid hormones. While sulfate conjugation of the phenolic hydroxyl group stimulates the 5-deiodination of T4 and T3, it blocks the 5'-deiodination of T4. We show that thyroxine sulfate (T4S) undergoes faster deiodination as compared to the parent thyroid hormone T4 by synthetic selenium compounds. It is also shown that ID-3 mimics, which are remarkably selective to the inner-ring deiodination of T4 and T3, changes the selectivity completely when T4S is used as a substrate. From the theoretical investigations, it is observed that the strength of halogen bonding increases upon sulfate conjugation, which leads to a change in the regioselectivity of ID-3 mimics towards the deiodination of T4S. It has been shown that these mimics perform both the 5'- and 5-ring deiodinations by an identical mechanism.
authors.affiliation: Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore 560012 (India) http://ipc.iisc.ernet.in/∼mugesh/
authors.forename: Debasish
authors.initials: D
authors.lastname: Manna
authors.forename: Santanu
authors.initials: S
authors.lastname: Mondal
authors.forename: Govindasamy
authors.initials: G
authors.lastname: Mugesh
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry / Q000378:metabolism; D006219:Halogens / Q000737:chemistry*; D007453:Iodide Peroxidase / Q000378:metabolism; D007700:Kinetics; D008968:Molecular Conformation; D055672:Static Electricity; D013237:Stereoisomerism; D013451:Sulfonic Acids / Q000737:chemistry; D013963:Thyroid Hormones / Q000737:chemistry*; D013974:Thyroxine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D014284:Triiodothyronine / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D001672:Biocompatible Materials; D006219:Halogens; D013451:Sulfonic Acids; D013963:Thyroid Hormones; D014284:Triiodothyronine; C045736:thyroxine sulfate; C109812:iodothyronine deiodinase type I; D007453:Iodide Peroxidase; D013974:Thyroxine
keywords: enzyme mimics; halogen bonding; iodothyronine deiodinase; sulfate conjugatation; thyroid hormones