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These reactions are catalyzed by three isoforms of the selenoenzymes, iodothyronine deiodinases (Dio1, Dio2 and Dio3), which are highly homologous in nature. Dio1 mediates 5\u2032\u2010 or 5\u2010deiodinations of T4 to produce T3 and rT3, respectively. In contrast, Dio2 and Dio3 are selective to 5\u2032\u2010 or 5\u2010deiodination to produce T3 and rT3, respectively. Understanding of the regioselectivity of deiodination at the molecular level is important as abnormal levels of thyroid hormone have been implicated in various clinical conditions, such as hypoxia, myocardial infarction, neuronal ischemia and cancer. In this paper, we report that the electronic properties of the iodine atoms in thyroxine (T4) can be modulated through a simple substitution in the 4\u2032\u2010phenolic moiety. This leads to the change in the regioselectivity of deiodination by different small molecule mimics of Dio enzymes. By using this chemical approach, we also show that the substitution of a strong electron withdrawing group facilitates the removal of all four iodine atoms in the T4 derivative. Theoretical investigations on the hydrogen bonded adducts of T4 with imidazole indicate that the charge on the iodine atoms depend on the nature of hydrogen bond between the \u2212OH group of T4 and the imidazole moiety. While the imidazole can act as either hydrogen bond acceptor (HBA) or hydrogen bond donor (HBD), the protonated imidazole acts exclusively as HBD in T4\u2010imidazole complex. These studies support the earlier observations that the histidine residue at the active sites of the deiodinases play an important role not only in the substrate binding, but also in altering the regioselectivity of the deiodination reactions.<\/jats:p>","DOI":"10.1002\/chem.202203111","type":"journal-article","created":{"date-parts":[[2022,11,16]],"date-time":"2022-11-16T02:24:58Z","timestamp":1668565498000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A Simple Substitution on Thyroid Hormones Remarkably Alters the Regioselectivity of Deiodination by a Deiodinase Mimic"],"prefix":"10.1002","volume":"29","author":[{"given":"Debasish","family":"Giri","sequence":"first","affiliation":[{"name":"Department of Inorganic and Physical Chemistry Indian Institute of Science  Bangalore 560012 India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karuppusamy","family":"Raja","sequence":"additional","affiliation":[{"name":"Department of Inorganic and Physical Chemistry Indian Institute of Science  Bangalore 560012 India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5389-5309","authenticated-orcid":false,"given":"Govindasamy","family":"Mugesh","sequence":"additional","affiliation":[{"name":"Department of Inorganic and Physical Chemistry Indian Institute of Science  Bangalore 560012 India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,12,27]]},"reference":[{"key":"e_1_2_8_1_1","unstructured":"\u00a0"},{"key":"e_1_2_8_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0303-7207(99)00088-X"},{"key":"e_1_2_8_3_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.2001.81.3.1097"},{"key":"e_1_2_8_4_1","unstructured":"\u00a0"},{"key":"e_1_2_8_5_2","author":"Leonard J. 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