Iodothyronine deiodinases: key enzymes behind the action of thyroid hormone

Thyroid hormone acts virtually on every cell of the vertebrate body and regulates numerous cellular functions by binding to nuclear thyroid hormone receptors. Circulating concentration of thyroid hormone is under the control of thyroid-stimulating hormone (TSH) secreted from the pituitary gland. Thyroid hormone mainly secreted from the thyroid gland is thyroxine (T4), while the nuclear thyroid hormone receptor prefers binding to triiodothyronine (T3) about tenfold. Therefore, T4 must be converted to T3 mostly in extra-thyroidal tissues to exert its actions. Recently more researchers have paid attention to the fact that this conversion is carried out by members of iodothyronine deiodinases, enzymes that reside in the cellular membranes, thereby enabling cell-specific regulation of T3/T4 balance largely independent of their circulating concentrations. Three different deiodinases (D1, D2 and D3) are characterized in vertebrate species, none of which is under the control of circulating TSH. D2 catalyzes deiodination of less active T4 to produce active T3. D3 removes iodine from T3 or T4 to produce diiodothyronine (T2) or reverse T3 (rT3), respectively, both of which are inactive. On the contrary, D1 is an inefficient enzyme in that it is three orders of magnitude less efficient in catalyzing T4 compared with D2 and D3. D1 may function like a futile enzyme, since it can both activate and inactivate T4 with almost the same velocity. However, D1 catalyzes removal of iodine from rT3 much more efficiently than from T4, and hence its possible importance in recycling iodine, especially in iodine deficiency such as in certain hypothyroid patients and avian embryos in the confined eggshells. In addition, deiodinase homologs of non-vertebrate chordates such as amphioxi and ascidians characterized recently have provided useful information to gain deep insight into thyroid hormone signaling system from evolutionary aspect. This review briefly summarizes the present status of research and perspectives of studying iodothyronine deiodinases, key enzymes behind the thyroid hormone action.