Deiodinases control local cellular and systemic thyroid hormone availability

Abstract

Iodothyronine deiodinases (DIO) are a family of selenoproteins controlling systemic and local availability of the major thyroid hormone l-thyroxine (T4), a prohormone secreted by the thyroid gland. T4 is activated to the active 3,3'-5-triiodothyronine (T3) by two 5'-deiodinases, DIO1 and DIO2. DIO3, a 5-deiodinase selenoenzyme inactivates both the prohormone T4 and its active form T3. DIOs show species-specific different patterns of temporo-spatial expression, regulation and function and exhibit different mechanisms of reaction and inhibitor sensitivities. The main regulators of DIO expression and function are the thyroid hormone status, several growth factors, cytokines and altered pathophysiological conditions. Selenium (Se) status has a modest impact on DIO expression and translation. DIOs rank high in the priority of selenium supply to various selenoproteins; thus, their function is impaired only during severe selenium deficiency. DIO variants, polymorphisms, SNPs and rare mutations have been identified. Development of DIO isozyme selective drugs is ongoing. A first X-ray structure has been reported for DIO3. This review focusses on the biochemical characteristics and reaction mechanisms, the relationships between DIO selenoproteins and their importance for local and systemic provision of the active hormone T3. Nutritional, pharmacological, and environmental factors and inhibitors, such as endocrine disruptors, impact DIO functions.

Keywords: Drug interference; EDC; Endocrine disruptor; Evolution; Inhibitor; Local T3 production; Mechanism of action; Regulation; Selenoprotein; Thyroid hormone metabolism.