Chemistry in thyroid gland: iodothyronine deiodinases and anti-thyroid drugs

Abstract

The monodeiodination of the prohormone thyroxine (T4) to the biologically active hormone 3,5,3'-triiodothyronine (T3) is the first step in thyroid hormone action and the type I iodothyronine deiodinase (ID-I), an enzyme containing selenocysteine in its active site, is responsible for most of this conversion. ID-I is an integral membrane protein present in highest amounts in liver, kidney, and thyroid. In the deiodinase cycle, the selenol group of the enzyme (E-SeH) first reacts with T4 to form a selenenyl iodide (E-SeI) with a release of the deiodinated iodothyronine. Subsequent reaction of the E-SeI with a thiol of other cofactors releases I^- and regenerates the active site. The thiourea drug, 6-n-propylthiouracil (PTU), reacts with the E-SeI intermediate to inhibit the enzyme active site regeneration. Owing to this property, PTU and related sulfur derivatives are often used in the acute treatment of severely hyperthyroid (Graves disease) patients and therefore commonly known as antithyroid drugs. Although the formation of a mixed selenenyl sulfide (ESe-S-PTU) adduct has been proposed to be a possible way of inhibition, it is still a matter of debate whether PTU reacts with a well-defined Se-I bond of it reacts with an equivalent species or directly with the enzyme active site. In view of this, the first successful model studies on the reactivity of PTU towards synthetic organoselenenyl iodides (RSeI) have been carried out and the results will be discussed as a basis for the deiodinase inhibition. On the basis of experimental data, a mechanism for the inhibition of ID-I by thiouracil drugs and possible amino acid residues responsible for the inhibition will be discussed.