Update on the human iodothyronine selenodeiodinases, the enzymes regulating the activation and inactivation of thyroid hormone.

It is over 40 years since the original demonstration that thyroxine (T4), the principal secretory product of the thyroid, is deiodinated, to 3,5,3'-tri-iodothyronine (T3) in peripheral mammalian tissues. Subsequently it was shown that the antithyroid drug propylthiouracil (PTU) also blocked the metabolic effects of administered T4 in proportion to its inhibition of T4 to T3 conversion, indicating that deiodination was critical for T4 activation [l]. Subsequently, the type 1 deiodinase (Dl) was identified in mammalian liver, kidney and thyroid and was shown to be sensitive to inhibition by PTU, thus explaining the earlier results [2-41. This enzyme catalyses both outerand inner-ring deiodination of T4, but the preferred substrates are 3,3',5'-tri-iodothyronine ('reverse' T3; rT3) for outer-ring deiodination and the sulphate ester of T3 for inner-ring deiodination. Subsequently, a second, PTU-insensitive enzyme catalysing only T4 to T3 conversion was identified (type 2 deiodinase, D2), which had a K,,, for T4 one-thousandth that of D1 [5,6]. The T3 produced by this enzyme was critically important as a source of T3 receptor (TR)-bound T3 in the pituitary and the brain [7]. Subsequently, a third deiodinase (D3) was identified that inactivated T3 or T4 by the removal of an iodine from the inner ring, producing either rT3 or 3,3'-di-iodothyronine [8]. This enzyme was found principally in placenta, but also in the central nervous system. Both D1 and D3 activities are increased by thyroid hormone, whereas D2 activity is negatively regulated at a post-translational level. These results pointed to a family of enzymes whose activities are carefully regulated to maintain T3 homoeostasis both extracellularly and intracellularly. Despite the 60-fold higher levels of total T4 than T3 in plasma, the T4-to-T3 ratio of the free (metabolically available) hormones is about 3: 1. Because the binding affinity of TR for T3 is