Research

Structural insight into iodine metabolism

Code:

J1-7479

Range:

01. January 2016 - 31. December 2018

Range:

0,2 FTE

Leader:

Stanislav Gobec

Field:

1.05 Natural sciences and mathematics/Biochemistry and molecular biology

Abstract:

Iodine is the heaviest essential trace element required by the higher living organisms. It is incorporated in T3/T4 hormones responsible for regulation of basal metabolism of almost any cell. T3 and T4 hormones are produced in the thyroid gland. The thyroid hormone metabolism involves selenium containing deiodinases and additional selenoperoxidases and thioredoxin protecting the thyroid gland from peroxide produced during the hormone synthesis. Improper function of the T3/T4 hormone results in impaired metabolism that severely decrease the quality of life, manifested as depression, weight loss, fatigue, mental problems, and may occasionally result in death. More than 10% of population is effected by thyroid disorders. Historically, most of the thyroid related disorders were the consequence of insufficient iodine uptake. In the last 30 years the WHO had issued guidelines to reduce the prevalence of thyroid hormone related disorders arising from the insufficient iodine uptake. Nowadays, however, more common cause of thyroid hormone related disorders is impaired iodine metabolism that can result in hypothyroidism (reduced hormone production) or in hyperthyroidism (increased hormone production). Hyperthyroidism is treated with thyrostatics to reduce the hormone production by inhibiting the thyroid peroxidase (TPO) or by inhibiting activation of T4 to T3 by the thyronine deiodinase (DIO) 1. The increased TPO activity can be inhibited by carbimazole, which is converted to the active compound methimazole, or propylthiouracil. Those compounds were approved by FDA for hyperthyroidism treatment already in 1950 and 1947 and are still in use. These calls for improvements, based on new approaches and research techniques used today. Most of the proteins involved in iodine metabolism are identified, however the few available structures provide a limited insight into their mechanism of action. Therefore we plan to provide the structural insight into the yet unknown parts of iodine metabolism and the T3/T4 hormone synthesis and processing. The crystal structures of TPO and DIOs alone will provide insight into the active site of these enzymes, whereas the complexes of inactive enzymes with their substrates or analogues will provide insight into their reaction mechanisms. 3D structure of thyroglobulin will reveal the substrate of TPO and help us to understand the synthesis and release of the T3/T4 hormones. The gathered structural data will serve as a starting point for structural-based drug design. We expect that the combined use of structural studies, ligand screening and chemical synthesis will enable us to gain a profound insight into the iodine metabolism. We hope that the gathered knowledge will assist us in drug discovery process targeting hyperthyroidism and hypothyroidism.