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Replacement with a single atom alters thyroid biochemical cascade in the body

More than 200 million people worldwide suffer from thyroid related disorders like hyperthyroidism, hypothyroidism, goitre, Hashimoto’s thyroiditis, thyroid cancer etc. Hyperthyroidism is also associated with various diseases like Grave’s disease, thyroid storm and toxic thyroid nodule. Most of these are treated with synthetic form of T4 for hypothyrodism and thiouracil-based drugs for hyperthyroidism. However, small variations in the drug concentration can lead to adverse effects.

Thyroxine or T4, having four iodine atoms is the thyroid pro-hormone, while the biologically more active metabolite tri-iodothyronine (T3) regulates body temperature, growth and heart rate. Thyroxine is produced by the thyroid gland and its metabolism is tightly regulated in human body. The activation or inactivation of thyroid hormones are mediated by enzymes in various cells/tissues. The activation occurs when T4 is converted to T3, but an inactivation occurs when T4 is converted to reverse T3 (rT3).

Earlier studies showed that simple chemical compounds containing sulfur or selenium atoms can remove iodine atoms selectively from T4 to produce rT3, thereby, mimicking the enzymes that mediate the inactivation pathway. For the first time, K Raja and Prof. G Mugesh from the department of Inorganic and Physical Chemistry, IISc, Bangalore, show that the replacement of sulfur or selenium by tellurium atoms dramatically alters the rate of the reaction. The compounds that mediated the conversion of T4 to rT3 can also mediate the conversion of T4 to T3 upon introduction of a tellurium atom. This study shows how a single atom change in a chemical compound can alter a very important biochemical reaction.

The team of scientists have developed a novel set of compounds that can mimic the function of the enzymes to activate or inactivate thyroxine (i.e. remove iodine atoms from T4 under physiologically relevant conditions). Prof. Mugesh said, “While the primary aim of this study is to understand the various mechanisms proposed for the model reactions as well as those catalysed by the natural deiodinases, the compounds developed are considered as potential candidates for the development of drugs for thyroid related disorders such as hyperthyroidism.”

The team aims to develop compounds that can control the thyroxine metabolism in the body rather than inhibiting the thyroxine biosynthesis or supplementing with thyroxine. Depending upon the nature of disease, a suitable enzyme mimic can be administered. The advantage of the current set of compounds is that they are highly reactive and the deiodination reactions can be performed in water at physiological conditions. The previous studies used organic solvents for the chemical transformations, and such conditions are not suitable for drug development. Though the current studies indicate that the compounds have potential applications in the treatment of hyperthyroidism, they need to be tested in human cell lines and animal models to understand the efficacy and toxicity. 

Authors

Prof. Dr. G. Mugesh, Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore-560012 (India). K Raja is a PhD student at Prof Mugesh’s lab at the Department of Inorganic and Physical Chemistry, IISc.

Website: http://ipc.iisc.ernet.in/~mugesh/

 

The article appeared in the “Early View” section of Angewandte Chemie on 12th May 2015. http://onlinelibrary.wiley.com/doi/10.1002/anie.201502762/abstract

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