Thyroid hormones (TH) are regulators of metabolism, growth, and development, manufactured exclusively by the thyroid gland in the neck. The two primary forms are thyroxine (T4) and triiodothyronine (T3). T4 is the major secretion product, while T3 is the most biologically active form. The unique arrangement of atoms in these hormones allows for precise control over nearly every cell’s metabolic rate.
Essential Chemical Components
The fundamental architecture of thyroid hormones is derived from the amino acid tyrosine, which provides the core two-ring carbon framework, classified as a thyronine derivative. The two phenyl rings of the tyrosine backbone are linked by an ether oxygen atom, creating the basic scaffold for both T3 and T4. This small, fat-soluble structure allows the hormone to pass through cell membranes and act on the cell’s nucleus.
The defining feature is the inclusion of iodine atoms, which are necessary for activity. T4 (thyroxine) possesses four iodine atoms attached to the tyrosine rings, while T3 (triiodothyronine) contains three. This difference of a single iodine atom drastically alters their biological potency, making T3 significantly more active than T4.
Biosynthesis and Storage in the Thyroid Gland
Synthesis begins with the active uptake of iodide from the bloodstream into the follicular cells, a process called iodide trapping. This iodide is then oxidized by the enzyme thyroperoxidase (TPO) to a reactive form of iodine at the apical membrane of the cell. The entire process relies on thyroglobulin (Tg), a large protein synthesized within the follicular cells and secreted into the colloid space.
Iodine is covalently linked to specific tyrosine residues on the thyroglobulin molecule, an action also catalyzed by TPO. This iodination creates two intermediate structures: monoiodotyrosine (MIT) and diiodotyrosine (DIT). The final hormones are formed through a coupling reaction, linking two iodinated tyrosine molecules on the thyroglobulin chain.
The combination of two DIT residues forms T4, while one DIT and one MIT residue form T3. After the coupling reaction, the newly formed T3 and T4 remain bound within the massive thyroglobulin protein. In this state, they are stored in the colloid, an inactive reservoir that maintains a reserve supply of hormone. When the body needs the hormone, thyroglobulin is reabsorbed and broken down by enzymes, releasing free T3 and T4 into the circulation.
Systemic Activation and Transport
Once released into the bloodstream, the chemical structure of thyroid hormones dictates their systemic behavior. T4 is the major hormone secreted by the thyroid gland, making up about 90% of the total output, but it functions primarily as a prohormone. The most significant structural modification occurs in peripheral tissues such as the liver and kidneys, where T4 is converted into the highly active T3.
This conversion is an activation step achieved through deiodination, the enzymatic removal of a single iodine atom from the outer ring of the T4 molecule. Enzymes called iodothyronine deiodinases catalyze this reaction, transforming the less potent T4 into the potent T3. This peripheral activation allows for fine-tuned control over the level of active hormone available to target cells.
Because T3 and T4 are lipophilic, they cannot travel freely dissolved in the aqueous environment of the blood and require specialized carriers. They bind tightly to specific transport proteins, primarily Thyroxine-Binding Globulin (TBG), but also transthyretin and serum albumin. The structure of the hormones allows them to fit into the binding sites of these proteins, ensuring they are shielded from premature degradation and delivered efficiently to distant tissues. Only a small fraction, less than 1% of the total circulating hormone, remains unbound or “free,” and this free hormone is the biologically active form that can enter cells to exert its metabolic effects.