Thyroid hormone biosynthesis

Thyroid hormone biosynthesis is a complex process that occurs in the Thyroid gland. The primary hormones produced by the thyroid gland are thyroxine (T4) and triiodothyronine (T3), which play crucial roles in regulating metabolism and various physiological processes in the body.

The synthesis of Thyroid Hormones begins with the uptake of iodine from the bloodstream by the thyroid follicular cells. Iodine is an essential component for the production of thyroid hormones. Once inside the thyroid follicular cells, iodine is oxidized to iodide (I-) by an enzyme called thyroid peroxidase (TPO). The iodide is then actively transported into the follicular lumen, which is the central cavity of the thyroid follicles.

Within the follicular lumen, a protein called thyroglobulin (Tg) is synthesized and released into the lumen. Thyroglobulin is a large glycoprotein that serves as a precursor for thyroid hormones. It contains tyrosine residues, which are the building blocks for the synthesis of thyroid hormones.

The next step involves the iodination of tyrosine residues within thyroglobulin. This process occurs in two stages. First, a single iodine atom is attached to the tyrosine residue, resulting in the formation of monoiodotyrosine (MIT). This iodination step is catalyzed by TPO. Then, a second iodine atom is added to another tyrosine residue, leading to the formation of diiodotyrosine (DIT). The formation of DIT can occur by the addition of iodine to another tyrosine residue on the same thyroglobulin molecule or by coupling MIT and DIT.

Once MIT and DIT are formed, they can undergo further reactions to produce the active thyroid hormones T3 and T4. The coupling of one molecule of DIT with one molecule of MIT results in the formation of T3 (triiodothyronine). Alternatively, the coupling of two molecules of DIT leads to the formation of T4 (thyroxine).

After the synthesis of T3 and T4, thyroglobulin is taken up by the follicular cells through endocytosis. The lysosomal enzymes in the follicular cells then digest thyroglobulin, releasing T3 and T4 into the bloodstream, where they can bind to transport proteins for distribution throughout the body. Once inside the target cells, T4 can be converted to the more biologically active T3 through the removal of one iodine atom by enzymes called deiodinases.

In addition to T3 and T4, there is another thyroid hormone called reverse T3 (rT3). rT3 is formed through the removal of an iodine atom from T4 in a different position than the deiodination that produces T3. rT3 has minimal biological activity and is considered an inactive form of thyroid hormone. It is believed to play a regulatory role in certain physiological conditions.

Overall, the biosynthesis of thyroid hormones involves the uptake of iodine, iodination of tyrosine residues within thyroglobulin, coupling of iodinated tyrosines to form T3 and T4, and subsequent release of T3 and T4 into the bloodstream for systemic effects.

Metabolism of iodide and iodine

Iodide (I-) and iodine (I2) are both forms of the element iodine that play important roles in the body’s metabolism. Let’s explore the metabolism of iodide and iodine separately:

Metabolism of Iodide (I-):

1. Absorption: Iodide is primarily obtained from dietary sources, such as iodized salt, seafood, and dairy products. It is absorbed in the stomach and the small intestine.
2. Transport: Once absorbed, iodide enters the bloodstream and is transported to the thyroid gland. The transport of iodide is facilitated by a sodium-iodide symporter (NIS) located on the cell membrane of thyroid follicular cells.
3. Thyroid Hormone Synthesis: Within the thyroid gland, iodide is actively transported into the follicular cells by NIS. Once inside the follicular cells, iodide undergoes a series of reactions to form thyroid hormones, primarily triiodothyronine (T3) and thyroxine (T4). These hormones play crucial roles in regulating metabolism, growth, and development.
4. Release of Thyroid Hormones: Thyroid hormones are stored in the thyroid gland as part of a protein complex called thyroglobulin. When stimulated, the thyroid gland releases thyroid hormones into the bloodstream, where they bind to carrier proteins for transport throughout the body.
5. Peripheral Tissue Activation: In various tissues throughout the body, T4 is converted into the more metabolically active form, T3, by the removal of one iodine atom. This conversion primarily occurs in the liver, kidneys, and certain other tissues.
6. Metabolic Effects: Thyroid hormones regulate metabolism by influencing cellular processes, including the synthesis of proteins, carbohydrates, and fats. They also control heat production, energy expenditure, and the function of various organs.

Metabolism of Iodine (I2):

1. Absorption: Iodine is less commonly consumed directly through the diet but can be formed from iodide in the stomach by oxidation. It is then absorbed in the stomach and small intestine.
2. Thyroid Hormone Synthesis: Similar to iodide, iodine can also be taken up by the thyroid gland through NIS and utilized in the synthesis of thyroid hormones (T3 and T4). However, iodine is not as efficient as iodide in this process.
3. Detoxification: Excess iodine that is not required for thyroid hormone synthesis is rapidly excreted by the kidneys. In cases of iodine overload, such as excessive consumption of iodine-rich supplements, the excess iodine is excreted to maintain balance.

It’s worth noting that the metabolism of iodide and iodine is interconnected, as iodine can be converted to iodide and vice versa. This conversion occurs through enzymatic reactions in various tissues and organs, ensuring a balance between these two forms of iodine in the body.

Thyroid Enzymes and Proteins

Thyroid stimulating hormone action via cAMP

Thyroid-stimulating hormone (TSH), also known as thyrotropin, plays a crucial role in the regulation of thyroid gland function. It acts through a complex signaling cascade involving the cyclic adenosine monophosphate (cAMP) pathway. Here’s a discussion of TSH action via cAMP:

1. TSH Receptor Activation: TSH binds to its specific receptor, the TSH receptor (TSHR), located on the surface of thyroid follicular cells. Binding of TSH to TSHR leads to receptor activation.
2. G Protein Coupling: TSHR is a G protein-coupled receptor (GPCR). Upon activation, the TSHR interacts with a heterotrimeric G protein composed of α, β, and γ subunits. The α subunit is associated with guanosine diphosphate (GDP) and is bound to the βγ subunit.
3. G Protein Activation: The binding of TSH to TSHR induces a conformational change in the receptor, leading to the exchange of GDP for guanosine triphosphate (GTP) on the α subunit of the G protein. This results in the dissociation of the α subunit from the βγ subunit.
4. Adenylyl Cyclase Activation: The free Gα subunit, carrying GTP, activates adenylyl cyclase (AC), an enzyme located in the plasma membrane. Adenylyl cyclase catalyzes the conversion of adenosine triphosphate (ATP) to cAMP.
5. cAMP Production: Activated adenylyl cyclase generates cAMP from ATP. cAMP serves as a second messenger, which means it relays the signal from the TSH receptor to downstream effectors in the cell.
6. Protein Kinase A (PKA) Activation: The increase in cAMP levels leads to the activation of protein kinase A (PKA), a serine/threonine kinase. PKA consists of catalytic subunits and regulatory subunits. The binding of cAMP to the regulatory subunits releases the catalytic subunits, enabling them to phosphorylate target proteins.
7. Phosphorylation of Target Proteins: Once released, the catalytic subunits of PKA phosphorylate various target proteins within the cell. These target proteins include transcription factors, ion channels, and enzymes involved in thyroid hormone synthesis, secretion, and metabolism.
8. Thyroid Hormone Synthesis and Secretion: TSH-induced cAMP signaling stimulates the expression of genes involved in thyroid hormone synthesis, such as thyroglobulin, thyroid peroxidase, and sodium-iodide symporter. These genes encode proteins necessary for iodide uptake, organification, and coupling reactions leading to the production of thyroid hormones (triiodothyronine or T3 and thyroxine or T4). The thyroid follicular cells then release these hormones into the bloodstream.
9. Feedback Regulation: As circulating T3 and T4 levels increase, they negatively feedback on the hypothalamus and pituitary gland, reducing the secretion of thyrotropin-releasing hormone (TRH) and TSH, respectively. This feedback loop helps maintain thyroid hormone homeostasis.

Regulating TSH with Hormones

The regulation of thyroid stimulating hormone (TSH) is a complex process involving various factors, including thyroid releasing hormone (TRH), T4 (thyroxine), T3 (triiodothyronine), somatostatin, and dopamine. Here’s a breakdown of how these substances interact in the regulation of TSH:

1. Thyroid Releasing Hormone (TRH): TRH is produced by the hypothalamus in the brain. It acts as a releasing hormone that stimulates the release of TSH from the anterior pituitary gland. TRH secretion is regulated by negative feedback mechanisms, meaning that when T4 and T3 levels are low, TRH release is increased to stimulate TSH release and subsequently boost thyroid hormone production.
2. Thyroxine (T4) and Triiodothyronine (T3): T4 and T3 are the primary thyroid hormones produced by the thyroid gland. T4 is the more abundant hormone, but T3 is the more active form. When T4 and T3 levels are low in the bloodstream, it triggers the hypothalamus to release more TRH, which, in turn, stimulates the release of TSH from the pituitary gland. TSH then acts on the thyroid gland to increase the production and release of T4 and T3. As T4 and T3 levels rise, they exert negative feedback on the hypothalamus and pituitary gland, inhibiting further TRH and TSH release, thus maintaining a balance.
3. Somatostatin: Somatostatin is a hormone produced by the hypothalamus and other tissues in the body. It has an inhibitory effect on TSH release. Somatostatin acts by suppressing the release of TRH from the hypothalamus and directly inhibiting TSH secretion from the pituitary gland. This helps to regulate the overall thyroid hormone levels in the body.
4. Dopamine: Dopamine is another inhibitory hormone that regulates TSH release. It is produced by the hypothalamus and acts on the pituitary gland. Dopamine inhibits the release of TSH by suppressing TRH production and release. Similar to somatostatin, dopamine helps to maintain the balance of thyroid hormone levels.

In summary, the regulation of TSH involves a delicate interplay between various factors. TRH stimulates TSH release, which, in turn, promotes the production and secretion of T4 and T3 by the thyroid gland. Negative feedback mechanisms involving T4, T3, somatostatin, and dopamine help regulate the release of TRH and TSH, ensuring the thyroid hormone levels remain within the appropriate range.

T4 & T3 Hormone Transport

T4 and T3 are two terms commonly used to refer to hormones produced by the thyroid gland in the human body. These hormones play crucial roles in regulating metabolism, growth, and development. Here’s a brief discussion on T4 (thyroxine) and T3 (triiodothyronine) transport:

1. Thyroxine (T4):
   • T4 is the main hormone secreted by the thyroid gland. It consists of four iodine atoms, hence the name T4.
   • After its production, the majority of T4 is bound to proteins in the blood, primarily to a protein called thyroxine-binding globulin (TBG), but also to albumin and transthyretin (prealbumin).
   • Protein-bound T4 acts as a reservoir for the hormone, providing a steady supply that can be gradually released and converted into T3 as needed by the body.
   • Only a small fraction of T4 remains unbound or “free,” which is the biologically active form that can enter cells and exert its effects.
2. Triiodothyronine (T3):
   • T3 is the more biologically active form of thyroid hormone. It contains three iodine atoms.
   • T3 is generated primarily by the conversion of T4 to T3 in peripheral tissues, including the liver, kidney, and certain organs.
   • Once produced, T3 can bind to nuclear receptors in the cells and regulate gene expression, influencing various metabolic processes.
   • Like T4, T3 can also bind to transport proteins such as TBG, albumin, and transthyretin, but it is mostly found in the unbound or “free” form.
3. Transport and Function:
   • While both T4 and T3 are transported in the bloodstream, it is important to note that the majority of thyroid hormones in the blood are bound to proteins rather than in their free form.
   • The binding proteins help regulate hormone levels, protect the hormones from rapid degradation, and provide a reservoir of hormone supply.
   • However, it is the free or unbound form of T4 and T3 that can enter cells and interact with specific receptors to exert their effects.
   • The binding and release of thyroid hormones from transport proteins are tightly regulated, ensuring a balance between hormone availability and the body’s requirements.

It is worth mentioning that disturbances in the transport, binding, or conversion of T4 and T3 can lead to thyroid disorders. For instance, low levels of binding proteins or abnormalities in the conversion process may result in altered hormone levels and related health issues.