Synthesis of Thyroid Hormones 

The synthesis of the thyroid hormones is unique, complex, and seemingly grossly inefficient. 

The major steps in the synthesis, storage, release, and interconversion of thyroid hormones are the following:

1. Uptake of Iodide (I-) ion by the gland; 
2. Oxidation of iodide and the iodination of tyrosyl groups of thyroglobulin;
3. Coupling of iodotyrosine  residues by ether linkage to generate the iodothyronines;
4. Resorption of Thyroglobulin colloid from the lumen into the cell 
5. Proteolysis of thyroglobulin. 
6.  Release of thyroxine and T3 into the Blood. 
7. Conversion of thyroxine (T4) to T3 in peripheral tissues. 

UPTAKE OF IODIDE

• Iodine is actively transported via a specific membrane bound protein termed as the sodium-iodide symporter (NIS).
• TSH stimulates the NIS controlled by an autoregulatory mechanism. Thus, decrease stores of Thyroid iodine enhances iodine uptake. 

OXIDATION & IODINATION (of tyrosyl group of thyroglobulin)

• The oxidation of iodine to its active form is carried out by thyroid peroxidase (a heme containing enzyme) that utilizes hydrogen peroxide (H2O2). 
• The peroxidase is membrane bound and is concentrated near surface of thyroid gland. 
• This reaction results in the formation of Monoiodotyrosyl and Diiodotyrosyl residues in thyroglobulin. 

FORMATION OF THYROXINE & TRIIODOTHYRININE FROM IODOTYROSINES 

• Formation of T4 (thyroxine): Coupling of 2 diiodotyrosyl residues result in the formation of thyroxine (T4).
• Formation of T3 (Try-iodothyronine): Coupling of 1 mono-iodotyrosyl & 1 diiodotyrosyl residue result in the formation of T3.
• These oxidative reactions apparently catalyzed by same Thyroid Peroxidase enzyme. 

Resorption, Proteolysis & Release of thyroxine and T3 into the Blood:

• After the synthesis of T4 and T3, there are stored into thyroglobulin. 
• Proteolysis is initiated by endocytosis of thyroglobulin colloid from the lumen into the cell, by the help of Thyroglobulin Receptor, MEGALIN. 
• These ingested Thyroglobulin appears as droplets inside cell and fused with LYSOSOME containing required proteolytic enzyme. 
• so, Thyroglobulin is completely broken down to release the hormones (MIT, DIO, T3 and T4).

NOTE: When Thyroglobulin is Protolyzed, MIO and DIO are also produced, but they do not leave the thyroid gland. they are metabolized and liberates the Iodine in form of Iodide and reused. 

Conversion of Thyroxine to Triiodothyronine in Peripheral Tissues:

• Although T3 is secreted by the thyroid, Metabolism of T4 in the peripheral tissue takes place to produce T3 (Active form).
• The enzyme that converts T4 to T3 is 5′-deiodinase. 
• 5′-deiodinase is found in 3 forms-

1. Type I 5′-deiodinase (D1): Expressed in Liver and Kidney mostly.
2. Type II 5′-deiodinase (D2): distributed in the brain, pituitary, skeletal and cardiac Muscle.
3. Type III deiodinase (D3): Placenta, skin, uterus, and brain. 

Transport of Thyroid Hormone 

The thyroid hormones are transported in the blood in strong but noncovalent association with certain plasma proteins. 

• Thyroxine-binding globulin (TBG) is the major carrier of thyroid hormones. It is an acidic glycoprotein.
• The primary transport protein is thyroxine-binding globulin (TBG), which has high affinity but low capacity for T3 and T4.
• TBG binds about 70-80% of circulating thyroxine (T4) and about 20% of circulating triiodothyronine (T3).
• Other plasma proteins that bind thyroid hormones include transthyretin (TTR) and albumin.

Mechanism

• Inside the thyroid follicular cells, T3 and T4 are cleaved from thyroglobulin. Free T3 and T4 are then released into the bloodstream, where they are bound to serum proteins for transport. 
• Binding of Thyroid hormones to plasma proteins protects the hormones from metabolism and excretion result in their long half-life in the circulation.

This transport mechanism is crucial as it allows the hormones to be transported from their sites of synthesis to their target organs. Every organ and tissue in the body must maintain a healthy level of T3 hormone activity to function properly.