Thyroid Hormone Synthesis

OVERVIEW OF THYROID HORMONE BIOSYNTHESIS

Thyroid hormone biosynthesis depends on intricate interactions between dietary iodine, tyrosine, thyroglobulin (TG), and thyroid peroxidase (TPO) within thyroid follicular cells. Regulated primarily by pituitary thyroid-stimulating hormone (TSH).

1. Iodine Uptake (Trapping)

• Unique avidity of thyroid tissue for iodide (I-).
• Recommended daily allowance: 110-130 μg (infants), 90-120 μg (children), 150 μg (adults).
• Transported from circulation into follicular cell via transmembrane Sodium-Iodide Symporter (NIS).
• NIS localized to basolateral membrane.
• TSH upregulates NIS expression.

2. Apical Transport

• Intracellular iodide diffuses across follicular cell.
• Transported across apical membrane into colloid by Pendrin (chloride-iodide transport protein).
• Anoctamin-1 (ANO1) acts as additional apical iodide channel.

3. Oxidation and Organification

• Occurs in follicular lumen/colloid at apical cell membrane.
• Iodide oxidized and covalently bound to tyrosine residues on TG.
• TG: large homodimeric glycoprotein containing 138 tyrosine residues.
• Catalyzed by Thyroperoxidase (TPO).
• Requires hydrogen peroxide (H2O2) generation by Dual Oxidase 2 (DUOX2) and Dual Oxidase Maturation Factor 2 (DUOXA2).
• Yields Monoiodotyrosine (MIT) and Diiodotyrosine (DIT).

4. Coupling

• Catalyzed by TPO.
• Coupling of MIT + DIT -> Triiodothyronine (T3).
• Coupling of DIT + DIT -> Thyroxine (T4).
• T4:T3 secretion ratio approximately 12:1.
• Hormones remain stored within colloid attached to TG.

5. Storage and Secretion

• TSH stimulates micropinocytosis (endocytosis) of colloid droplets.
• Endolysosomal degradation of TG releases T4 and T3.
• Secretion into circulation via basolateral membrane.

6. Intrathyroidal Iodine Recycling (Dehalogenation)

• Uncoupled MIT and DIT undergo deiodination by Iodotyrosine Deiodinase (DEHAL1/IYD).
• Liberated iodide recycled for new hormone synthesis.
• Prevents urinary iodine loss.

7. Peripheral Conversion and Metabolism

• T4 acts primarily as prohormone; T3 acts as biologically active hormone.
• 70-90% circulating T3 derived from peripheral conversion of T4.
• Catalyzed by iodotyrosine deiodinases.
• Type 1 Deiodinase (DIO1): Outer ring monodeiodination. High-Km enzyme. Converts T4 to T3. Predominant in liver, kidney, thyroid.
• Type 2 Deiodinase (DIO2): Outer ring monodeiodination. Low-Km enzyme. Converts T4 to T3. Increases local tissue T3 (brain, pituitary, brown adipose tissue).
• Type 3 Deiodinase (DIO3): Inner ring monodeiodination. Converts T4 to inactive reverse T3 (rT3) and T3 to diiodothyronine (T2). Prominent in fetal tissues and placenta.