Figure 2.

Thyroid hormone biosynthesis. The biosynthesis of thyroid hormones can be summarized through six steps. 1. Iodide reaches the cytosol of thyroid follicular cells via an active transport mechanism, mediated by sodium-channel iodine - Na+/I− - symporter (NIS; also known as SLC5A5). NIS activity is generated by the sodium gradient created by the Na/K-ATPase and KCNQ1-KCNE2 potassium channel. After crossing the basolateral membrane, iodide reaches the apical membrane after which it will undergo organification. The movement of iodine across the apical border is mediated by a passive transport system, through potentially the specific channels Pendrin (also known as PDS or SLC26A4) and ANO1 (Anoctamin-1). SLC26A7 may be an additional such transporter. 3. After crossing the apical membrane, the enzyme thyroid-peroxidase (TPO) oxidizes iodide to atomic iodine (I) using a source of hydrogen peroxide (H₂O₂) provided by dual function oxidases (DUOX2 and DUOXA2). 4. In the presence of iodide and H₂O₂, TPO catalyzes the iodination of thyroglobulin (TG) tyrosine residues, at the apical plasma membrane; both singly iodinated tyrosine residues (mono-iodotyrosine—MIT) and doubly iodinated tyrosine residues (di-iodotyrosine—DIT) are formed during iodination of thyroglobulin. 5. After the re-internalization of TG from the follicular lumen into the follicle, TG undergoes lysosomal degradation via proteolysis, which liberates thyroid hormones 3,5,3′-triiodothyronine (T3) and 3,5,3′,5′-tretraiodothyronine (T4). Surplus MITs and DITs are deiodinated by the iodotyrosine deiodinase 1 (DEHAL1/IYD) and iodine is transported to the intrathyroidal iodide pool 6. Finally, T4 and T3 exit the thyroid gland via the monocarboxylate transporter 8 (MCT8) and potentially other modalities. The transcription of specific thyroid genes and thyroid function in vivo is under the control of thyrotropin (TSH) via its protein G-coupled receptor (TSHR).