Thyroid synthesis, steps

Synthesis of thyroid hormones occurs in several steps. At first, inorganic iodide is actively concentrated by... 

Figure 42-11. Model of iodide metabolism in the thyroid follicle. A follicular cell is shown facing the follicular lumen (top) and the extracellular space (at bottom). Iodide enters the thyroid primarily through a transporter (bottom left). Thyroid hormone synthesis occurs in the follicular space through a series of reactions, many of which are peroxidase-mediated. Thyroid hormones, stored in the colloid in the follicular space, are released from thyroglobulin by hydrolysis inside the thyroid cell. (Tgb, thyroglobulin MIT, monoiodotyrosine DIT, diiodotyro-sine Tj, triiodothyronine T4, tetraiodothyronine.) Asterisks indicate steps or processes that are inherited enzyme deficiencies which cause congenital goiter and often result in hypothyroidism.

Thyroid peroxidase An enzyme that catalyzes the organification and coupling steps of thyroid hormone synthesis. 

Levothyroxine is used to treat hypothyroidism (an underactive thyroid gland). Thyroid hormone can be made from beef and pork thyroid, but this lacks standardization and it is difficult to control dosage. The synthetic drug is more desirable. Levothyroxine is one of two important thyroid hormones. It is converted into the second important hormone, liothyronine, in the body. The key step in the synthesis of structures such as levothyroxine is the substitution of an iodonium salt by an iodinated phenol. Siql-like reactions on an aromatic ring are not common, but an iodonium salt provides a good leaving group. 

The final step in thyroid hormone synthesis is the coupling of two iodotyrosines within a single peptide chain of Tg to form the iodothyronine T4 or T3. Both the coupling of two DITs to form T4 and the coupling of a MIT with a DIT to form T3 are catalyzed by the enzyme TPO. 

Steps in the synthesis of thyroid hormone include the following,... 

The thyroid gland is made up of multiple follicles that consist of a single layer of epithelial cells surrounding a lumen filled with colloid (thyroglobulin), the storage form of thyroid hormone. A diagram of the steps in thyroid hormone synthesis and secretion is shown in Figure 25.6. 

The third step in thyroid hormone synthesis is cleavage of the aromatic R group from one of the iodinated tyrosines in the dimer. As a result, one of the iodotyros-... 

The second step in thyroid hormone synthesis is the covalent bridging of two different residues of iodinated tyrosine. A dimer is formed, reminiscent of the dimers of cysteine in proteins (the cysteine dimer is called cystine). Only a small fraction of the iodinated tyrosines is bridged in this way. More specifically, only four of the iodinated tyrosines, located at positions 5,2555,2569, and 2748, participate in the reaction. The numbers refer to the amino acid, cormting from the amino terminus of the protein. Thyroglobulin has 2748 amino acids. The first and second steps are catalyzed by thyroperoxidase, a heme protein. It requires hydrogen peroxide for activity. To summarize, thyroperoxidase catalyzes the attachment of iodine atoms to residues of tyrosine as well as the subsequent cross-linking of the iodinated tyrosine residues. 

Each step in the synthesis of thyroid hormones is regulated by pituitary TSH. TSH stimulates the iodide pump, Tg synthesis, and colloidal uptalce by foUicular cells. TSH also regulates the rate of proteolysis of Tg for the fib-eration of T4 and T3 is also regulated by TSH. In addition, TSH induces an increase in the size and number of the thyroid foUicular ceUs. Prolonged TSH stimulation leads to increased vascularity and eventual hypertrophic enlargement of the thyroid gland (goiter). 

The steps in thyroid hormone synthesis and the antithyroid agents effects upon them are summarized in Table VII-2-2. The clinical uses and their potential complications are presented in greater detail for the thioamides (propylthiouracil and methimazole) and iodine. 

It has also been mentioned that salt iodization efficacy, the preferred strategy for IDD, might be influenced by ID, because this disorder impairs thyroid metabolism (WHO, 2001, Zimmermann et al., 2000). It has been observed that two initial steps in thyroid hormone synthesis are catalyzed by Fe-dependent thyroid peroxidase (TPO). One Fe-defl-ciency anemia study in rats showed reduced TPO activity, and decreased plasma T4 and triiodothyronine (T3) levels (Hess et al, 2002). IDA may also alter the central nervous systems thyroid metabolism control, and reduce T4 to T3 peripheral conversion (Beard etal, 1998), modify nuclear T3 binding (Smith et al, 1994), and increase circulating thyrotropin (TSH) (Beard et at, 1990). The therapeutic response to oral iodized oil is impaired in children with IDA compared with Fe-sufficient children (Zimmermann et al, 2000). 

Thyroid hormone synthesis takes place at the follicular cell level through a number of different steps (Figure 56.1). The active transport of iodide into the follicular cells is... 

Figure 56.1 This figure gives a schematic representation of the foiiicuiar thyroid ceii. Thyroid hormone synthesis takes piace across a number of different steps, starting from iodide uptake and ending with the reiease of free thyroid hormones in the bioodstream.

Figure 57.4 The possible link between thyroid hormone synthesis, oxidative stress and mutagenesis in the thyroid gland. This figure illustrates the mechanism, the sequence of steps and the key moleoules that link thyroid hormone synthesis, iodine deficiency, oxidative stress, DNA damage and possible mutagenesis. ThOX, thyroid oxidase TPO, thyroid peroxidase T3, T4, thyroid hormones.

The synthesis of thyroid hormones occurs in several steps. At first, inorganic iodide is actively concentrated by thyroid follicular cells by the sodium iodide sym-porter. Lotv iodide levels stimulate the intake of iodide via increased expression of the sodium iodide symporter. Iodide is mostly coupled to tyrosine residues of thyroglob-uhn (Tg) and stored extracellularly in the foUicular lumen. 

---