Tyrosine thyroid hormone synthesis

Thioamides are reducing agents. They inhibit thyroid hormone synthesis by inhibiting the peroxidase enzymatic system, which catalyzes oxidation of iodide ions and iodine that are consumed in food, which is necessary for iodination of tyrosine derivatives. Thus they reduce the concentration of free iodine necessary to react with tyrosine derivatives, and they can also block oxidative addition reactions of mono- and diiodtyrosines, which form L-thyroxine and L-triiodothyronin. 

Thyroid hormone synthesis requires oxidation of dietary iodine, followed by iodination of tyrosine to mono- and diiodotyrosine coupling of iodotyrosines leads to formation of the active molecules, tetraiodo-tyrosine, (T or L-th3rroxine) and triiodotyrosine (Tj or L-thyronine). 

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. 

This peroxidase catalyzes two important reactions in the thyroid hormone synthesis (i) the iodination of tyrosines in thyroglobulin to yield protein-bound mono- and di-iodotyrosines... 

It was further found by these authors that the dehalogenase was inactive towards the iodinated tyrosines when they were bound in thyroglobulin only free amino acids were attacked (personal communication). The metabolism of the iodinated tyrosines can therefore be regarded as taking place entirely within the thyroid after proteolysis from thyroglobulin they are completely dehalogenated and the iodide formed can be re-utilized for the cycle of thyroid hormone synthesis. 

The amino acid tyrosine is the starting point in the synthesis of the catecholamines and of the thyroid hormones tetraiodothyronine (thyroxine T4) and triiodothyronine (T3) (Figure 42-2). T3 and T4 are unique in that they require the addition of iodine (as T) for bioactivity. Because dietary iodine is very scarce in many parts of the world, an intricate mechanism for accumulating and retaining T has evolved. 

The thyroid hormones T3 and T4 are unique in that iodine (as iodide) is an essential component of both. In most parts of the world, iodine is a scarce component of soil, and for that reason there is htde in food. A complex mechanism has evolved to acquire and retain this cmcial element and to convert it into a form suitable for incorporation into organic compounds. At the same time, the thyroid must synthesize thyronine from tyrosine, and this synthesis takes place in thyroglobuhn (Figure 42-11). 

Isoflavones have been implicated in goiter induction. Soybean extracts inhibit reactions catalyzed by thyroid peroxidase (TPO), essential to the synthesis of thyroid hormones (Divi et al., 1997). Genistein and daidzein (at about 1-10 p,M of IC50) may act as alternative substrates for tyrosine iodination (Divi et al., 1997). Furthermore, genistein and daidzein have also been shown to cause the irreversible inactivation of TPO in the presence of hydrogen peroxide. Genistein also inhibits thyroxine synthesis in the presence of iodinated... 

In addition to their well known role in protein structure, amino acids also act as precursors to a number of other important biological molecules. For example, the synthesis of haem (see also Section 5.3.1), which occurs in, among other tissues, the liver begins with glycine and succinyl-CoA. The amino acid tyrosine which maybe produced in the liver from metabolism of phenylalanine is the precursor of thyroid hormones, melanin, adrenaline (epinephrine), noradrenaline (norepinephrine) and dopamine. The biosynthesis of some of these signalling molecules is described in Section 4.4. 

The thyroid hormone thyroxine (tetraiodo-thyronine, T4) and its active form triiodothyronine (T3) are derived from the amino acid tyrosine. The iodine atoms at positions 3 and 5 of the two phenol rings are characteristic of them. Post-translational synthesis of thyroxine takes place in the thyroid gland from tyrosine residues of the protein thyro-globulin, from which it is proteolytically cleaved before being released, iodothyronines are the only organic molecules in the animal organism that contain iodine. They increase the basal metabolic rate, partly by regulating mitochondrial ATP synthesis, in addition, they promote embryonic development. 

Thiram also leads to thyroid dysfunction. This effect is thought to be a result of metabolic release of sulfur in follicular cells, causing inhibition of tyrosine iodination and ultimately hormone synthesis. Thiram... 

Phenylalanine and tyrosine are also metabolized in higher organisms by two routes which are quantitatively less important but physiologically of the highest importance. The first leads to the adrenal hormones adrenaline (epinephrine) and noradrenaline (norepinephrine),which may be formed as in diagram 11 this pathway also leads to melanin (diagram 12). The second leads to the thyroid hormones thyroxine and triiodothyronine, the synthesis and breakdown of which are also discussed. 

FIGURE 66 Methimazole inhibits the synthesis of thyroid hormone by interfering with the incorporation of iodine into tyrosine and the formation of iodothyronine. 

Thyroxine and triiodothyronine are thyroid hormones made by modifying tyrosine residues in the protein, thyroglobulin (Figure HO 21.19). Degradation of thyroglobulin yields the free hormones. Synthesis occurs in the thyroid gland, which concentrates iodide from the blood. 

Iodide decreases the release of thyroid hormone and also decreases the synthesis of iodi-nated tyrosine and thyronine residues. 

Fig. 43.10. Synthesis of the thyroid hormones (T3 and T4). The protein thyroglobulin (Tgb) is synthesized in thyroid follicular cells and secreted into the colloid, lodination and coupling of tyrosine residues in Tgb produce T3 and T4 residues, which are released from Tgb by pinocytosis (endocytosis) and lysosomal action. The coupling of a monoiodotyrosine with a diiodotyrosine (DIT) to form triiodothyronine (Tj) is not depicted here.

Thioamides Propylthiouracil (PTU) and methimazole are small sulfur-containing molecules that inhibit thyroid hormone production by several mechanisms. The most important effect is to block iodination of the tyrosine residues of thyroglobulin (Figure 38-2). In addition, these drugs may block coupling of DIT and MIT. The thioamides can be used by the oral route and are effective in most patients with uncomplicated hyperthyroidism. Since synthesis of thyroid hormone rather than release is inhibited, the onset of activity of these drugs is usually slow, of-... 

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