Tyrosine, biosynthesis iodination

It is not well known at what stage of the thyroglobu-lin molecule s biosynthesis tyrosine is iodinated. Three proposals have been submitted (1) iodination of the amino acid before its incorporation into the polypeptide chain (but puromycin does not impair iodination, and no enzymes capable of activating iodotyrosine have been found) (2) iodination of the finished tetra-meric globulin and (3) iodination of the 12 S subunits with concomitant condensation of the unit to yield new protein. However, there seems to be no doubt that thyroglobulin continues to be iodinated even after its excretion into the colloid, indeed the ratio... 

FIGURE 31-2 Thyroid hormone biosynthesis. Iodide is taken into the follicle cell, where it is converted by thyroid peroxidase to an oxidized form of iodine (Ip). h is transported to the follicle lumen, where it is bonded to tyrosine residues of the thyroglobulin [TGB] molecule. Iodinated TGB is incorporated back into the cell, where it undergoes lysis to yield the thyroid hormones T3 and T4. See text for further discussion. 

The biosynthesis of thyroid hormones involves the trapping of circulating iodide (iodide transport) by the thyroid gland, the incorporation of iodine into tyrosine, and the coupling of iodinated tyrosyl residues to form the thyronines (T4 and... 

Thyroid hormone biosynthesis (Figure 45-2) involves the concentrative uptake of iodide into thyroid cells where it is converted into iodine by thyroid peroxidase in the colloid space of the folhcular lumen. Iodine is incorporated into tyrosine residues of thyroglobuhn contained within the colloid space at the basal surface of the thyroid follicular cell. Tyrosine residues are iodinated... 

Figure 38.2 Possible sites of inhibitory actions of soy isoflavones on iodine utilization and thyroid hormone biosynthesis and actions. Soy isoflavonoids, genistein and daidzein, inhibit oxidation of iodide by thyroid peroxidase at the apical membrane of thyroid follicular cells, followed by iodination of tyrosine residues in thyroglobulin and their coupling in colloid. In addition, they may affect deiodination of iodothyronines and interfere with thyroid hormone binding to transthyretin. Full arrows indicate the sites of inhibition. So far, only few reports concern the effect of thyroid hormone actions in target cells.

The chemical steps in the biosynthesis of thyroid hormones are also well established and are shown in a simplified form in Fig. 1. There are three main phases in biosynthesis, namely trapping of iodide and its conversion into an activated form, iodination of the tyrosines (organification), and finally coupling of the iodotyrosines to form iodothyronines. Only a brief outline of the biosynthesis will be given here, as the subject has been well reviewed by others (e.g., D2, P13, S6). 

Apart from surgery, blocking of the biosynthesis of the thyroid hormones is of particular interest. There are several hundred thionamides known, which exert their activity by inhibiting thyroperoxidase, an enzyme required for iodination and coupling of the tyrosine residues. However, only a few of these drugs are approved and in clinical use. Their synthesis employs conventional heterocyclic chemistry. 

The biosynthesis starts from tyrosine, which is iodinated and oxidatively coupled. 

A noteworthy example of electrophilic aromatic substitution in nature, as mentioned in the introduction, is biosynthesis of the thyroid hormone thyroxine, where iodine is incorporated into benzene rings that are derived from tyrosine. 

It is clearly not possible to discuss here at any length, the metabolism of individual amino acids. In addition, the details of the biosynthesis and catabolism of amino acids, well reviewed in Volume II of Meister s recent book , are concerned more with the formation and breakdown of the carbon skeleton than with the introduction or loss of the amino group. Modifications of some of the twenty amino cicids normally found in proteins have been detected in some protein hydrolysates, e.g. iodinated tyrosine, phosphoserine and hydroxylysine. In some cases the modification appears to be made before the amino acid is incorporated into protein (e.g. iodination of tyrosine) while in other cases modification is believed to occur when the amino acid is already present in proteins (e.g. hydroxylation of lysine, and in some cases, of... 

Thyroxine (see the model above ) is an aromatic compound and a key hormone that raises metabolic rate. Low levels of thyroxine (hypothyroidism) can lead to obesity, lethargy, and an enlarged thyroid gland (goiter). The thyroid gland makes thyroxine from iodine and tyrosine, which are two essential components of our diet. Most of us obtain iodine from iodized salt, but iodine is also found in products derived from seaweed, like the kelp shown above. An abnormal level of thyroxine is a relatively common malady, however. Fortunately, low levels of thyroxine are easily corrected by hormone supplements. After we study a new class of reaction in this chapter called electrophilic aromatic substitution, we shall return to see how that reaction is related to thyroxine in "The Chemistry of... Iodine Incorporation in Thyroxine Biosynthesis."... 

Phenols and related compounds occur widely in nature. Tyrosine is an amino acid that occurs in proteins. (See The Chemistry of. .. Iodine Incorporation in Thyroxine Biosynthesis in Chapter 15.) Methyl salicylate is found in oil of wintergreen, eugenol is found in oil of cloves, and thymol is found in thyme. 

Electrophilic aromatic halogenations occur in the biosynthesis of numerous naturally occurring molecules, particularly those produced by marine organisms. In humans, the best-known example occurs in the thyroid gland during the biosynthesis of thyroxine, a thyroid hormone involved in regulating growth and metabolism. The amino acid tyrosine is first iodinated by thyroid peroxidase, and two of the iodinated tyrosine molecules then couple. The... 

Numerous L-tyrosine containing peptides and proteins may be utilised to synthesise thyroxine (80) by iodination and without enzymic mediation . Iodine reacts with the L-tyrosine residues in the peptide to form mono- and di-iodo-L-tyrosine residues. An oxidative coupling of two, appropriately placed, di-iodo-L-tyrosyl residues then occurs to give thyroxine (80). Considerable evidence has been accumulated to surest that thyroxine biosynthesis follows the same pathway in vivo, but other mechanisms have been suggested and examined . The exact role of the protein thyroglobulin in thyroxine biosynthesis is, however, not clear for although L-tyrosine residues of other proteins may be readily iodinated in vitro only thyroglobulin is known to make thyroxine in vivo. 

Biosynthesis. Thyroxine is formed in the thyroid gland (Greek, thyreoides = shield-shaped) from protein-bound tyrosine (Greek, tyros = cheese), which is iodinated first. Iodine ions are removed from blood (against a concentration gradient), oxidized to elemental iodine, and inserted into the tyrosine radical. Thyronine seems to be formed with particular ease in fact, it arises nonenzymically from iodinated protein or iodinated tyrosine peptides. The reaction probably proceeds via semiquinone radicals as shown on page 341. 

Many antagonists of hormones are known. For example, some substances decreased the biosynthesis of the thyroid hormones by inhibiting the process of concentrating iodine in the thyroid gland, others by preventing the iodination of tyrosine. The clinically useful thio-drugs, such as propylthiouracil and carbimazole (i-i6), have the latter type of action. 

---