Qoj

proximal conformer distal conformer

Triiodothyronine (T3)

Monoiodotyrosine (MIT)

Monoiodotyrosine (MIT)

Oiiodotyrosine (DIT)

Oiiodotyrosine (DIT)

3,5,3',5'-Tetraiodothyronine (L-thyroxine) (TJ

3,5,3'-Triiodothyronine (T3)

3,5,3',5'-Tetraiodothyronine (L-thyroxine) (TJ

3,5,3'-Triiodothyronine (T3)

3,3'-Diiodo thyronine

3,3'-Diiodo thyronine

3,3',5-Triiodothyronine-reverse-T3

3,3',5-Triiodothyronine-reverse-T3

Tetraiodothyropropionic acid

Tetraiodothyropyruvic acid

Tetraiodothyropropionic acid

Tetraiodothyropyruvic acid

Tetraiodothyroacetic acid (TETRAC)

Tetraiodothyroformic acid

FIGURE 6-3 Structure of thyroxine, triiodothyronine, precursors, and analogs. (A) The numbering system of the carbons for the two aromatic rings of thyroxine or 3,5,3',5'-tetraiodothyronine (T4) is indicated. (B) Schematic representation of the conformation of triiodothyronine (T3), illustrating that the phenyl rings exist in planes that are normal to one another and intersect at an angle of —120°. Two conformations are possible for T3 analogs that are monosubstituted in the ortho position relative to the 4'-OH group: (1) the proximal conformer with the single outer ring substituent oriented toward the inner ring; (2) the distal conformer with the same substituent directed away from the inner ring. The distal conformation is believed to correspond to the active conformation of the molecule. (C) Structure of other thyroxine analogs.

Tetraiodothyroacetic acid (TETRAC)

Tetraiodothyroformic acid

FIGURE 6-3 Structure of thyroxine, triiodothyronine, precursors, and analogs. (A) The numbering system of the carbons for the two aromatic rings of thyroxine or 3,5,3',5'-tetraiodothyronine (T4) is indicated. (B) Schematic representation of the conformation of triiodothyronine (T3), illustrating that the phenyl rings exist in planes that are normal to one another and intersect at an angle of —120°. Two conformations are possible for T3 analogs that are monosubstituted in the ortho position relative to the 4'-OH group: (1) the proximal conformer with the single outer ring substituent oriented toward the inner ring; (2) the distal conformer with the same substituent directed away from the inner ring. The distal conformation is believed to correspond to the active conformation of the molecule. (C) Structure of other thyroxine analogs.

TABLE 6-1 Biological Activity of Some Thyroxine Analogs"

Percentage of thyroxine-like activity

Compound Goiter prevention Calorigenic

Iodinated thyronines l-Thyroxine (3,5,3'5'-tetraiodo-l-thyronine) 100 100

3,5,3'-Triiodo-l-thyronine 500-800 300-500

3,3',5'-Triiodo-l-thyronine (reverse T3) <1 <1

3-lodo-dl-thyronine <2 <2 3' or 5' position phenolic ring substituents

3',5'-Dibromo-3,5-diiodothyronine 7-10

3 ' -Bromo-3,5-diiodothy ronine 130-200

3',5'-Dichloro-3,5-diiodo-l-thyronine 15-27

3 ' -Chloro-3,5-diiodo-l-thy ronine 27 3 or 5 position phenolic ring substituents

3,5-Dibromo-3',5'-diiodo-dl-thyronine 12

3,5-Dichloro-3',5'-diiodo-dl-thyronine 0.2 Side chain alterations

3,5,3',5'-Tetraiodothyroacetic acid 57 10-15

3,5,3',5'-Tetraiodothyropyruvic acid 75 10-20 4'-Phenolic hydroxyl substituents

O-Methyl-dl-thyroxine 50

" Abstracted from Pittman, C. S., and Pittman, J. A. (1974). Relation of chemical structure to the action and metabolism of thyroactive substances. In "Handbook of Physiology" (M. A. Greer and D. H. Solomon, eds.), Sect. 7, Vol. Ill, p. 233. American Physiological Society, Washington, DC.

intestine after reduction to iodide; iodate in the food is also reduced to iodide prior to absorption. The inorganic iodide is then transported in the blood by a variety of plasma proteins. The concentration of total iodide in the blood plasma is 8-15 pig /100 ml, while the protein-bound concentration is normally 6-8 ¡jlg/100 ml. After arrival at the thyroid gland, the iodide is converted to the thyroid hormones in a series of seven metabolic steps, which are summarized as follows:

(a) Active transport of iodide into the thyroid gland follicular cells

(b) Peroxidase-catalyzed oxidation of iodide followed by iodination of tyrosyl residues within the protein thyroglobulin

(c) Transfer and coupling of iodotyrosines within thyroglobulin to form T4 and T3 (mediated by thyroper-oxidase)

(d) Storage of thyroglobulin in the lumen of the thyroid follicle as colloid

(e) Endocytosis of colloid

(f) Proteolysis of thyroglobulin with concomitant release of T4 and T3 as well as free iodotyrosines and iodothyronines

(g) Secretion of iodothyronines into the blood

(h) Scavenger deiodination of iodotyrosines within the thyroid follicular cells for reutilization of the liberated iodine

The biosynthesis of thyroid hormones requires access to four major components: thyroglobulin (Tg), thyroperoxidase (TPO), H2O2, and iodide. Thyroglobulin is the most abundant protein of thyroid tissue. An understanding of the biochemistry and biological properties of thyroglobulin is integral to an understanding of the generation of thyroid hormone.

The mature human Tg is a dimeric molecule with a molecular mass of 669 kDa; about 10% of the Tg mass comprises carbohydrates. The monomeric subunit is 330 kDa and consists of 2748 amino acid residues. Tg is synthesized as a prehormone that contains a leader sequence of 19 amino acids. The human gene for Tg is a single copy that extends more than 300 kb and contains 42 exons. The pathway of biosynthesis of thyroglobulin is initiated by thyroid-stimulating hormone through interaction with its membrane receptor (see Figure 6-4). After its biosynthesis, Tg is subject to extensive glycosylation; the carbohydrate units are linked to 20 potential glycosylation sites on the protein.

As shown in Figure 6-5, the primary structure of human Tg is divided into four domains. Bovine Tg has an almost identical organization. Interestingly, Tg contains 134 tyrosine residues, only 25-30 of which have been shown to become iodinated; only 4 of these iodotyrosines are actively utilized to form iodothyronines. Four principal hormonogenic sites have been

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