Synthesis, secretion and metabolism of thyroid hormones

The precursor of T4 _and T3 _is the amino acid L-tyrosine. The addition of iodine to the phenolic ring of tyrosine provides the formation of mono- or diiodotyrosines. If a second phenolic ring is added to tyrosine via an ether bond, thyronine is formed. One or two iodine atoms can be attached to each of the two or both phenolic rings of thyronine in the meta position relative to the amino acid residue. T4 is 3,5,3',5'-tetraiodothyronine, and T3 _is 3,5,3'-triiodothyronine, i.e. it contains one less iodine atom in the "outer" (devoid of an amino acid grouping) ring. When an iodine atom is removed from the "inner" ring, T ₄ is converted into 3,3',5'-triiodothyronine or into reverse T ₃ (pT ₃ ). Diiodothyronine can exist in three forms (3',5'-T ₂, 3,5-T ₂ or 3,3'-T ₂ ). When the amino group is split off from T ₄ or T ₃, tetraiodo- and triiodothyroacetic acids are formed, respectively. The significant flexibility of the spatial structure of the thyroid hormone molecule, determined by the rotation of both thyronine rings relative to the alanine part, plays a significant role in the interaction of these hormones with binding proteins of blood plasma and cellular receptors.

The main natural source of iodine is seafood. The minimum daily requirement for iodine (in terms of iodide) for humans is about 80 mcg, but in some areas where iodized salt is used for preventive purposes, iodide consumption can reach 500 mcg/day. Iodide content is determined not only by the amount that comes from the gastrointestinal tract, but also by "leakage" from the thyroid gland (normally about 100 mcg/day), as well as peripheral deiodination of iodothyronines.

The thyroid gland has the ability to concentrate iodide from blood plasma. Other tissues, such as the gastric mucosa and salivary glands, have a similar ability. The process of iodide transfer into the follicular epithelium is energy-dependent, saturable, and is carried out in conjunction with the reverse transport of sodium by membrane sodium-potassium-adenosine triphosphatase (ATPase). The iodide transport system is not strictly specific and causes the delivery of a number of other anions (perchlorate, pertechnetate, and thiocyanate) into the cell, which are competitive inhibitors of the process of iodide accumulation in the thyroid gland.

As already noted, in addition to iodine, a component of thyroid hormones is thyronine, which is formed in the depths of the protein molecule - thyroglobulin. Its synthesis occurs in thyrocytes. Thyroglobulin accounts for 75% of the total protein contained and 50% of the protein synthesized at any given moment in the thyroid gland.

Iodide entering the cell is oxidized and covalently attached to tyrosine residues in the thyroglobulin molecule. Both oxidation and iodination of tyrosyl residues are catalyzed by peroxidase present in the cell. Although the active form of iodine that iodinates the protein is not precisely known, hydrogen peroxide must be formed before such iodination (i.e., the process of iodine organification) occurs. In all likelihood, it is produced by NADH-cytochrome B or NADP-H-cytochrome C reductase. Both tyrosyl and monoiodotyrosyl residues in the thyroglobulin molecule undergo iodination. This process is influenced by the nature of adjacent amino acids, as well as the tertiary conformation of thyroglobulin. Peroxidase is a membrane-bound enzyme complex whose prosthetic group is formed by heme. The hematin group is absolutely necessary for the enzyme to exhibit activity.

Iodination of amino acids precedes their condensation, i.e., the formation of thyronine structures. The latter reaction requires the presence of oxygen and can occur through the intermediate formation of an active metabolite of iodotyrosine, such as pyruvic acid, which then attaches to the iodotyrosyl residue in thyroglobulin. Regardless of the exact mechanism of condensation, this reaction is also catalyzed by thyroid peroxidase.

The molecular weight of mature thyroglobulin is 660,000 daltons (sedimentation coefficient - 19). It apparently has a unique tertiary structure that facilitates the condensation of iodotyrosyl residues. Indeed, the tyrosine content of this protein differs little from that of other proteins, and iodination of tyrosyl residues can occur in any of them. However, the condensation reaction is carried out with sufficiently high efficiency, probably, only in thyroglobulin.

The content of iodine amino acids in native thyroglobulin depends on the availability of iodine. Normally, thyroglobulin contains 0.5% iodine in the form of 6 monoiodotyrosine (MIT), 4 - diiodotyrosine (DIT), 2 - T ₄ and 0.2 - T3 residues per protein molecule. Reverse T ₃ and diiodothyronines are present in very small quantities. However, under conditions of iodine deficiency, these ratios are disrupted: the MIT/DIT and T ₃ /T ₄ ratios increase, which is considered an active adaptation of hormogenesis in the thyroid gland to iodine deficiency, since T ₃ has greater metabolic activity compared to T ₄.

The entire process of thyroglobulin synthesis in the follicular cell of the thyroid gland is directed in one direction: from the basal membrane to the apical membrane and then into the colloid space. The formation of free thyroid hormones and their entry into the blood presupposes the existence of a reverse process. The latter consists of a number of stages. Initially, thyroglobulin contained in the colloid is captured by the processes of the apical membrane microvilli, forming pinocytosis vesicles. They move into the cytoplasm of the follicular cell, where they are called colloidal droplets. In turn, they fuse with microsomes, forming phagolysosomes, and migrate to the basal cell membrane as part of them. During this process, thyroglobulin proteolysis occurs, during which T4 and T3 are formed _. The _latter diffuse from the follicular cell into the blood. In the cell itself, partial deiodination of T ₄ also occurs with the formation of T ₃. Some of the iodotyrosines, iodine and a small amount of thyroglobulin also enter the blood. The latter circumstance is of great importance for understanding the pathogenesis of autoimmune diseases of the thyroid gland, which are characterized by the presence of antibodies to thyroglobulin in the blood. In contrast to previous ideas, according to which the formation of such autoantibodies was associated with damage to thyroid tissue and the entry of thyroglobulin into the blood, it has now been proven that thyroglobulin enters there normally.

During the intracellular proteolysis of thyroglobulin, not only iodothyronines but also iodotyrosines contained in the protein in large quantities penetrate into the cytoplasm of the follicular cell. However, unlike T4 _and T3 _, they are quickly deiodinated by an enzyme present in the microsomal fraction, forming iodide. Most of the latter is reutilized in the thyroid gland, but some of it still leaves the cell into the blood. Deiodination of iodotyrosines provides 2-3 times more iodide for new synthesis of thyroid hormones than the transport of this anion from the blood plasma to the thyroid gland, and therefore plays a major role in maintaining the synthesis of iodotyronines.

_{The thyroid gland produces approximately 80-100 μg of T4} per day. The half-life of this compound in the blood is 6-7 days. About 10% of secreted T4 is broken down in the body daily _. The rate of its degradation, like T3 _, depends on their binding to serum and tissue proteins. Under normal conditions, more than 99.95% of T4 and more than 99.5% of T3 present in the blood _are bound to plasma proteins. The latter act as a buffer for the level of free thyroid hormones and simultaneously serve as a place for their storage. The distribution of T4 _and T3 _among various binding proteins is affected by the pH and ionic composition of the plasma. In plasma, approximately 80% of T4 _is complexed with thyroxine-binding globulin (TBG), 15% with thyroxine-binding prealbumin (TBPA), and the rest with serum albumin. TSH binds 90% of T3 _, and TSPA binds 5% of this hormone. It is generally accepted that only that tiny fraction of thyroid hormones that is not bound to proteins and is capable of diffusing through the cell membrane is metabolically active. In absolute figures, the amount of free T4 _in serum is about 2 ng%, and T3 _- 0.2 ng%. However, recently a number of data have been obtained on the possible metabolic activity of that part of thyroid hormones that is associated with TSPA. It is possible that TSPA is a necessary mediator in the transmission of the hormonal signal from the blood to the cells.

TSH has a molecular weight of 63,000 daltons and is a glycoprotein synthesized in the liver. Its affinity for T4 _is approximately 10 times higher than for T3 _. The carbohydrate component of TSH is sialic acid and plays a significant role in hormone complexation. Liver production of TSH is stimulated by estrogens and inhibited by androgens and high doses of glucocorticoids. In addition, there are congenital anomalies in the production of this protein, which can affect the total concentration of thyroid hormones in the blood serum.

The molecular weight of TSPA is 55,000 daltons. The complete primary structure of this protein has now been established. Its spatial configuration determines the existence of a channel passing through the center of the molecule, in which two identical binding sites are located. Complexation of T4 _with one of them sharply reduces the affinity of the second to the hormone. Like TSH, TSPA has a much higher affinity for T4 _than for T3 _. Interestingly, other sites of TSPA are able to bind a small protein (21,000) that specifically interacts with vitamin A. The attachment of this protein stabilizes the TSPA complex with T4 _. It is important to note that severe nonthyroidal diseases, as well as starvation, are accompanied by a rapid and significant drop in the level of TSPA in the serum.

Serum albumin has the lowest affinity for thyroid hormones of the proteins listed. Since albumin normally binds no more than 5% of the total amount of thyroid hormones present in the serum, changes in its level have only a very weak effect on the concentration of the latter.

As already noted, the combination of hormones with serum proteins not only prevents the biological effects of T3 _and T4 _, but also significantly slows down the rate of their degradation. Up to 80% of T4 _is metabolized by monodeiodination. In the case of the splitting off of an iodine atom in the 5'-position, T3 is formed, which has much greater biological activity; when iodine is split off in position 5, pT3 is formed _, the biological activity of which is extremely insignificant. Monodeiodination of T4 _in one position or another is not a random process, but is regulated by a number of factors. However, normally, deiodination in both positions usually occurs at an equal rate. Small amounts of T4 _undergo deamination and decarboxylation with the formation of tetraiodothyroacetic acid, as well as conjugation with sulfuric and glucuronic acids (in the liver) with subsequent excretion of conjugates with bile.

Monodeiodination of T ₄ outside the thyroid gland is the main source of T ₃ in the body. This process provides almost 80% of the 20-30 μg of T ₃ formed per day. Thus, the secretion of T ₃ by the thyroid gland accounts for no more than 20% of its daily requirement. Extrathyroidal formation of T3 from T ₄ is catalyzed by T ₄ -5'-deiodinase. The enzyme is localized in cellular microsomes and requires reduced sulfhydryl groups as a cofactor. It is believed that the main conversion of T ₄ to T3 occurs in the tissues of the liver and kidneys. T ₃ is less bound to serum proteins than T ₄, and therefore undergoes more rapid degradation. Its half-life in the blood is about 30 hours. It is converted mainly into 3,3'-T ₂ and 3,5-T ₂; Small amounts of triiodothyroacetic and triiodothyropropionic acids, as well as conjugates with sulfuric and glucuronic acids, are also formed. All of these compounds are virtually devoid of biological activity. The various diiodothyronines are then converted into monoiodothyronines and, finally, into free thyronine, which is found in the urine.

The concentration of various iodothyronines in the serum of a healthy person is, μg%: T4 _- 5-11; ng%: T3 _- 75-200, tetraiodothyroacetic acid - 100-150, pT3 _- 20-60, 3,3'-T2 _- 4-20, 3,5-T2 _- 2-10, triiodothyroacetic acid - 5-15, 3',5'-T2 _- 2-10, 3-T, - 2.5.