Iodine is an essential trace element required for the synthesis of thyroid hormone. The basolateral membrane of the follicular cell requires an active transporter that mediates uptake of I− together with Na+. This human sodium- iodide symporter (NIS) consists of 618 amino acids and 13 transmembrane domains. Supposedly, these domains form a channel through which I− and Na+ are trans ported in a stoichiometry of 1:2. The surplus of positive charge indicates that I− transport is electrogenic and further driven by the Na+ gradient. TSH stimulates the expression of the NIS gene to such an extent that the intracellular iodide concentration is about 30– 50 times higher than its extracellular level. NIS can also bind other an ions, some of which are even transported.

An important example is perchlorate (ClO4−) which potently inhibits iodide uptake by the NIS, an effect utilized in the perchlorate discharge test used for the diagnosis of an organification defect (i.e. impaired incorporation of iodine in thyroglobulin). Perchlorate inhibits the uptake but not the release of iodide from the thyroid. Therefore, if perchlorate is administered after a dose of radioactive iodide, it will provoke a marked release of radioactivity from the thyroid in case of an organification defect but not from a normal thyroid gland. Pertechnetate (TcO4−) is another anion transported by the NIS, and this observation is utilized in the scanning of the thyroid gland using radioactive ^99mTcO4−.

Since the iodination of thyroglobulin takes place at the luminal surface of the apical membrane, iodide also has to pass this mem brane. A transporter putatively involved in this process has been identified and termed pendrin, since the gene coding for this protein is mutated in patients with Pendred’s syndrome. This is a congenital condition characterized by deafness due to a cochlear defect and hypothyroidism due to an organification defect as indicated by a positive perchlorate discharge test. Pendrin is cap able of transporting bicarbonate, chloride, and iodide, and is expressed only in the thyroid and the cochlea. The exact function of pendrin in the transport of iodide across the follicular apical mem brane is subject to debate. There is likely another protein capable of releasing iodide into the follicular lumen of which anoctamin is a likely candidate. Efflux of iodide from thyroid follicular cells is acutely stimulated by TSH, which may involve recruitment and/ or activation of an iodide exporter such as pendrin.

Thyroglobulin, DUOX2, and TPO

Thyroglobulin is an exceptionally large glycoprotein consisting of two identical subunits. Each mature subunit in human thyroglobulin contains 2748 amino acids and has a molecular weight of approximately 330 kDa. The TG gene is located on human chromosome 8q24.2- q24.3; it covers about 300 kb of genomic DNA and consists of 48 exons.

DUOX2 is a large glycoprotein embedded in the apical membrane of the thyrocyte. Mature human DUOX2 contains 1527 amino acids and has seven putative transmembrane domains, an NADPH- binding domain, an FAD- binding domain, a haem- binding domain, two calcium- binding EF hands, and a peroxidase domain. It catalyses the oxidation of NADPH from the cytoplasm and delivers its product H2O2 to the luminal surface of the membrane. Functional expression of DUOX2 requires the presence of the maturation factor DUOXA2, a protein consisting of 320 amino acids and five putative transmembrane domains.

TPO is a glycoprotein consisting of 933 amino acids and featuring a single transmembrane domain. A short C- terminal domain is located in the cytoplasm but most of the protein is exposed on the luminal surface of the apical membrane, which also contains a haem- binding domain, the active centre of the enzyme. The human TPO gene covers about 150 kb on chromosome 2p25, dis tributed over 17 exons.

Formation of Iodothyronines

 Thyroid hormone synthesis takes place at the luminal surface of the apical membrane in the scaffold of the thyroglobulin molecule and consists of two important reactions that are both catalysed by TPO (i.e. the iodination of Tyr residues and the subsequent coupling of iodotyrosine to iodothyronine residues). The structures of these compounds are illustrated in Figure 1. The prosthetic haem group of TPO undergoes a two- electron oxidation by H2O2 (sup plied by DUOX2) to the intermediate compound 1 (Cpd1). Cpd1 may carry out either a one- electron oxidation reaction, by which it is converted to the intermediate Cpd2, or a two- electron oxidation by which native TPO is regenerated. TPO- catalysed iodination prob ably involves a two- electron oxidation of I− to I+ with subsequent electrophilic substitution of Tyr residues in thyroglobulin, producing 3- iodotyrosine (monoiodotyrosine, MIT). Substitution of MIT residues with a second iodine produces 3,5- diiodotyrosine (DIT).

Fig1. Structures of the iodotyrosines MIT and DIT and the iodothyronines T3 and T4.

Coupling of two suitably positioned iodotyrosine residues results in the formation of an iodothyronine residue at the site of the acceptor iodotyrosine, leaving a dehydroalanine residue at the site of the donor iodotyrosine. Coupling of the diiodophenol moiety of one DIT residue to the phenolic oxygen of a second DIT residue results in the formation of T4, while coupling of the iodophenol moiety of MIT to a DIT residue yields T3. Coupling of DIT and MIT to generate reverse T3 or MIT and MIT to form 3,3′- T2 are apparently rare events, since thyroidal secretion of reverse T3 and 3,3′- T2 are negligible.

Although Tyr is the building block of thyroid hormone, the Tyr content of thyroglobulin is not greater than that of most other proteins. Each thyroglobulin subunit has only four hormonogenic sites, Tyr residues that can ultimately be transformed into iodothyronines. At three sites (positions 5, 1290, and 2553 in the mature protein) T4 can be formed, while at the fourth site (position 2746) T3 is preferentially produced. However, at normal levels of iodination the average yield is 1– 1.5 molecules of T4 and approximately 0.1 molecule of T3 per thyroglobulin subunit. The ratio between T3 and T4 formation is under control of TSH. At this stage the iodothyronines are still in peptide linkage with the thyroglobulin backbone and remain stored as such in the lumen until their secretion is required.

Release of Thyroid Hormone

 In response to TSH stimulation, thyroglobulin is resorbed from the lumen largely by both macro- and micropinocytosis. The former type of endocytosis is associated with the formation of large pseudopodia that engulf colloid and the thyroglobulin contained therein, resulting in the formation of large cytoplasmic vesicles also known as colloid droplets. The second process concerns the receptor- mediated endocytosis of thyroglobulin, involving the binding of thyroglobulin to apical membrane proteins. Megalin, a very large (c.600 kDa) cargo protein located in the apical mem brane of different cell types, including thyrocytes, may be involved although it appears to function primarily in the transcellular trans port of poorly iodinated thyroglobulin.

Both types of endosomes fuse with lysosomes, generating so- called phagolysosomes. In these vesicles thyroglobulin is hydrolysed by lysosomal proteases, (i.e. cathepsins), resulting in the liberation of T4, a small amount of T3, as well as excess MIT and DIT molecules. MIT and DIT are probably exported from the vesicles via a specific transporter. Thus, they have access to the iodotyrosine dehalogenase (DEHAL1), located in the endo plasmic reticulum, which catalyses their deiodination by NADH. The iodide thereby released is reutilized for iodination of thyroglobulin.

Human DEHAL1 is a homodimer of a 289- amino acid protein containing an N- terminal membrane anchor and a conserved nitroreductase domain with an FMN- binding site. The DEHAL1 gene is located on chromosome 6q24- q25 and consists of five exons. Since DEHAL1 lacks an NADH- binding sequence, iodotyrosine deiodinase activity requires the involvement of a reductase, which has not yet been identified.

The most important mechanism of thyroid hormone secretion involves the secretion from the gland through membrane trans porters. This requires iodothyronines to be released via transporters from the vesicles into the cytoplasm, and subsequently secreted through transporters located in the basolateral membrane. In the latter route, some T4 may be converted before secretion to T3 by iodothyronine deiodinases present in the thyrocyte (see next). The thyroid hormone transporter MCT8 (see next) is crucial for the excretion of the hormones from the gland into the circulation.

In an average human subject, T4 and T3 are secreted in a ratio of about 15:1 (i.e. about 100 μg (130 nmol) T4 and 6 μg (9 nmol) T3 per day). The latter represents approximately 20% of daily total T3 production. Hence, most T3 is produced by deiodination of T4 in peripheral tissues.

Inhibitors of Thyroid Hormone Production and/ or Secretion

Administration of a large amount of iodide usually results in an acute but transient decrease in thyroid hormone secretion. The mechanism of this inhibition of thyroid hormone secretion by excess iodide is unknown. Excess iodide will also induce an inhibition of the synthesis of thyroid hormone; this phenomenon is known as the Wolff– Chaikoff effect. The mechanism ap pears to involve, among others, the formation of an iodinated lipid (iodolactone) that inhibits several steps in thyroid hormone syn thesis. This includes the inhibition of iodide uptake by the NIS, which results in a decrease in the intracellular iodide concentration and, thus, a decrease in iodolactone formation. This relieves the inhibited hormone synthesis, known as the escape from the Wolff– Chaikoff effect, that occurs despite the continued administration of excess iodide.

Thiourea derivatives have been known since long as potent inhibitors of thyroid hormone synthesis. Two of these, 6- propyl- 2- thiouracil and particularly methimazole are widely used in the medical treatment of patients with hyperthyroidism (Figure 2). Their antithyroid activity is based on the potent inhibition of TPO, the mechanism of which depends on the available iodide concentration. In the presence of iodide, the thiourea inhibitors compete with the Tyr residues in thyroglobulin for the TPO– I+ iodination complex, preventing the formation of thy roid hormone. The thiourea inhibitors are thus converted to the sulfenyl iodide derivatives which undergo further oxidation of the sulphur ultimately to sulphate.

Fig2. Structures of the TPO inhibitors methimazole and propylthiouracil. The thiourea moiety of the drugs is shaded.

Methimazole is a more potent inhibitor of TPO than propylthiouracil [18], and lower doses of methimazole (or the prodrug carbimazole) are required for the treatment of hyperthyroidism compared with propylthiouracil. Besides inhibiting thyroid hormone (i.e. T4) synthesis by TPO, propylthiouracil also inhibits conversion of T4 to T3 by the type 1 iodothyronine deiodinase located not only in the thyroid but also in liver and kidney (see next).

اخر الاخبار

اخبار العتبة العباسية المقدسة

قسم العلاقات العامة ينظّم برنامجًا ثقافيًّا لوفد أكاديمي من جامعة كربلاء

قسم الشؤون الخدمية ينفّذ حملة لتنظيف محيط مرقد أبي الفضل العباس (عليه السلام)

معهد القرآن الكريم النسوي يواصل برنامج الختمات القرآنية الرمضانية

ضمن برنامج يبلغون.. محافظة المثنى تشهد إقامة 8 مجالس قرآنية رمضانية

المزيد

الآخبار الصحية

الماء المملح.. فائدة حقيقية أم "صيحة زائفة"؟

عادة بسيطة تدعم الصحة وتحافظ على الوزن المثالي

الغذاء النباتي يقلل مخاطر السرطان.. مع استثناء مهم

الحليب قليل أم كامل الدسم.. أيهما أفضل؟

المزيد

الآخبار التكنلوجية

أنثروبيك تتحدى البنتاغون.. وترامب يأمر بوقف التعامل معها

ميزة جديدة من "إنستغرام" لحماية المراهقين من الانتحار

الأولى من نوعها.. "تقنية مذهلة" في هاتف سامسونغ الجديد

لماذا تشعر المرأة بالألم أكثر من الرجل؟.. دراسة تجيب

المزيد

مواضيع ذات صلة

Transport of Thyroid Hormone: Plasma Transport

Biosynthesis of Thyroid Hormone

Regulation of Thyroid Function

Regulation of Thyroid Hormone Secretion : The Hypothalamic-Pituitary Thyroid Axis

Transport and Metabolism of Thyroid Hormones

−Secretion of T4 and T3 and Recycling of I

Thyroglobulin Storage, Endocytosis, and Breakdown

Thyroid Peroxidase and DUOX: Tyrosine Iodination and Coupling

Thyroglobulin

The Thyroid Epithelial Cell

Introduction to Thyroid Hormones

 Regulation of Calcemia and Calcium- Phosphorus Homeostasis