1. Transport

Table 51 lists the blood concentrations and some kinetic properties in humans of the two main iodine containing molecules released from the thyroid gland. Note that the concentration of T4 is approximately 70 times that of T3 and that only 0.02–0.2 % of either hormone is circulating free (i.e., not protein bound) in the blood. Table 1 also gives the half-lives of these com pounds which show that T3 turns over much more rap idly than T4. Since T4 is effectively biologically inactive until it is peripherally deiodinated to form T3 (see the following) its circulating pool can be thought of as a large, slowly turning over reservoir of stored hormone in addition to that which is stored in the lumen of the thy roid gland. T3, on the other hand, has a small vascular pool with a high turnover rate, as befits the active form of the hormone.

Table1. Properties of Circulating T4 and T3

In vertebrates, over 99% of T4 and T3 circulates in the blood bound to proteins. The three serum proteins responsible for systemic transport of the thyroid hormones are thyroxine-binding globulin (TBG), transthyre tin (TTR; also known as thyroxine-binding prealbumin, TBPA), and albumin. Some of the properties of these proteins, all of which are synthesized in the liver, are shown in Table 2. TBG binds about 75% of both T4 and T3. Most of the remaining hormone is carried either by transthyretin or albumin (T3). Since it is generally held that it is the free fraction of hormone that is available to enter cells and initiate biological responses, the role of the serum binding proteins in maintaining the equilibrium between the bound and free fractions is an important physiological one.

Table2. Properties of Thyroid Hormone Serum Binding Proteins

TBG is a single subunit glycoprotein. It contains four heterosaccharide moities which account for approximately 20% of the total molecular mass of the protein. Each molecule of TBG has a single iodothyronine binding site with a higher affinity for T4 than for T3. TBG levels in the blood are increased approximately 2.5-fold during pregnancy due to increased estrogen levels. As TBG increases, T4 secretion is increased to maintain free T4 levels, increasing the pool of T4 in the blood.

Transthyretin (TTR) is composed of four identical polypeptide subunits, each containing 127 amino acids. Although x-ray structural studies indicate two apparently identical binding sites, only one is usually occupied because the affinity of the second is dramatically decreased by negative cooperativity following binding of the first molecule of T4. TTR contains a separate specific binding site for retinol-binding protein which binds vitamin A (retinol). The two functions of TTR are independent of one another. Although TTR circulates in much higher concentrations in the blood than TBG, it plays a smaller role in the physiology of the thyroid hormones. Much of it is unoccupied by T4 and even large changes in its concentration have little effect on T4 production or secretion. One clinical aspect of the protein, unrelated to the thyroid, is its role in systemic amyloid disorders, particularly in the heart, due to genetic variants of TTR which self-associate and contribute to amyloid fibrils.

Human serum albumin (HSA) comprises more than half of the total serum protein and binds a wide variety of small molecules, mostly with low affinity. The affinity of HSA for T4 is four orders of magnitude lower than that of TBG, yet the total amount of T3 and T4 bound by this protein is a significant, if small, portion of the bound hormone.

2. Metabolism

The blood concentration of the thyroid hormones is dependent not only upon the amount of hormone secreted by the thyroid gland but also the hormone’s affinity for its carrier proteins, affinity for target tissues, rate of catabolism, and, finally, its rate of clearance. The major pathways of thyroid hormone deiodination to other thyronines are outlined in Figure 1.

Fig1. Peripheral transformations of T4. At the top are shown the result of oxidative deamination (left) and cleavage of the ether bond between the two tyrosyl rings (top right). The remainder of the figure summarizes the deiodination steps that are catalyzed by one of three deiodonases, D1, D2, or D3. The actions and properties of these important enzymes are more fully described in the text and in Table 5-3. OR, outer ring; IR, inner ring.

The figure also shows (top left) the oxidative deamination of T4 and T3, yielding tetraiodoacetic acid (TETRAC) or triiodoacetic acid (TRIAC), respectively, as well as the production of DIT through the cleavage of the ether bond between the two rings (top right). Not shown in Figure 1 but also important in the overall thyroid hormone economy of the organism is the conjugation of the hormone with either sulfate or glucuronide.

Finally it has been recognized that monoiodinated derivatives of T4, which arise by its deiodination and decarboxylation, exist in human serum and have specific biologic activities. These compounds are referred to as iodothyronamines, the most potent of which is 3-iodothyronamine, seen in Figure 2. This com pound and thyronamine have a high affinity for the trace amine receptor (TAR1) and have suppressive effects on heart rate, body temperature, and physical activity. This is currently a very active area of research.

Fig2. 3-iodothyronamine.

The deiodinases that convert T4 to either T3 or rT3, a biologically inactive metabolite, are an integral part of thyroid hormone physiology and deserve a closer look. They are selenocysteine enzymes whose characteristics are summarized in Table 3. Deiodinase Type I, or D1 is found in the thyroid, pituitary, liver, and kidney. Depending on the substrate, D1 removes the iodine atom from either the outer or inner ring, to activate or inactivate the molecule, respectively. In the liver D1 provides the majority of circulating T3 and is also responsible for the deiodination of sulfated T4 and rT3. The expression of D1 in the liver is regulated by thyroid status such that T4 degradation is decreased when the hormone is deficient and increased when it is present in excess. D1 expression in the pituitary is also increased when hormone levels are high, resulting in increased T3 being made available to suppress TSH secretion (see section V.A).

Table3. Properties of Iodothyronine Deiodinases

D2 has only 5′ deiodinase activity; its main physiological function is thought to be the production of intracellular T3 in the pituitary, certain localized areas of the brain, and in brown adipose tissue. D2 activity is inversely related to thyroid hormone status, allowing some protection against the production of excessive or inadequate intracellular T3 in the face of hyper- or hypothyroidism.

D3 has only inner ring deiodinase activity and therefore is only involved in the degradation of iodothyronines. In adult mammals D3 occurs primarily in the brain. It is more abundant in fetal tissues, where it may be important in protecting some tissues against high T3 level concentrations that occur during certain differentiation processes.

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تزامنًا مع أيام الشهر المعظم.. المجمع العلمي يقيم أنشطة قرآنية في بابل والمثنى

الهيأة العليا لإحياء التراث تنهي استعداداتها لإقامة المؤتمر التمهيدي الأول لإحياء ألفية حوزة النجف الأشرف

قسم صناعة الشبابيك يواصل أعمال إدامة الشباك السابق لمرقد الإمامين العسكريين (عليهما السلام)

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خبراء تغذية يكشفون "أفضل وقت لتناول الإفطار"

أطعمة تزيد فرص وفاة مرضى السرطان 60 بالمئة.. ما هي؟

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خبير يكشف عن اقتراب العلماء من فك شفرات "لغات الحيوانات" !

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علماء حاصلون على "نوبل": الذكاء الاصطناعي لن يستبدل الإنسان

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مواضيع ذات صلة

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

−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

Biological Actions of Parathormone (PTH)

Synthesis, Secretion, Metabolism, and Mechanism of Action of Parathormone (PTH)

Regulation of Thyroid Hormone Secretion and TSH

Biosynthesis and Secretion of Thyroid Hormones