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FIGURE 6-4 Biosynthetic pathway for the production of thyroglobulin. TSH initiates the process via stimulation of the cAMP pathway. The mature mRNA is translated into the 2748-amino acid subunit of 330 kDa. The mature Tg is a dimer of two subunits. Before Tg is secreted, extensive glycosylation occurs. [Modified with permission from Medeiros-Neto, G., Targovnik, H. M., and Vassart, G. (1993). Defective thyroglobulin synthesis and secretion causing goiter and hypothyroidism. Endocr. Rev. 14, 165-183.]

identified in Tg at amino acid residues 5, 2553, 2567, and 2746. By definition, a hormonogenic site contains a tyrosine that ultimately becomes iodinated and is converted to a thyroid hormone (see later discussion).

B. Iodide Transport

A summary of iodine physiology and metabolism in adults is given in Figure 6-6. The transfer of iodide from the blood across the basal lateral membrane

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0 1200 2768

FIGURE 6-5 Schematic diagram of the primary amino acid organization of thyroglobulin (Tg). The mature human Tg is composed of 2748 amino acid residues. Domain A is composed of 10 type 1 repeats of 28 highly conserved residues, including 6 cysteines from aa 29 to 1196. Domain B lies between amino acids 1436 and 1483 and contains 3 type 2 repeats of 12-17 residues. Domain C extends from aa 1583 to 2100 and consists of a type 3 motif that is repeated 5 times. Domain D comprises aa 2109-2748 and has no internal homology. The hormonogenic sites at aa positions 5, 2553, 2567, and 2746 are indicated by the bold lines. [Modified with permission from Bacolla, A., Brocas, H., Christophe, D., de Martynoff, G., Leriche, A., Mercken, L., Parmaj, J., Pohl, V., Targovnik, H., and van Heuverswyn, V. (1985). Structure, expression and regulation of the thyroglobulin gene. Mol. Cell. Endocrinol. 40, 89-97.]

]436-i_j|483 Domain C Domain D

Domain B

FIGURE 6-5 Schematic diagram of the primary amino acid organization of thyroglobulin (Tg). The mature human Tg is composed of 2748 amino acid residues. Domain A is composed of 10 type 1 repeats of 28 highly conserved residues, including 6 cysteines from aa 29 to 1196. Domain B lies between amino acids 1436 and 1483 and contains 3 type 2 repeats of 12-17 residues. Domain C extends from aa 1583 to 2100 and consists of a type 3 motif that is repeated 5 times. Domain D comprises aa 2109-2748 and has no internal homology. The hormonogenic sites at aa positions 5, 2553, 2567, and 2746 are indicated by the bold lines. [Modified with permission from Bacolla, A., Brocas, H., Christophe, D., de Martynoff, G., Leriche, A., Mercken, L., Parmaj, J., Pohl, V., Targovnik, H., and van Heuverswyn, V. (1985). Structure, expression and regulation of the thyroglobulin gene. Mol. Cell. Endocrinol. 40, 89-97.]

of the thyroid follicular cell occurs by an active transport process. Under normal conditions, the relative amounts of the halide in the thyroid as compared with the serum or plasma (T : S or T:P ratio) are in the range of 20-30:1, but can be as high as 300:1 under circumstances of dietary iodine deprivation. The iodine is accumulated by the cell against both an electrical and a chemical gradient. The iodide transport is inhibited

FIGURE 6-6 Iodine physiology and metabolism. The values indicated are typical for a healthy adult with a dietary intake of 400 /u.g of iodine (I) per day. ECF: extracellular fluid. Since the ECF volume is 25 liters, the ECF iodide concentration is 0.6 yu.g/100 ml. Approximately 115 ¡xg of I is accumulated per day across the thyroid membrane by an active transport process; of this amount, 75 ¿tg is converted to hormone-bound iodine, with the remaining 40 ¿tg/day leaking back to the ECF pool.

(urine)

FIGURE 6-6 Iodine physiology and metabolism. The values indicated are typical for a healthy adult with a dietary intake of 400 /u.g of iodine (I) per day. ECF: extracellular fluid. Since the ECF volume is 25 liters, the ECF iodide concentration is 0.6 yu.g/100 ml. Approximately 115 ¡xg of I is accumulated per day across the thyroid membrane by an active transport process; of this amount, 75 ¿tg is converted to hormone-bound iodine, with the remaining 40 ¿tg/day leaking back to the ECF pool.

by ouabain, suggesting the involvement of a Na+,K+ ATPase. The Km for iodide transport into the follicular cell is ~3 X 10"5 M; the maximum concentration of iodide attainable by the rat thyroid is 1 mM.

The rate of iodide transport is proportional to the extracellular Na+ concentration, which suggests the existence of a Na+1~ cotransport system. In this model, the putative iodide carrier must bind Na+ ions on the external surface of the cells (which then move up a concentration gradient as they enter the cell) in order to transport I~ ions into the cell against the electrochemical gradient.

Certain monovalent anions such as C104", SCN", and pertechnetate (Tc04~~) are able to effectively compete with I" for access to the transport process on the follicular cell. It has been proposed that the charged group of the iodide carrier may be either the guanidi-nium group of nitrogen or the quaternary nitrogen of phosphatidylcholine.

A similar transport system for iodide exists in the mammary gland, salivary glands, parietal cells of the gastric mucosa, choroid plexus, and ciliary body. These tissues, however, do not organify or store the iodide.

Thyrotropin or TSH is the most important physiological factor affecting iodide uptake by the thyroid. After TSH occupies its membrane receptors on the thyroid follicular cell, there is a stimulation of cAMP and an elevation in [Ca2+]r Further molecular details are not yet available on how these changes are coupled to the iodide uptake process. Once the iodide has entered the follicle cell, it is believed that a significant proportion moves across the cell and is stored in the lumen with the colloid. As yet, no specific iodide-binding protein has been identified in the colloid compartment.

The iodide transport system of the follicle is controlled in an autoregulatory fashion by the gland. Under conditions of a chronic dietary excess of iodine, the activity of the iodide transport system is down-regulated. A small number of patients with familial goiter have been studied in which the disease is attributable to a defective thyroid gland iodide transport system.

C. Iodide Organification and Thyroid Peroxidase

1. Introduction

The process of incorporation of 3-4 iodide atoms on the aromatic rings of a tyrosine followed by conversion to a thyroid hormone form is complex; it involves three general steps:

(a) Oxidation of iodide to iodine

(b) Addition of iodine to a limited number of specific tyrosine acceptor residues present in thyroglobulin, particularly at the four hormonogenic sites (see Figure 6-5)

(c) Coupling of two iodotyrosyl residues to generate equimolar amounts of thyroid hormone and dehydroalanine residues within the thyroglobulin molecule

The release of the thyroid hormone coupled to the thyroglobulin occurs in a separate process involving reabsorption of the Tg from the colloid compartment of the follicle followed by selective proteolysis; this process will be discussed separately. Figure 6-7 presents a general overview of the steps of thyroid hormone biosynthesis and secretion.

2. Thyroid Peroxidase

After the entry of iodide into the follicular cell, it must first be oxidized to a higher oxidation state before organification. The redox potential for the couple is

This is relatively high in relation to the E° values for most biological oxidants. Only 02 and H202 are sufficiently good electron acceptors at pH 7 to be able to receive the electrons derived from the oxidation of iodide to iodine.

Much evidence has accumulated indicating that the enzyme thyroid peroxidase (TPO) is responsible for both the oxidation of iodide to iodine and the iodin-ation of tyrosine residues on thyroglobulin (Tg). In rat thyroid cells, TPO is widely distributed in the membranes of the rough endoplasmic reticulum, in the Golgi apparatus, and along the apical plasma membrane facing the plasma surface. In contrast, TPO is not present in the membranes of the pseudopods extending into the follicular lumen.

Human TPO is a heme-containing enzyme comprising 933 amino acid residues (~101 kDa). The deduced amino acid sequence contains both a putative signal peptide at the NH2-terminus and 25 hydrophobic amino acids at the COOH-terminus, which probably create a transmembrane domain that anchors the TPO to the plasma membrane of the thyroid follicular cells.

3. Catalytic Properties of TPO

TPO has the capability to catalyze two separate reactions utilizing iodide as a substrate:

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