The document summarizes thyroid hormone synthesis. It discusses how iodine is transported into thyroid cells and used to iodinate tyrosine residues on thyroglobulin in the follicular lumen, catalyzed by thyroperoxidase. The iodinated tyrosines are then coupled to form the thyroid hormones T3 and T4. Factors that control hormone synthesis like iodine availability and TSH are described. Disorders of thyroid hormone synthesis including iodine deficiency, Graves' disease, and Hashimoto's thyroiditis are also summarized.

1. KENYATTA UNIVERSITY
SCHOOL OF MEDICINE.
DEPARTMENT OF MEDICAL BIOCHEMESTRY
NAME: LANDO ELVIS OTIENO
REG NO: P29S/16344/2015.
COURSE: MBCHB
UNIT:SPECIAL AMINO ACIDS SYNTHESIS
CODE:HMB 202
LECTURER: Prof Njagi
HANDING DATE: 10 /11/2016
SUBJECT: Take away on special amino acids (thyroid hormones
synthesis)CAT 1 .
Elvis
©

2. Thyroid Hormone Synthesis
OVERVIEW:
The main function of the thyroid gland is to make hormones, T4 and T3, which are essential for the
regulation of metabolic processes throughout the body. As at any factory, effective production depends on
three key components – adequate raw material, efficient machinery, and appropriate controls. Iodine is
the critical raw material, because 65% of T4 weight is iodine. Ingested iodine is absorbed and carried in
the circulation as iodide. The thyroid actively concentrates the iodide across the basolateral plasma
membrane of thyrocytes by the sodium/iodide symporter protein, NIS(The human NIS gene located on
chromosome 19 (35) codes for a protein of 643 amino acids that is 84% homologous with rat NIS (36)).
Iodide transport is energy-dependent and requires O2. Ouabain, digitoxin, and other cardiac glycosides
block transport in vitro . Iodide uptake by thyroid cells is dependent on membrane ATPase. Intracellular
iodide is then transported in the lumen of thyroid follicles. Meanwhile, the thyrocyte endoplasmic
reticulum synthesizes two key proteins, TPO and Tg. Tg is a 660kDa glycoprotein secreted into the lumen
of follicles, whose tyrosyls serve as substrate for iodination and hormone formation. TPO sits at the apical
plasma membrane, where it reduces H2O2,elevating the oxidation state of iodide to an iodinating species,
and attaches the iodine to tyrosyls in Tg. H2O2 is generated at the apex of the thyrocyte by Duox, a
NADPH oxydase.
Thyroid hormone synthesis is dependent on the cell polarity that conditions the targeting of specific
membrane protein, either on the externalside of the follicle (facing the blood capillaries) or on the
internal side (at the cell-lumen boundary) and on the tightness of the follicle lumen that allows the
gathering of substrates and the storage of products of the reactions.
The thyroid contains two hormones, L-thyroxine (tetraiodothyronine, T4) and L-triiodothyronine (T3).
Iodine is an indispensable component of the thyroid hormones, comprising 65% of T4‘s weight, and 58%
of T3‘s. The thyroid hormones are the only iodine-containing compounds with established physiologic
significance in vertebrates.
Structural formula of thyroid hormones and precursor compounds

3. THYROGLOBULIN IODINATION ANDHORMONE SYNTHESIS
The first step in the synthesis of thyroid hormones is the organification of iodine. Ingested iodine is
absorbed through the small intestine and transported in the plasma to the thyroid, where it is taken up,
converted to iodine, and then condensed onto tyrosine residues which reside along the polypeptide
backbone of a protein molecule called thyroglobulin(Tg). This reaction results in either a mono-iodinated
tyrosine (MIT) or di-iodinated tyrosine (DIT) being incorporated into thyroglobulin. This newly formed
iodothyroglobulin forms one of the most important constituents of the colloid material, present in the
follicle of the thyroid unit.
The process requires the presence of iodide, a peroxidase (TPO),a supply of H2O2,and an iodine acceptor
protein (Tg).
Thyroperoxidase oxidizes iodide in the presence of H2O2. In crude thyroid homogenates, enzyme activity
is associated to cell membranes. It can be solubilized using detergents such as deoxycholate or digitonin.
The enzyme activity is dependent on the association with a heme, the ferriprotoporphyrin IX or a closely
related porphyrin . Chemical removal of the prosthetic group inactivates the enzyme, and recombination
with the heme protein restores activity . The apoprotein from human thyroid is not always fully saturated
with its prosthetic group. Some congenitally goitrous children have poor peroxidase function because the
apoprotein has weak binding for the heme group.
The other synthetic reaction, that is closely linked to organification, is a coupling reaction, where
iodotyrosine molecules are coupled together. If two di-iodotyrosine molecules couple together, the result
is the formation of thyroxin (T4). If a di-iodotyrosine and a mono-iodotyrosine are coupled together, the
result is the formation of tri-iodothyronine (T3).
From the perspective of the formation of thyroid hormone, the major coupling reaction is the di-
iodotyrosine coupling to produce T4. Although T3 is more biologically active than T4, the major

4. production of T3 actually occurs outside of the thyroid gland. The majority of T3 is produced by
peripheral conversion from T4 in a deiodination reaction involving a specific enzyme which removes one
iodine from the outer ring of T4.
The T3 and T4 released from the thyroid by proteolysis reach the bloodstream where they are bound to
thyroid hormone binding proteins. The major thyroid hormone binding protein is thyroxin binding
globulin (TBG) which accounts for about 75% of the bound hormone.

5. In order to attain normal levels of thyroid hormone synthesis, an adequate supply of iodine is essential.
The recommended minimum intake of iodine is 150 micrograms a day. Intake of less than 50 micrograms
a day is associated with goiter. High iodine levels inhibit iodide oxidation and organification.
Additionally, iodine excess inhibits thyroglobulin proteolysis (this is the principal mechanism for the
antithyroid effect of inorganic iodine in patients with thyrotoxicosis). Oxidation of iodotyrosines may
produce iodotyrosyl radicals. The free radicals could combine to generate the iodothyronine residue (at
the tyrosine acceptor site) and a dehydroalanine residue (at the tyrosine donor site), which in the presence
of H2O converts into a serine
The distribution of hormone among severalsites in the Tg molecule has been studied in a number of
species .The most important is at tyrosyl 5, quite close to Tg N-terminus. It usually contains about 40% of
Tg total T4. The second most important site is at tyrosyl 2554, which may contain for 20-25% of total T4.
A third important site is at tyrosyl 2747, which appears favored for T3 synthesis in some species. Tyrosyl
1291 is prominent in T4 formation in guinea pigs and rabbits and very responsive to TSH stimulation.
Incremental iodination of low iodine hTg in vitro,with lactoperoxidase as surrogate for TPO,led to the
identification of the favored sites for iodination. Small increments of iodine go first to tyrosyl residues
2554, 130, 685, 847, 1448, and 5, in that order. Further addition increases the degree of iodination at these
sites, iodinates some new tyrosyls, and results in thyroid hormone formation at residues 5, 2554, 2747,
and 685, with a trace found at 1291, in that quantitative order.Three consensus sequences associated with
iodination and hormone formation has been recognized : i) Asp/Glu-Tyr at three of the four most
important sites for hormone synthesis, ii) Ser/Thr-Tyr-Ser associated with hormone formation, including
the C-terminal hormonogenic site that favors T3 in some species and iii)Glu-X-Tyr favoring early
iodination, although usually not with hormone formation
CONTROL OF HORMONE SYNTHESIS
The most important controlling factors are iodine availability and TSH. Inadequate amounts of iodine
lead to inadequate thyroid hormone production, increased TSH secretion and thyroid stimulation, and
goiter in an attempt to compensate. Excess iodide acutely inhibits thyroid hormone synthesis, the Wolff-
Chaikoff effect (243), apparently by inhibiting H2O2 generation, and therefore,blocking Tg iodination
(127). A proposed mechanism is that the excess iodide leads to the formation of 2-iodohexadecanal (255),
which is endowed with an inhibitory action on H2O2 generation.
TSH influences virtually every step in thyroid hormone synthesis and release. In humans the effects on
secretion appear to be mediated through the cAMP cascade (see chapter 1) while the effects on synthesis
are mediated by the Gq/phospholipase C cascade (338). Elsewhere in this chapter, we have mentioned
instances of TSH regulation. To summarize, TSH stimulates the expression of NIS, TPO,Tg and the
generation of H2O2 , increases formation of T3 relative to T4, alters the priority of iodination and
hormonogenesis among tyrosyls and promotes the rapid internalization of Tg by thyrocytes. These several
steps are interrelated and have the net effects of increasing the amount of iodine available to the cells and
of making and releasing a larger amount and a more effective type of thyroid hormone (T3).
Anti-thyroid drugs are external compounds influencing thyroid hormone synthesis. The major inhibitory
drugs are the thionamides: propylthiouracil and methimazole. In the thyroid, they appear to act by
competing with tyrosyl residues of Tg for oxidized iodine, at least in the rat (219). Iodotyrosyl coupling is
also inhibited by these drugs and appears more sensitive to their effects than does tyrosyl iodination.

6. Thyroid Hormones Synthesis Disorders
Iodine Deficiency
Iodine is a trace mineral that is high in seafood, and is found in variable amounts in fruits and vegetables,
depending on the iodine content of the local soil. In many parts of the world, the soils are naturally
deficient in iodine, and iodine deficiency disorders due to hypothyroidism will occur without iodine
supplementation. Thyroid hormone has a crucial role in the development of the nervous system, being
involved in the growth of synapses and the formation of myelin. Endemic cretinism is a disorder of
cognitive development with reduced physical growth that occurs if thyroid hormone is deficient during
gestation and early post-natal life. “Endemic” means prevalent in a particular region. This disorder is
entirely preventable by making sure that pregnant women have sufficient iodine in their diet to
be euthyroid (having adequate thyroid hormone levels). The World Health Organization is actively
working to reduce iodine deficiency by supplying iodized salt to communities, and developing effective
monitoring programs.
Goiter is the term that means enlargement of the thyroid gland. Iodine deficient goiter results because
iodine is a crucial component of active thyroid hormones. If there is a low level of iodine in the diet, then
less active T3 (triiodothyronine) and T4 (thyroxine) can be synthesized. As diagrammed in the figure,
when there is less T3 and T4, there is reduced negative feedback inhibition of secretion of the tropic
hormones, TRH (thyrotropin releasing hormone; released by the hypothalamus) and TSH (thyroid
stimulating hormone or thyrotropin; released by the anterior pituitary). TSH stimulates all aspects of
thyroid hormone synthesis; it also stimulates proliferation of follicle cells. When iodine in the diet is low
but not too low, individuals may have goiter and yet be euthyroid, because the enlarged thyroid gland is
better able to use the limited amount of iodine available. This is an example of how negative feedback
regulation works to keep hormone secretion within the appropriate physiological range.
Graves Disease
Graves disease is the most common cause of hyperthyroidism. Graves disease is an autoimmune disorder
in which antibodies are produced that bind to the TSH receptor. Instead of causing destruction of follicle
cells, these antibodies act as agonists, stimulating the receptor to cause synthesis of T3 and T4, and
proliferation of follicle cells. Negative feedback inhibition is increased,so the levels of TRH and TSH
decrease,but this does not decrease thyroid hormone production because the stimulation of the thyroid
gland is independent of TSH. Measurement of low TSH levels is a key diagnostic test for
hyperthyroidism. (This is because hyperthyroidism caused by pituitary hypersecretion of TSH is very
rare.)
The symptoms of hyperthyroidism in Graves disease are related to the effects of thyroid hormone on
metabolism and cardiac function. Because thyroid hormone increases basalenergy expenditure, there is
increased heat production and individuals will become heat intolerant. Individuals
experience tachycardia (fast heart rate) because thyroid hormone affects expression of cardiac ion
channels and contractile proteins so that the force and rate of the heart beat are both increased. Because
thyroid hormone increases the responsiveness to epinephrine and norepinephrine, excess thyroid hormone
can cause symptoms that occur due to increased sympathetic activation, such as nervousness, sweating
and increased heart rate. For this reason, beta-adrenergic antagonists may be used to relieve symptoms.
Graves disease can be treated by drugs that inhibit thyroid hormone synthesis. Other treatment approaches
involve reduction of thyroid tissue. The thyroid gland may be removed surgically (thyroidectomy).
Another approach is to administer radioactive iodine, which concentrates in the thyroid gland, where the
radiation ablates thyroid tissue.

7. Hashimoto's Thyroiditis
The most common cause of hypothyroidism in the United States is due to autoimmune destruction of the
thyroid gland that occurs in Hashimoto’s thyroiditis. In this case,antibodies to thyroid antigens, as well as
infiltration by cytotoxic T cells lead to destruction of thyroid tissue. Because the thyroid gland stores
large amounts of thyroid hormone as thyroglobulin, a patient with Hashimoto’s thyroiditis may initially
develop goiter, (which occurs due to inflammation), rather than symptoms due to hypothyroidism. As the
store of thyroid hormone decreases,negative feedback inhibition decreases and TSH levels will rise.
As Hashimoto's thyroiditis progresses, it will eventually lead to overt hypothyroidism. The symptoms of
hypothyroidism result from decreased metabolic rate,and are opposite to the symptoms of
hyperthyroidism. Patients may gain weight, feelsluggish and cold, and have a slowed heart rate.
Hypothyroidism is treated with replacement therapy with thyroxine (T4).
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