Download Thyroid metabolic hormones: Biosynthesis and secretion

Biochemical aspects of thyroid
hormone metabolism
Reading material ; Clinical Chemistry. Principles techniques and correlations.
Chapter 23
Mahmoud A. Alfaqih BDS PhD
Jordan University of Science and
Technology
Overview
•
The thyroid gland, located
immediately below the larynx on
each side of and anterior to the
trachea
•
Thyroid gland is one of the largest of
the endocrine glands, normally
weighing 15 to 20 grams in adults
•
The thyroid secretes two major
hormones, thyroxine and
triiodothyronine, commonly called
T4 and T3, respectively
•
Calcitonin is secreted by parafollicular cells (Involved in calcium
metabolism
Overview
• About 93% of the metabolically active hormones
secreted by the thyroid gland is thyroxine (T4).
• 7% is triiodothyronine.
• Almost all the thyroxine is eventually converted to
triiodothyronine in the tissues.
Differences between T4 and T3
• They differ in rapidity and intensity of action.
How?
Triiodothyronine is about four times as potent
as thyroxine.
Triiodothyronine is present in the blood in
much smaller quantities
 T3 has a shorter half life than T4
Note
• In tissues, most of the effect of T4 results from its
conversion to T3.
• This reaction is catalyzed by selenium-containing
enzyme iodothyronine deiodinases.
• Deiodination can also produce reverse
triiodothyronine (rT3) (physiologically inactive)
Congenital Hypothyroidism
• Thyroid hormone is critical to neurologic development of the fetus.
• Congenital hypothyroidism occurs in 1 of 4,000 live births.
• If the mother has normal thyroid function, the fetus is protected during
development by maternal thyroid hormone crossing the placenta.
• Postpartum, newborns require initiation of appropriate doses of thyroid
hormone or neurologic development will be impaired
• Screening tests are performed on all newborns to diagnose congenital
hypothyroidism and prevent complications
Cretinism
Physiologic anatomy of the thyroid
gland
• The thyroid gland is composed of
closed follicles filled with colloid.
• Follicles are lined with cuboidal
epithelial cells that secrete colloid
• Colloid is mainly made from
thyroglobulin (large glycoprotein)
• Thyroid hormones are found
within thyroglobulin.
Major Actions of thyroid hormones
• Thyroid hormones are essential for normal
growth and development and have many
effects on metabolic processes
• They stimulate the synthesis of a number of
hormones and enzymes.
• One of the key enzymes stimulated is
cytochrome oxidase
• Their overall effect on metabolism is to
stimulate the basal metabolic rate, oxygen
consumption and heat production.
• Thyroid hormones increase net catabolism.
• Weight loss, muscle wasting and heat
intolerance are features of excessive secretion
of thyroid hormones.
• Thyroid hormones increase the sensitivity of
the cardiovascular and nervous systems to
catecholamines.
• This leads to an increases in heart rate, cardiac
output, and to increased arousal.
Synthesis of thyroid hormones
• Thyroid hormone synthesis involves a number
of specific enzyme-catalysed reactions.
• Synthesis begins with the uptake of iodide by
the gland and ends in the iodination of
tyrosine residues in the protein thyroglobulin.
• All of these reactions are stimulated by TSH
Synthesis: Detailed reactions
1. Iodide trapping
• The first stage in the formation of thyroid hormones, is transport
of iodides from the blood into the thyroid gland.
• The basal membrane of the thyroid cell has the specific ability to
pump the iodide actively to the interior of the cell.
• The iodide pump concentrates the iodide to about 30 times its
concentration in the blood.
• The rate of iodide trapping by the thyroid is influenced by the
concentration of TSH.
Radioactive iodine uptake (RAIU) can help
diagnose thyroid disease
Thiocyanate Ions
Decrease Iodide
Trapping
A note about thyroglobulin
• Each molecule of thyroglobulin contains about 70 tyrosine
amino acid residues.
• These tyrosine residues are the substrates that bind with
iodine to form the thyroid hormones.
• Thyroid hormones form within the thyroglobulin molecule.
• Thyroid hormones remain part of thyroglobulin during
synthesis and later on during storage of the colloid.
Synthesis: Detailed reactions
2. Oxidation of iodide ion.
• This is conversion of the iodide ions to an oxidized form of
iodine
• Iodide ion is converted to I2 that is capable of combining
directly with tyrosine.
• Oxidation of iodine is catalyzed by peroxidase and its
accompanying hydrogen peroxide, which provide a potent
system capable of oxidizing iodides.
• When the peroxidase system is blocked rate of synthesis falls
down to zero.
Synthesis; Detailed reactions
3. Organification and coupling
• The binding of iodine with the thyroglobulin molecule is called
organification of the thyroglobulin.
• This process is catalyzed by the enzyme iodinase
• Tyrosine is first iodized to monoiodotyrosine (MIT) and then to
diiodotyrosine (DIT)
• Iodotyrosine residues become coupled with one another and the
coupling reactions result in the formation of thyroid hormones T4 and T3
• Under normal condition 70% of tyrosine residues of thyreoglobulin are in
the form MIT and DIT and 30% as thyroxine (with minor part of T3)
Organification and coupling
Organification and coupling
Propylthiouracil inhibit
peroxidase enzyme as well as
coupling of iodinated tyrosine
residues
Storage of thyroglobulin
• Thyroid gland can store large amounts of hormone (unlike
other endocrine glands).
• Each thyroglobulin molecule contains up to 30 thyroxine
molecules and a few triiodothyronine molecules.
• The thyroid hormones stored in the follicles are sufficient to
supply the body with thyroid hormones for 2 to 3 months.
• When synthesis of thyroid hormone ceases, the physiologic
effects of deficiency are not observed for several months.
Release and Secretion of thyroid
hormones
• Thyroglobulin itself is not released into the
circulating blood.
• Thyroxine and Triiodothyronine are cleaved
from the thyroglobulin and then released.
Release and secretion of thyroid
hormones
1. Thyroid cells sends out pseudopod extensions that close
around portions of the colloid to form pinocytic vesicles.
2. Lysosomes in the cell cytoplasm immediately fuse with these
vesicles.
3. Multiple proteases digest the thyroglobulin molecules and
release thyroxine and triiodothyronine in free form.
4. T4 and T3 then diffuse through the base of the thyroid cell
into the surrounding capillaries.
Figure 22.14 Cellular mechanisms for T3 and T4 release into bloodstream.
Redrawn from Berne, R. M., and Levy, M. L.(Eds.). Physiology, 2d ed. New York: Mosby, 1990, 938.
Textbook of Biochemistry with Clinical Correlations, 7e edited by Thomas M. Devlin © 2011 John Wiley & Sons, Inc.
Recycling of iodine
 During the digestion of the thyroglobulin molecule to release
thyroxine and triiodothyronine, MIT and DIT released from
thyroglobulin
 MIT and DIT are not secreted into the blood in large amounts.
 Instead, their iodine is cleaved by deiodinase enzyme that
makes iodine available for making thyroid hormones.
Regulation of thyroid hormone secretion:
1. TSH
• TSH (thyrotropin) an anterior pituitary hormone is chemically a
glycoprotein.
• This hormone, increases the secretion of thyroxine and triiodothyronine
by the thyroid gland.
• Specific effects on thyroid gland:
1. Increased proteolysis of the stored thyroglobulin.
2. Increased activity of the iodide pump.
3. Increased iodination of tyrosine to form the
thyroid hormones.
4. Increased size and increased secretory activity of
the thyroid cells (hypertrophy).
5. Increased number of thyroid cell (hyperplasia).
Note
• The most important early effect after
administration of TSH is to initiate proteolysis
of thyroglobulin.
• Thyroxine and triiodothyronine will get
released into the blood within 30 minutes.
• Most of the effects of TSH are mediated by
cAMP second messenger system.
Regulation of thyroid hormone secretion
2. Thyrotropin-Releasing Hormone (TRH)
• Anterior pituitary secretion of TSH is controlled by a
hypothalamic hormone, thyrotropin-releasing hormone (TRH).
• TRH is secreted by nerve endings in the median eminence of
hypothalamus.
• TRH is transported to the anterior pituitary by hypothalamic
hypophysial portal blood.
• TRH causes an increase in the output of TSH by anterior
pituitary.
Regulation of thyroid hormone secretion
3. Cold and Anxiety
• Cold is a stimuli for increasing the rate of TRH
secretion by the hypothalamus and therefore
TSH secretion by the anterior pituitary gland.
• Excitement and anxiety cause an acute
decrease in the rate of secretion of TSH.
Feedback Effect of Thyroid Hormone
to Decrease Anterior Pituitary
Secretion of TSH
Transport of thyroid hormones
• When released into the circulation, only 0.04% of T4 and 0.4% of T3 are
unbound by proteins (physiologically active)
• The three major binding proteins, in order of significance, are thyroxinebinding globulin (TBG), thyroxine-binding prealbumin, and albumin
• The quantity of T4 and T3 in the circulation can be affected by the amount
of binding protein available for carrying these hormones
• High TBG levels result in higher levels of bound thyroid hormones, leading
to high levels of total T3 and total T4
• Measurement of free T4 and free T3 may be necessary to eliminate any
confusion caused by abnormal binding protein levels
Mechanism of action of thyroid hormones
Mechanism of action of thyroid hormones
• Free thyroid hormone receptor (TR) without bound hormone
is bound to hormone response element of DNA (HRE) and
corepressor (CoR)
• Binding T3 to its receptor liberates co-repressor and recruits
coactivator and RNA polymerase which drives mRNA
transcription
Thyroid autoantibodies