Investigation of thyroid
hormones in the regulation of metabolism. Hormonal regulation of calsium
and phosphorus homeostasis.
Tissue hormones. Investigation of molecular – cellular mechanisms of adrenal and sex glands hormones.
Hormones of thyroid and parathyroid, structure, mechanism of action.
Thyroid synthesizes two kinds of hormones: iodine
containing hormones and calcitonin.Iodine containing
hormones - thyroxine and triiodthyronine.
Thyroxine and triiodthyronine are
iodinated derivatives of amino acid tyrosine.
Functions: these hormones are necessary for growth of
organism, mental, physical and sex development, they
regulate the rate of basal metabolism.
Effect of thyroxine and triiodthyronine on the protein metabolism:
1.
in normal
concentration stimulate the synthesis of proteins and nucleic acids;
2. in excessive concentration activate the catabolic
processes.
Effect of thyroxine and triiodthyronine on the carbohydrate metabolism:
1.
promote the
absorption of carbohydrates in the intestine;
2.
activates the
decomposition of glycogen.
Effect of thyroxine and triiodthyronine on the lipid metabolism:
-
activate the lipid
oxidation and mobilization.
Effect of thyroxine and triiodthyronine on the energy metabolism:
1.
activates dehydrogenases of mitochondria;
2.
in excessive amount of these
hormones the disconnection of tissue respirstion and
oxidative phosphorylation takes place. As result the
formation of ATP is decreased and the temperature of the organism is increased.
Excessive secretion of thyroid hormones, called hyperthyroidism, is responsible for Graves' disease, or exophthalmic goiter,
exophthalmic goiter
while deficiency in thyroid
hormones, hypothyroidism, is
characteristic of the disease myxedema.
•
Receptors
for thyroid hormones are
members of a large family of nuclear receptors that include those of the
steroid hormones. They function as hormone-activated transcription factors
and thereby act by modulating gene expression. In contrast to steroid
hormone receptors, thyroid hormone receptors bind DNA in the absence of
hormone, usually leading to transcriptional repression. Hormone binding is
associated with a conformational change in the receptor that causes it to
function as a transcriptional activator.
•
Currently, four
different thyroid hormone receptors are recognized: alpha-1, alpha-2, beta-1
and beta-2.
•
The presence of
multiple forms of the thyroid hormone receptor, with tissue and stage-dependent
differences in their expression, suggests an extraordinary level of complexity
in the physiologic effects of thyroid hormone.
Calcitonin.
Calcitonin is synthesized by the parafollicle cells of
thyroid.
Chemical structure: peptide.
Functions: - promotes the transition of calcium from
blood in bones;
-
inhibits the reabsorption of phosphorus in kidneys.
Thus, calcitonin decreases the
Ca and P contents in blood.
Parathyroid
glands.
Parathyroid hormone. Chemical structure: protein.
Functions:
1. promotes
the transition of calcium from bones to blood;
2. promotes
the absorption of Ca in the intestine;
3. inhibits the reabsorption of phosphorus in kidneys.
Thus,
parathyroid hormone increases the Ca amount in blood and decreases the P amount in blood.
There are three major pools of calcium in
the body:
As with calcium, the majority of body phosphate
(approximately 85%) is present in the mineral phase of bone. The remainder of
body phosphate is present in a variety of inorganic and organic compounds
distributed within both intracellular and extracellular
compartments. Normal blood concentrations of phosphate are very similar to
calcium.
Maintaining
constant concentrations of calcium in blood requires frequent adjustments,
which can be described as fluxes of calcium between blood and other body
compartments. Three organs participate in supplying calcium to blood and
removing it from blood when necessary:
The
kidney is critcally important in calcium
homeostasis. Under normal blood calcium concentrations, almost all of the
calcium that enters glomerular filtrate is reabsorbed
from the tubular system back into blood, which preserves blood calcium levels.
If tubular reabsorption of calcium decreases, calcium
is lost by excretion into urine.
Maintaining normal blood calcium and phosphorus
concentrations is managed through the concerted action of three hormones that
control fluxes of calcium in and out of blood and extracellular
fluid:
Parathyroid hormone serves to increase
blood concentrations of calcium. Mechanistically, parathyroid hormone preserves
blood calcium by several major effects:
Four small masses of epithelial tissue are embedded in
the connective tissue capsule on the posterior surface of the thyroid glands.
These are parathyroid glands, and they secrete parathyroid hormone or parathormone. Parathyroid hormone is the most important
regulator of blood calcium levels. The hormone is secreted in response to low
blood calcium levels, and its effect is to increase those levels.
Hypoparathyroidism, or insufficient
secretion of parathyroid hormone, leads to increased nerve excitability. The
low blood calcium levels trigger spontaneous and continuous nerve impulses,
which then stimulate muscle contraction.
Since
parathyroid gland disease (hyperparathyroidism) was first described in 1925,
the symptoms have become known as "moans, groans, stones, and bones...with
psychic overtones". Although about 5-7% of people with parathyroid disease
(hyperparathyroidism) claim they don't have symptoms and to feel fine when the
diagnosis of hyperparathyroidism is made, almost 100% of parathyroid patients
will actually say they feel better after the parathyroid problem has been
cured--proving they had symptoms. The bottom line: Nearly ALL patients
with parathyroid problems have symptoms. Sometimes the symptoms are real
obvious, like kidney stones, frequent headaches, and depression. Sometimes the
symptoms are not so obvious, like high blood pressure and the inability to
concentrate. If you have symptoms, you are almost guaranteed to feel remarkably
better once the parathyroid tumor has been removed.
As we often tell our parathyroid patients: "you will be amazed at how a 16
minute mini-procedure will change your life!"
About 95 percent of
the active thyroid hormone is thyroxine, and most of
the remaining 5 percent is triiodothyronine. Both of these
require iodine for their synthesis. Thyroid hormone secretion is regulated by a
negative feedback mechanism that involves the amount of circulating hormone,
hypothalamus, and adenohypophysis.
If there is an iodine deficiency, the thyroid cannot
make sufficient hormone. This stimulates the anterior pituitary to secrete
thyroid-stimulating hormone, which causes the thyroid gland to increase in size
in a vain attempt to produce more hormones. But it cannot produce more hormones
because it does not have the necessary raw material, iodine. This type of
thyroid enlargement is called simple goiter or iodine
deficiency goiter.
Calcitonin is secreted by the
parafollicular cells of the thyroid gland. This
hormone opposes the action of the parathyroid glands by reducing the calcium
level in the blood. If blood calcium becomes too high, calcitonin
is secreted until calcium ion levels decrease to normal.
Calcitonin is a hormone that
functions to reduce blood calcium levels. It is secreted in response to hypercalcemia and has at least two effects:
Although calcitonin has significant
calcium-lowing effects in some species, it appears to have a minimal influence
on blood calcium levels in humans.
Vitamin D acts also to
increase blood concentrations of calcium. It is generated through the
activity of parathyroid hormone within the kidney. Far and away the most
important effect of vitamin D is to facilitate absorption of calcium from the
small intestine. In concert with parathyroid hormone, vitamin D also enhances
fluxes of calcium out of bone.
Mechanism of steroid hormones action (permeating into the cells):
In
difference to hormones of protein and peptide nature, receptors for steroid
hormones are located within the cells - in the cytoplasm. From cytoplasm the
hormone-receptor complexes is translocated into the nucleus where they interact with
DNA of nuclear chromatin causing the activation of genes for respective enzyme
proteins. So, if hormones of the first group cause the activation of existing
enzyme molecules, the acting on the target cells of steroids and thyroid
hormones results in the biosynthesis of new enzyme molecules.
•
Receptors for thyroid hormones are members of a large family of nuclear
receptors that include those of the steroid hormones. They function as
hormone-activated transcription factors and thereby act by modulating gene
expression. In contrast to steroid hormone receptors, thyroid hormone
receptors bind DNA in the absence of hormone, usually leading to
transcriptional repression. Hormone binding is associated with a conformational
change in the receptor that causes it to function as a transcriptional
activator.
•
Currently, four different thyroid
hormone receptors are recognized: alpha-1, alpha-2, beta-1 and beta-2.
•
The presence of multiple forms of the
thyroid hormone receptor, with tissue and stage-dependent differences in their
expression, suggests an extraordinary level of complexity in the physiologic
effects of thyroid hormone.
•
Thyroid hormone receptors bind to
short, repeated sequences of DNA called thyroid or T3 response elements
(TREs), a type of hormone response element. A TRE is
composed of two AGGTCA "half sites" separated by four nucleotides.
The half sites of a TRE can be arranged as direct repeats, pallindromes
or inverted repeats.
•
The DNA-binding domain of the
receptor contains two sets of four cysteine residues,
and each set chelates a zinc ion, forming loops known
as "zinc fingers". A part of the first zinc finger interacts directly
with nucleotides in the major groove of TRE DNA, while residues in the second
finger interact with nucleotides in the minor groove of the TRE. Thus, the zinc
fingers mediate specificity in binding to TREs.
•
Thyroid hormone receptors can bind to
a TRE as monomers, as homodimers or as heterodimers with the retinoid X receptor (RXR), another
member of the nuclear receptor superfamily that binds
9-cis retinoic acid. The heterodimer affords the
highest affinity binding, and is thought to represent the major functional form
of the receptor.
•
Thyroid hormone receptors bind to TRE
DNA regardless of whether they are occupied by T3. However, the
biological effects of TRE binding by the unoccupied versus the occupied
receptor are dramatically different. In general, binding of thyroid hormone
receptor alone to DNA leads to repression of transcription, whereas binding of
the thyroid hormone-receptor complex activates transcription.
Hormones of adrenal cortex.
Adrenal
glands consist of two parts: external - cortex, internal - medulla.
Each
part secrets specific hormones.
Hormones synthesized in adrenal cortex are named
corticosteroids. Corticosteroids have potent regulatory effect on
all kinds of metabolism. Cholesterol is the precursor of corticosteroids.
According to the biological effect corticosteroids are divided on two groups: glucocorticoids and mineralocorticoids. Glucocorticoids
regulate the protein, lipid and carbohydrate metabolism, mineralocorticoids
- metabolism of water and mineral salt.
The most important glucocorticoids:
corticosterone, hydrocortisone, cortisol. The most important mineralocorticoid:
aldosterone.
All biological active hormones of adrenal cortex
consist of 21 carbon atom and can be reviewed as derivatives of carbohydrate pregnane.
The synthesis of corticosteroids is
regulated by ACTH.
In the blood corticosteroids are connected with
proteins and transported to different organs.
Time half-life for corticosteroids is about 1
hour.
Ways of metabolism of
corticosteroids:
1. Reduction.
Corticosteroids accept 4 or 6 hydrogen atoms and form couple compounds with glucuronic acid. These compounds ere excreted by kidneys.
2. Oxidation
of 21-st carbon atom.
3. Reduction
of ring and decomposition of side chain. As result 17-ketosteroids are
formed that are excreted with urine. The
determination of 17-ketosteroids in urine - important diagnostic indicator.
This is the indicator of adrenal cortex function. In men 17-ketosteroids are
also the terminal products of sex hormones metabolism giving important
information about testicles function.
4. Corticosteroids can be excreted by kidneys in
native structure.
The natural steroid hormones are generally synthesized from cholesterol
in the gonads and adrenal
glands. These forms of hormones are lipids. They can enter the cell
membrane quite easily and enter right into the nuclei. Steroid hormones are
generally carried in the blood bound to specific carrier proteins such as
sex hormone binding globulin or corticosteroid binding globulin. Further
conversions and catabolism occurs in the liver, other "peripheral" tissues,
and in the target tissues.
Because steroids and sterols are lipid soluble, they
can diffuse
fairly freely from the blood through the cell
membrane and into the cytoplasm of target cells. In the cytoplasm the steroid may
or may not undergo an enzyme-mediated alteration such as reduction, hydroxylation,
or aromatization. In the cytoplasm, the steroid binds to the specific receptor,
a large metalloprotein. Upon steroid binding, many
kinds of steroid receptor dimerizes, two
receptor subunits join together to form one functional DNA-binding unit that can
enter the cell nucleus. In some of the hormone systems known,
the receptor is associated with a heat shock protein which is released on the
binding of the ligand, the hormone. Once in the nucleus, the
steroid-receptor ligand complex binds to specific DNA sequences and induces
transcription of its target genes.
It discussing steroid
hormones, one is required to talk about cholesterol; cholesterol is know as a
sterol, which is a natural product from the steroid nucleus. CHOLESTEROL Cholesterol is very important, as we learned, in the
production of steroid hormones, in fact they are the precursor for bile acids (bile
acids aid in fat digestion), steroid hormones, and provitamin
D (When irradiated by sunlight it changes to vitamin D3.
Cholesterol, if we recall, is incorporated into the
cell membrane by lipoproteins.There it plays a role
in the regulation of membrane fluidity. It has been stated that cholesterol is probably responsible for
permitting steroid hormones to enter the cell.
Synthesis of steroid hormons
Functions of glucocorticoids.
Glucocorticoids
have antiinflammatory, antiallergic,
antiimmune
effect. They support the blood pressure and constancy of the extracellular liquids.
The effect of glucocorticoids
on protein metabolism:
1. stimulate
the catabolic processes (protein decomposition) in connective, lymphoid and
muscle tissues and activate the processes of protein synthesis in liver;
2. stimulate
the activity of aminotransferases;
3. activate
the synthesis of urea.
The effect of glucocorticoids
on carbohydrate metabolism:
1. activate
the gluconeogenesis;
2. inhibit
the activity of hexokinase;
3. activate
the glycogen synthesis in liver.
Glucocorticoids
causes the hyperglycemia.
The effect of glucocorticoids
on lipid metabolism:
1. promote
the absorption of lipids in intestine;
2. activate
lipolisis;
3.
activate the conversion of
fatty acids in carbohydrates.
Functions of mineralocorticoids.
Secretion of mineralocorticoids
is regulated by renin-angiotensine system
-
activates the reabsorption of Na+, Cl-
and water in kidney canaliculuses;
-
promote the excretion of K+
by kidneys, skin and saliva.
Deficiency of corticosteroids causes Addison's disease. For this disease the hyperpigmentation is typical because the deficiency of
corticosteroids results in the excessive synthesis of ACTH.
Hyperfunction of adrenal cortex causes Icenko-Kushing
syndrome. This state is called steroid diabetes. Symptoms:
hyperglycemia, glucosuria, hypercholesterolemia, hypernatriemia, hyperchloremia, hypokaliemia.
Adrenal cortex hormones and their artificial analogs are often used
in clinic: for treatment of allergic and autoimmune diseases, in hard shock
states.
Blood and urine cortisol, together with the determination of
adrenocorticotropic hormone (ACTH), are the three most important tests in the
investigation of Cushing's syndrome (caused by an overproduction of
cortisol) and Addison's disease (caused by the underproduction of
cortisol).
Reference ranges for cortisol vary from laboratory to laboratory but are
usually within the following ranges for blood:
Reference ranges for cortisol vary from laboratory to laboratory, but are
usually within the following ranges for 24-hour urine collection:
Abnormal results
Increased levels of cortisol are found in Cushing's syndrome, excess
thyroid (hyperthyroidism), obesity, ACTH-producing tumors, and
high levels of stress.
Decreased levels of cortisol are found in Addison's disease, conditions of
low thyroid, and hypopituitarism, in which pituitary activity is
diminished.
Addison's disease
A rare disorder in which
symptoms are caused by a deficiency of hydrocortisone (cortisol)
and aldosterone, two corticosteroid hormones normally
produced by a part of the adrenal glands called the adrenal cortex. Symptoms
include weakness, tiredness, vague abdominal pain, weight loss, skin
pigmentation and low blood pressure.
.
Cushing's syndrome
A hormonal disorder caused by
an abnormally high level of corticosteroid hormones. Symptoms include high
blood sugar levels, a moon face, weight gain, and increased blood pressure
In
Since cortisol production by
the adrenal glands is normally under the control of the pituitary (like the thyroid
gland), overproduction can be caused by a tumor in
the pituitary or within the adrenal glands themselves. When a pituitary tumor secretes too much ACTH (Adrenal Cortical Tropic
Hormone), it simply causes the otherwise normal adrenal glands to produce too
much cortisol. This type of Cushings
syndrome is termed "Cushings Disease" and
it is diagnosed like other endocrine disorders by measuring the appropriateness
of hormone production. In this case, serum cortisol
will be elevated, and, serum ACTH will be elevated at the same time.
When the adrenal glands develop a tumor, like
any other endocrine gland, they usually produce excess amounts of the hormone
normally produced by these cells. If the adrenal tumor
is composed of cortisol producing cells, excess cortisol will be produced which can be measured in the
blood. Under these conditions, the normal pituitary will sense the excess cortisol and will stop making ACTH in an attempt to slow
the adrenal down. In this manner, physicians can readily distinguish whether
excess cortisol is the result of a pituitary tumor, or an adrenal tumor.
Even more rare (but placed here for completion sake) is when excess ACTH
is produced somewhere other than the pituitary. This is extremely uncommon, but
certain lung cancers can make ACTH (we don't know why) and the patients develop
Cushings Syndrome in the same way they do as if the
ACTH was coming from the pituitary.
Causes of Cushings Syndrome
ACTH Dependent (80%)
Pituitary Tumors (60%)
Lung Cancers (5%)
ACTH Independent (20%)
Benign Adrenal Tumors (adenoma) (25%)
Malignant Adrenal Tumors (adrenal cell
carcinoma) (10%) [new page on this topic]
Testing for Cushings Syndrome
The most sensitive
test to check for the possibility of this disease is to measure the amount of cortisol excreted in the during during a 24 hour time period. Cortisol
is normally secreted in different amounts during the day and night, so this
test usually will be repeated once or twice to eliminate the variability which
is normally seen. This normal variability is why simply checking the amount of cortisol in the blood is not a very reliable test. A 24
hour free cortisol level greater than 100 ug is diagnostic of Cushings
syndrome. The second test which helps confirms this diagnosis is the
suppression test which measures the cortisol
secretion following the administration of a powerful synthetic steroid which
will shut down steroid production in everybody with a normal adrenal gland.
Subsequent tests will distinguish whether the disease is due to an ACTH
dependent or independent cause.
Invariably, once the diagnosis is made, patients will undergo a CT scan
(or possibly an MRI or Ultrasound) of the adrenal glands to look for tumors in one or both of them (more information on
adrenal x-ray tests on another page). If the laboratory test
suggest a pituitary origin, a CT or MRI of the brain (and possibly of the chest
as well) will be performed.
Treatment of Cushings Syndrome
Obviously, the
treatment of this disease depends upon the cause. Pituitary tumors
are usually removed surgically and often treated with radiation therapy.
Neurosurgeons and some ENT surgeons specialize in these tumors.
If the cause is determined to be within a single adrenal gland, this is treated
by surgical removal. If the tumor has characteristics
of cancer on any of the x-ray tests, then a larger, conventional operation is
in order. If a single adrenal gland possesses a small, well defined tumor, it can usually be removed by the new technique of
laparoscopic adrenalectomy.
Glucocorticoids originate in the adrenal
cortex and affect mainly metabolism in diverse ways; decrease inflammation and
increase resistance to stress.
Mineralocorticoids originate in adrenal cortex
and maintain salt and water balance.
Estrogens originate in the adrenal cortex and gonads and primarily
affect maturation and function of secondary sex organs (female sexual
determination).
Androgens originate in the adrenal cortex and gonads and primarily
affect maturation and function of secondary sex organs (male sexual determination).
Progestins originate from both ovaries
and placenta, and mediate menstrual cycle and maintain pregnancy.
Androgens
and estrogens play a major role in the development of both sexes secondary
characteristics. Androgens, or testosterone and androsterone
give the male its sex characteristics during puberty and for promoting tissue
and muscle growth. Estrogens, or estrone and estradiol are forms of testosterone synthesized in the
ovaries, which control female secondary characteristics and regulation of the
menstrual cycle. Another sex hormone is needed for preparing the uterus for
implantation of the ovum, this hormone is progesterone.
Hormones
are needed throughout the body for various functions, however, just as
important as these function is the regulation and control of these steroids.
Studies have shown that dietary cholesterol
(polyunsaturated fatty acids) suppresses synthesis of cholesterol: Two
mechanisms exist.
1. Synthesis of enzymes is inhibited at transcription
level. This makes sense since this conserves energy by stopping the production
of synthesis at the start and not by going through useless processes that would
waste energy.
2. Activity of
the enzyme is modulated through a mechanism involving cyclic phosphorylation and dephosphorylation
of the reductase protein (enzyme) itself. Levels of
steroid hormones present at any given time is regulated by its rate of
synthesis, which is ultimately controlled by brain signals.
Estrogene and testosterone
are very useful steroid hormones, however, excessive amounts of both can have
serious effects. For example; we are aware that estrogen
regulates female characteristics just as testosterone does for males. However, estrogen is also a crucial risk factor in breast cancer.
There is a component known as indole-3-carbinol (I3C for short) that regulates
the production of the malignant estrogen by altering
the process by which the body synthesizes this. I3C causes the body to produce
the benign byproduct instead of the highly estrogenic
and potentially carcinogenic one. I3C is found in cabbage and broccoli, so
better eat your vegetables.
Sex hormones.
Sex hormones are synthesized in testicles,
ovaries. Smaller amount of sex hormones are produced in adrenal cortex and
placenta. Small amount of male sex hormones are produced in ovaries and female
sex hormones - in testicles.
Male sex hormones are called androgens and female - estrogens.
Chemical structure - steroids.
Synthesis and secretion of the sex hormones are
controlled by the pituitary honadotropic hormones.
Sex hormones act by means of the activation of gene apparatus of cells.
Catabolism of sex hormones takes place in liver. The time half-life is 70-90
min.
The main estrogens: estradiol, estrole, estriole (are produced by
follicles) and progesterone (is produced by yellow body and placenta). The
main biological role of estrogens - conditioning for the reproductive female
function (possibility of ovum fertilization). Estradiol
results in the proliferation of endometrium and
progesterone stimulates the conversion of endometrium
in decidual tissue which is ready for ovum
implantation. Estrogens also cause the development of secondary sexual
features.
The main androgen is testosterone. Its synthesis is regulated by
the luteinizing hormone. Testosterone forms the
secondary sexual features in males.
Effect of sex hormones on protein metabolism:
1. stimulate
the processes of protein, DNA, RNA synthesis;
2. cause
the positive nitrogenous equilibrium.
Effect of sex hormones on carbohydrate
metabolism:
1. activate
the Krebs cycle;
2. activate
the synthesis of glycogen in liver.
Effect of sex hormones on lipid metabolism:
1. enhance
the oxidation of lipids;
2. inhibit
the synthesis of cholesterol.
Effect of sex hormones on energy metabolism:
-
stimulate the Krebs cycle,
tissue respiration and ATP production.
Sex hormones are used for treatment of variety
diseases. For example, testosterone and its analogs are used as anabolic
remedies; male sex hormones are used for the treatment of malignant tumor of
female sex organs and vice versa.
Tissue hormones.
Prostaglandins. The precursor of prostaglandins is arachidonic acid. Time half-life - 30 s. There are
different prostaglandins and they have a lot of physiological and
pharmacological effects and different prostaglandins have different effects.
Prostaglandins: - decrease the activity of lipid
tissue lipase;
-
regulate the calcium metabolism
in muscle tissue and as result effect on the contraction and relaxation of
muscles;
-
inhibit the gastric secretion;
-
stimulate the formation of
steroids.
Kallicrein-kinin system.
Kinins
- group of peptides with similar structure and biological properties. The main kinins - bradykinin and kallidine.
Kinins
are formed from their precursors kininogens that
are synthesized in liver owing to acting of kallicreins.
Kallicreins are also formed from inactive precursors prekallicreins by means of proteolysis.
Functions: - kinins
relax the smooth muscles of blood vessels and decrease the blood pressure;
-
increase the capillaries
permeability;
-
takes part in the inflammatory
processes.
Renin-angiotensin system. Renin - enzyme that
is synthesized in special cells located near the renal glomerules.
Renin
acts on angiotensinogen. As result angiotensin-I is formed. Under the effect of peptidase angiotensin-I is converted to angiotensin-II. Angiotensin-II
causes 2 effects:
-
narrows the vessels and
increases the blood pressure;
-
stimulates the secretion of aldosterone.
The decrease of renal blood stream is the
specific stimulant for renin secretion.
References:
1.
John Mc Murry,
Mary E. Castellion. General, Organic and Biological
Chemistry.- New Jersy: Prentice Hall, 1992.- 764 p.
2.
John W. Suttie.
Introduction to Biochemistry. – New York: Holt, Rinehart and Winston, Inc.,
1992.- 364 p.
3.
Robert K. Murray, Daryl K. Granner. Harper’s illustrated Biochemistry. – India:
International Education, 2003.- 693 p.
4.
VK Malhotra. Biochemistry
for students. – India: Jaypee Brothers, Medical
Publishers LTD, 1998. – 334p.
5.
Lehninger A. Principles of
Biochemistry. – New York: Worth Publishers, Inc., 1982. – 1010 p.
6.
Stryer L. Biochemistry. –
New York: W.H.Freeman and Company, 1988. – 1086 p.