General concept of hormones. Biologically active substances

Hormones- substances of an organic nature, produced in specialized cells of the glands internal secretion that enter the blood and have a regulatory effect on metabolism and physiological functions.

Specific features of the biological action of hormones:

a) hormones exhibit their biological effect in negligible concentrations (from 10~6 to 10~12 M);

b) the hormonal effect is realized through protein receptors and intracellular second messengers (messengers);

c) hormones at the same time carry out their action by increasing the rate of de novo enzyme synthesis or changing the rate of enzymatic catalysis;

d) the action of hormones in the whole organism is determined to a certain extent by the controlling influence of the central nervous system;

e) the endocrine glands and the hormones produced by them constitute a single system, closely connected with the help of direct and feedback mechanisms.

The modern classification of hormones is based on their chemical nature.

1. Peptide and protein hormones include from 3 to 250 or more amino acid residues. These are hormones of the hypothalamus and pituitary gland (tyroliberin, somatoliberin, somatostatin, growth hormone, corticotropin, thyrotropin, etc.), as well as pancreatic hormones (insulin, glucagon). Peptide hormones after their synthesis are included in secretory granules. The hormone is released into the blood by the fusion of the granule with the plasma membrane of the cell (exocytosis).

2. Hormones - derivatives of amino acids are mainly represented by derivatives of the amino acid tyrosine. These are low molecular weight compounds adrenaline and norepinephrine, synthesized in the adrenal medulla, and hormones thyroid gland(thyroxine and its derivatives). Hormones of the 1st and 2nd groups are highly soluble in water.

3. Steroid hormones- a group of compounds related in origin and structure: they are all formed from cholesterol. These are hormones of the adrenal cortex (corticosteroids), sex hormones (estrogens and androgens), the hormonal form of vitamin D. Steroid hormones are lipophilic substances that easily penetrate cell membranes. Therefore, they do not accumulate in cells, and an increase in their concentration in the blood is determined by an increase in the rate of synthesis.

The main steroid hormones are cortisol (regulation of carbohydrate and amino acid metabolism), aldosterone (regulation water-salt metabolism), testosterone, estradiol and progesterone (regulation of reproductive functions).

4. Eicosanoids- hormone-like substances local action. They are derivatives of a polyunsaturated fatty acid (arachidonic), represented by three subclasses of compounds: prostaglandins, thromboxanes and leukotrienes. These water-insoluble and unstable compounds exert their effects on cells near their site of synthesis. They cause smooth muscle contraction and constriction blood vessels or, conversely, relaxation of smooth muscles and vasodilation, suppression of platelet aggregation or stimulation of their aggregation in the area of ​​vessel damage. Eicosanoids act on target cells through specific membrane receptors.

By biological functions Hormones are divided into the following groups:

1. Regulating the metabolism of carbohydrates, fats, amino acids: insulin, glucagon, adrenaline, glucocorticosteroids (cortisol).

2. Regulating water-salt metabolism: mineralocorticosteroids (aldosterone), antidiuretic hormone (vasopressin).

3. Regulating the exchange of calcium and phosphates: parathyroid hormone, calcitonin, calcitriol (a derivative of vitamin D 4).

4. Regulatory metabolism associated with reproductive function (sex hormones): estradiol, progesterone, testosterone.

5. Regulating functions endocrine glands(tropic hormones): corticotropin, thyrotropin, gonadotropin.

The study of hormones allocated to an independent science - endocrinology. Modern endocrinology studies the chemical structure of hormones produced in the endocrine glands, the relationship between the structure and function of hormones, mechanisms of action, physiology and pathology of the endocrine system. Specialized research institutes, laboratories, scientific journals have been established, international conferences, symposiums and congresses dedicated to the problems of endocrinology are being convened. Endocrinology has become one of the most rapidly developing branches of biological science today. It has its own goals and objectives, specific methodological approaches and research methods.

Hormones are biologically active substances that determine to a certain extent the state of the physiological functions of the whole organism, the macro- and microstructure of organs and tissues, and the rate of biochemical processes. Thus, hormones are substances of an organic nature that are produced in specialized cells of the endocrine glands, enter the bloodstream and have a regulatory effect on metabolism and physiological functions.

One of amazing features living organisms is their ability to maintain the constancy of homeostasis with the help of self-regulation mechanisms, in the implementation (coordination) of which one of the main places belongs to hormones. In higher animals, the coordinated flow of all biological processes not only in the whole organism, but also in the microspace of an individual cell and even in a separate subcellular formation (mitochondria, microsomes) is determined by neurohumoral mechanisms that have developed in the course of evolution. With the help of these mechanisms, the body perceives various influences of the external and internal environment, finely regulating the intensity of metabolic processes. In the regulation of these processes, in the implementation of the sequence of many reactions, hormones occupy an intermediate place between the nervous system and the action of enzymes, and, as you know, the regulation of metabolism is realized by changing the rate of enzymatic reactions. The rate of chemical reactions depends, in turn, on the catalytic activity of enzymes. Hormones cause either a fast (urgent) reaction, increasing the activity of enzymes preformed in tissues, or, which is more likely, for example for steroid hormones, a slow reaction associated with the de novo synthesis of enzymes. There is now evidence that steroid hormones affect the genetic apparatus of the cell, causing the synthesis of the corresponding mRNA, which, having entered the ribosome, serves as a template for the synthesis of the enzyme molecule (see Protein biosynthesis). It is assumed that other hormones (protein nature) indirectly through the phosphorylation of non-histone proteins can affect genes, thereby controlling the rate of synthesis of the corresponding enzymes. Thus, any violation of the synthesis or breakdown of hormones caused by a variety of causal factors, including diseases of the endocrine glands (states of hypo- or hyperfunction), lead to a change in the normal synthesis of enzymes and, accordingly, to metabolic disorders.

The origin of the science of the endocrine glands and hormones dates back to 1849, when Addison first described the so-called bronze disease associated with damage to the adrenal glands and accompanied by specific pigmentation of the skin. Claude Bernard introduced the concept of endocrine glands, that is, organs that secrete their secret directly into the blood, since they do not have excretory ducts. Later, Brown-Séquard showed that insufficiency of the endocrine glands leads to the development of diseases and that extracts from these glands give a good therapeutic effect when they are deficient. Currently, there is indisputable evidence that almost all diseases of the endocrine glands (thyrotoxicosis, diabetes mellitus, etc.) develop as a result of a violation of the molecular mechanisms of regulation of metabolic processes caused by insufficient or, conversely, excessive synthesis of the corresponding hormones in the human body.

The term "hormone" (from the Greek. hormao - excite, encourage) was introduced in 1905 by Beilis and Starling while studying the hormone secretin produced in duodenum and stimulating the production of pancreatic juice and the separation of bile. To date, more than 60 different substances have been discovered, endowed with hormonal activity, synthesized in the endocrine glands and regulating metabolic processes. The specific features of the biological action of hormones can be expressed in three positions:

• hormones have a biological effect in negligible concentrations from (10-9 to 10-12 g);
• the action of hormones in the whole organism is determined to a certain extent by the controlling influence of the central nervous system;
• the endocrine glands and the hormones produced by the name constitute a single system, closely connected through the mechanisms of direct and feedback.

It has been shown that under the influence of various external and internal stimuli, impulses arise in specialized formations called receptors, which are very sensitive to minimal stimuli. The impulses then enter the central nervous system, from there - to the hypothalamus, where the first biologically active hormonal substances are synthesized, which have a "distant" effect and are called releasing factors. A feature of releasing factors is that they do not enter the general bloodstream, but through portal system vessels reach specific cells of the pituitary gland, providing a stimulating (or inhibitory) effect on the biosynthesis and release of tropic hormones of the pituitary gland, which are brought with the bloodstream to the corresponding endocrine gland, stimulating the production of the necessary hormone. This hormone then has an effect on organs and tissues, causing the corresponding chemical and physiological responses of the whole organism. Least explored final stage this peculiar arc, in particular the effect of hormones on tissue chemistry. Most likely, this action is carried out through the so-called hormonal receptors, which are understood as the chemical structures of the corresponding target tissues containing highly specific sites for binding hormonal compounds; the result of such binding is the initiation by receptors of specific biochemical reactions that ensure the realization of the final effect of the corresponding hormone.

As has now been established, protein and peptide hormone receptors are located on outer surface cells (on the plasma membrane), while steroid hormone receptors are localized in the cytoplasm and nucleus. common feature of all receptors, regardless of localization, is the presence of a strict spatial and structural correspondence of the receptor with a specific hormone. In addition to the direct connection, there is also a feedback in the endocrine system. In particular, increased amount thyroxine (thyroid hormone) reflexively causes inhibition of the synthesis of the corresponding releasing factor in the hypothalamus, which leads to the cessation of the formation of thyrotropin in the pituitary gland and, accordingly, restoration physiological level concentration of thyroxine in the body.

NOMENCLATURE AND CLASSIFICATION OF HORMONES

Despite the fact that the chemical nature of almost all known hormones has been elucidated in detail (including the primary structure of protein and peptide hormones), general principles their nomenclature. Because chemical names for many hormones based on their exact chemical structure would be very cumbersome, the commonly used (so-called working) names for hormones are more common. The accepted nomenclature indicates the source of origin of the hormone (for example, insulin from Latin insula - islet) or reflects its function (for example, prolactin, vasopressin). For some pituitary hormones (in particular, for luteinizing and follicle-stimulating hormones), as well as for all hypothalamic factors (hormones), missing or new working names have been created (see below).

A similar situation exists with respect to the classification of hormones. First, hormones are classified according to their natural source, according to which hormones of the hypothalamus, pituitary, thyroid, adrenal, pancreas, gonads, goiter, etc. are distinguished. anatomical classification insufficiently perfect, since some hormones are either not synthesized in the endocrine glands from which they secrete into the blood (for example, the hormones of the posterior pituitary gland, vasopressin and oxytocin, are synthesized in the hypothalamus, from where they are transferred to the posterior pituitary), or are synthesized in others glands (for example, partial synthesis of sex hormones in the adrenal glands, synthesis of prostaglandins not only in the prostate gland, but also in other organs), etc. Given these circumstances, attempts were made to create a classification of hormones based on their chemical nature. Obviously, the classification presented in the monograph edited by N. A. Yulaev should be recognized as the most acceptable. According to this classification, all known hormones can be divided into five groups.

Since ancient times, scientists have wondered why all people are so different from each other in terms of skin and hair color, eyes, face shape, body structure, character and ingenuity, behavior and even dreams. What is the effect of hormones on the body? Individuality is given to us by hormones that regulate mental and physical features in organism. The secret of conception and the further development of the fetus, how the little man will grow: thin or fat, tall or short, smart or simply gifted, how quickly he can adapt to the world around him, what addictions will form, what emotions will prevail - everything is decided hormonal changes that leave a genetic background.

What is the role of hormones in the human body

Thanks to the well-coordinated work of hormones, all organs, tissues and cells are connected into one powerful system that clearly regulates the work of the whole organism as a whole and this system is called the endocrine system. Hormones (from the Greek hormamo means to set in motion, induce) are active chemical substances secreted into the blood and lymph (extracellular space), which deliver hormones to Right place- it can be one cell or many, an organ or tissue. The action of hormones depends on the functions:

• humoral regulation of processes in the body - from the pituitary gland (in the brain), with the help of hormones, human life is controlled;
• ensuring constant communication between organs, cells, processes, tissues in the body, harmonic interaction of the internal environment;
• management of the processes of reproduction, growth and maturation.

The pituitary gland (the main endocrine gland) in the brain secretes a number of hormones responsible for controlling the adrenal glands, thyroid gland, and sex glands. The thyroid gland, in turn, releases hormones that affect growth and metabolism. The adrenal glands secrete hormones to control metabolism: carbohydrates and fats, and are directed to work of cardio-vascular system. The most famous hormones secreted by the adrenal glands are cortisol and adrenaline. The pancreas releases insulin, and if insulin levels fall, diabetes begins to develop. The sex glands are responsible for the production of hormones to regulate the process of maturation, growth and reproductive function.

How are hormones different from other biological substances?

Distinctive properties of hormones:

1. distant character - impact on organs that are at a great distance from the gland;
2. specific features- some hormones can affect one organ or many cells and organs involved in the process;
3. high biological activity, quickly destroyed;
4. Hormones act on living cells of the body.

The scope of hormones in the body

The action of hormones is distinguished by two directions: water-soluble hormones that do not penetrate into cells, but act at the level of the cell membrane, and the second type is transient (fat-soluble), which penetrate the cell membrane and begin to act in the cytoplasm. Consider the example of adrenaline. This hormone can activate its action if it connects to the desired receptor on the cell and forms secondary processes in the cell, which are already starting cellular metabolism. Penetrating hormones, such as insulin, have a faster action pattern. It passes through the membrane and is activated when a cell molecule and a hormone combine, which sets in motion a hormonal effect.

Varieties: the action of hormones and features

Pituitary hormones: prolactin is responsible for the functioning of the mammary glands during pregnancy, thyrotropin - produces thyroxine in the thyroid gland, corticotropin (adrenocorticotropic hormone) - acts in the adrenal glands and releases cortisol, oxytocin is responsible for the course of childbirth, vasopressin (antidiuretic hormone) is aimed at maintaining fluid in the body , growth hormone - somatotropin is aimed at ensuring proper physical development organism.

Thyroid hormones: thyroxine is aimed at accelerating metabolism, triiodothyronine controls the accumulation of calcium in the body and its distribution.

Pancreatic hormones: glucagon increases blood glucose, insulin is responsible for regulating blood sugar levels.

Adrenal hormones: cortisol activates protective function the body during stress, adrenaline is released when a person feels fear or danger to a person, aldosterone controls the level of salt in the body.

Sex hormones: estrogens regulate menstrual cycle and the passage of pregnancy, progesterone is responsible for the successful bearing of the fetus, androgens are called male hormones also called testosterone.

Hormones - biologically active substances of diverse structure, produced in specialized organs - endocrine glands - coming with blood to various organs and exerting a regulatory effect on metabolism and physiological functions in them.

In cells that hormones act on - target cells - there are special proteins on cell membranes called receptors. Hormones are attached to them.

Intracellular mechanisms of action of hormones are diverse. It is possible, however, to distinguish three main mechanisms inherent in most hormones.

1. Hormones affect the rate of enzyme synthesis, accelerating or slowing it down. As a result of such exposure in target organs, the concentration of certain enzymes increases or decreases, which is accompanied by a corresponding change in the rate of enzymatic reactions.

2. Hormones affect the activity of enzymes in these organs. In some organs they act as activators, and in others as inhibitors of enzymatic reactions.

3. Hormones affect the permeability of cell membranes in relation to certain chemical compounds. As a result of such exposure, more or less substrates for enzymatic reactions enter the cells, which also necessarily affects the rate of chemical processes.

All of these mechanisms affect the metabolic rate, which in turn affects physiological functions.

According to the chemical structure, hormones can be divided into several groups.

1. Protein hormones: hypothalamic hormones, pituitary hormones, thyroid calcitonin, hormone parathyroid glands, pancreatic hormones.

2. Hormones derivatives of the amino acid tyrosine: iodine-containing thyroid hormones, hormones of the adrenal medulla.

3. Steroid hormones: Hormones of the adrenal cortex, hormones of the gonads.

Synthesis and release of hormones into the blood is under the control of the nervous system and other hormones. Moreover, the nervous system acts through the humoral, mainly through the hormones of the hypothalamic-pituitary system.

9. Biochemistry of blood.

In sports practice, a blood test is used to assess the impact of training and competitive loads on the athlete's body, to assess the functional state of the athlete and his health. Therefore, a specialist in the field of physical culture should have an idea about the chemical composition of the blood.

The volume of blood in a person is about 5 liters, which is approximately 1/13 of the volume or weight of the body.

Blood is known to be plasma(55% volume ) and shaped elements ( 45%).

Functions of the blood. (from the course of physiology)

The functions of the blood can be divided into two groups:

Functions exclusively of blood plasma,

Functions performed jointly by blood plasma and formed elements.

On one's own blood plasma performs the following functions:

Transfer of soluble organic matter from the small intestine to various bodies and tissues where these substances are stored in reserve or are involved in metabolism.

Transport of substances to be excreted from the tissues where they are formed to the excretory organs.

The transfer of metabolic by-products from their places of origin to other parts of the body.

Transport of hormones from endocrine glands to target organs.

The transfer of heat from deep-seated organs, preventing overheating of these organs and maintaining an even distribution of heat in the body.

jointly With shaped elements blood plasma performs the following functions:

Delivery of oxygen from the lungs to all tissues of the body (erythrocytes) and the transfer of carbon dioxide in the opposite direction.

Protection against diseases in which three mechanisms are involved: blood coagulation, phagocytosis, antibody synthesis.

The chemical composition of blood plasma at rest is relatively constant. Here are its main components:

Proteins 6 - 8%

Other organic matter approx. 2%

Minerals about 1%

Plasma proteins divided into two main groups albumins and globulins.

Albumins - low molecular weight proteins. They perform two main functions.

1. Transport. Due to their good solubility, they carry water-insoluble substances with the bloodstream.

2. Retain water in the bloodstream. There is more water in the bloodstream than in other tissues, so it tends to leave it. Albumins prevent this.

Globulins - These are high molecular weight proteins. They are also involved in transport and holding functions. However, in addition to this, many blood globulins are involved in building immunity and blood clotting.

Plasma proteins are synthesized in the liver.

(In the figure below, there is a table that summarizes the main properties of blood plasma proteins, their functions and how protein electrophoresis is performed.)

GENERAL CONCEPT OF HORMONES
The doctrine of hormones is singled out as an independent science - endocrinology. Modern endocrinology studies the chemical structure of hormones produced in the endocrine glands, the relationship between the structure and function of hormones, the molecular mechanisms of action, as well as the physiology and pathology of the endocrine system. Specialized research institutes and laboratories have been established, and scientific journals have been published; international conferences, symposiums and congresses devoted to the problems of endocrinology are convened. Nowadays, endocrinology has become one of the most rapidly developing branches of biological science. It has its own goals and objectives, specific methodological approaches and research methods. In our country, the leading scientific institution uniting research on these problems is the Endocrinological Research Center of the Russian Academy of Medical Sciences.
Hormones are biologically active substances that determine to a certain extent the state of the physiological functions of the whole organism, the macro- and microstructure of organs and tissues, and the rate of biochemical processes. Thus, hormones are substances of an organic nature, produced in specialized cells of the endocrine glands, entering the bloodstream and exerting a regulatory effect on metabolism and physiological functions. Appropriate adjustments should be made to this definition in connection with the discovery of typical mammalian hormones in unicellular organisms (for example, insulin in microorganisms) or the possibility of hormone synthesis by somatic cells in tissue culture (for example, lymphocytes under the influence of growth factors).
One of the amazing features of living organisms is their ability to maintain the constancy of the internal environment - homeostasis - with the help of self-regulation mechanisms, in which one of the main places belongs to hormones. In higher animals, the coordinated flow of all biological processes not only in the whole organism, but also in the microspace of an individual cell and even in a separate subcellular formation (mitochondria, microsomes) is determined by neurohumoral mechanisms that have developed in the course of evolution. With the help of these mechanisms, the body perceives a variety of signals about changes in the environment and internal environment and finely regulates the intensity of metabolic processes. In the regulation of these processes, in the implementation of the sequence of many reactions, hormones occupy an intermediate link between the nervous system and the action of enzymes that directly regulate the metabolic rate. Currently, evidence has been obtained that hormones cause either a quick (urgent) response, increasing the activity of preformed enzymes present in tissues (this is typical for hormones of a peptide and protein nature), or, which is more typical, for example, for steroid hormones, a slow response, associated with the synthesis of enzymes ee POUO. As will be shown below, steroid hormones affect the genetic apparatus of the cell, causing the synthesis of the corresponding mRNA, which, having entered the ribosome, serves as a template for the synthesis of the protein-enzyme molecule. It is assumed that other hormones (having a protein nature) indirectly through the phosphorylation of non-histone proteins can affect genes, thereby controlling the rate of synthesis of the corresponding enzymes. Thus, any disturbances in the synthesis or breakdown of hormones caused by a variety of causative factors, including diseases of the endocrine glands (a state of hypo- or hyperfunction) or changes in the structure and functions of receptors and intracellular mediators, lead to a change in the normal synthesis of enzymes and, accordingly, to a metabolic disorder.
The origin of the science of the endocrine glands and hormones dates back to 1855, when T. Addison first described a bronze disease associated with damage to the adrenal glands and accompanied by specific pigmentation of the skin. Claude Bernard introduced the concept of endocrine glands, i.e. organs that secrete secretions directly into the blood. Later, S. Brown-Sequard showed that the insufficiency of the function of the endocrine glands causes the development of diseases, and the extracts obtained from these glands have a good therapeutic effect. Currently, there is indisputable evidence that almost all diseases of the endocrine glands (thyrotoxicosis, diabetes mellitus, etc.) develop as a result of a violation of the molecular mechanisms of regulation of metabolic processes caused by insufficient or, conversely, excessive synthesis of the corresponding hormones in the human body.
The term "hormone" (from the Greek. Lorshao-encourage) was introduced in 1905 by W. Bayliss and E. Starling while studying the hormone secretin discovered by them in 1902, which is produced in the duodenum and stimulates the production of pancreatic juice and the separation of bile. To date, more than a hundred different substances have been discovered, endowed with hormonal activity, synthesized in the endocrine glands and regulating metabolic processes. Specific features of the biological action of hormones have been established: a) hormones exhibit their biological action in negligible concentrations (from 10-6 to 1012 M); b) the hormonal effect is realized through protein receptors and intracellular second messengers (messengers); c) being neither enzymes nor coenzymes, hormones at the same time carry out their action by increasing the rate of synthesis of enzymes of its POUO or changing the rate of enzymatic catalysis; d) the action of hormones in the whole organism is determined to a certain extent by the controlling influence of the central nervous system; e) the endocrine glands and the hormones produced by them constitute a single system, closely connected with the help of direct and feedback mechanisms.
Under the influence of various external and internal stimuli, impulses arise in specialized, very sensitive receptors. The impulses then enter the central nervous system, from there to the hypothalamus, where the first biologically active hormonal substances that have a "distant" effect, the so-called releasing factors, are synthesized. A feature of releasing factors is that they do not enter the general blood stream, but through the portal vascular system they reach specific cells of the pituitary gland, while stimulating (or inhibiting) the biosynthesis and release of tropic hormones of the pituitary gland, which reach the corresponding endocrine gland with the blood stream and contribute to production of the required hormone. This hormone then has an effect on specialized organs and tissues (target organs), causing the corresponding chemical and physiological responses of the whole organism.
Until recently, the last stage of this peculiar arc, the action of hormones on intracellular metabolism, remained the least studied. Currently, evidence has been obtained that this action is carried out through the so-called hormonal receptors, which are understood as the chemical structures of the corresponding target tissues containing highly specific sites (carbohydrate fragments of glycoproteins and gangliosides) for hormone binding. The result of such binding is the initiation by receptors of specific biochemical reactions that ensure the realization of the final effect of the corresponding hormone. Protein and peptide hormone receptors are located on the outer surface of the cell (on the plasma membrane), and steroid hormone receptors are located in the nucleus. A common feature of all receptors, regardless of localization, is the presence of a strictly spatial and structural correspondence between the receptor and the corresponding hormone.
The molecular mechanisms of hormonal signal transmission and the role of second messengers (mediators) in the implementation of the hormonal effect are detailed at the end of this chapter.
NOMENCLATURE AND CLASSIFICATION OF HORMONES
The chemical nature of almost all known hormones has been elucidated in detail (including the primary structure of protein and peptide hormones), but so far no general principles for their nomenclature have been developed. The chemical names of many hormones accurately reflect their chemical structure and are very cumbersome. Therefore, trivial names of hormones are more often used. The accepted nomenclature indicates the source of the hormone (for example, insulin, from Lat. tzi1a-islet) or reflects its function (for example, prolactin, vasopressin). For some pituitary hormones (for example, luteinizing and follicle-stimulating), as well as for all hypothalamic hormones, new working names have been developed.
A similar situation exists with respect to the classification of hormones. Hormones are classified depending on the place of their natural synthesis, according to which the hormones of the hypothalamus, pituitary, thyroid, adrenal, pancreas, gonads, goiter, etc. are distinguished. However, such an anatomical classification is not perfect enough, since some hormones or are not synthesized in those endocrine glands from which they are secreted into the blood (for example, the hormones of the posterior pituitary gland, vasopressin and oxytocin are synthesized in the hypothalamus, from where they are transferred to the posterior pituitary gland), or are synthesized in other glands (for example, partial synthesis of sex hormones is carried out in the adrenal cortex, the synthesis of prostaglandins occurs not only in the prostate gland, but also in other organs), etc. Given these circumstances, attempts have been made to modern classification hormones based on their chemical nature. In accordance with this classification, three groups of true hormones are distinguished: 1) peptide and protein hormones, 2) hormones derived from amino acids, and 3) hormones of a steroid nature. The fourth group consists of eicosanoids, hormone-like substances that have a local effect.
Peptide and protein hormones include from 3 to 250 or more amino acid residues. These are hormones of the hypothalamus and pituitary gland (thyroliberin, somatoliberin, somatostatin, growth hormone, corticotropin, thyrotropin, etc. - see below), as well as pancreatic hormones (insulin, glucagon). Hormones-derivatives of amino acids are mainly represented by derivatives of the amino acid tyrosine. These are low-molecular compounds adrenaline and norepinephrine, synthesized in the adrenal medulla, and thyroid hormones (thyroxine and its derivatives). Hormones of the 1st and 2nd groups are highly soluble in water.
Hormones of a steroid nature are represented by fat-soluble hormones of the adrenal cortex (corticosteroids), sex hormones (estrogens and androgens), as well as the hormonal form of vitamin D.
Eicosanoids, which are derivatives of a polyunsaturated fatty acid (arachidonic), are represented by three subclasses of compounds: prostaglandins, thromboxanes and leukotrienes. These water-insoluble and unstable compounds exert their effects on cells near their site of synthesis.
Next will be considered chemical structure, functions and pathways of biosynthesis and breakdown of the main classes of hormones, divided into individual groups in accordance with the classification, which is based on the chemical nature of hormones.
HORMONES OF THE HYPOTHALAMUS
The hypothalamus serves as a site of direct interaction higher departments CNS and endocrine system. The nature of the connections that exist between the CNS and endocrine system, began to clear up in recent decades, when the first humoral factors were isolated from the hypothalamus, which turned out to be hormonal substances with extremely high biological activity. It took a lot of work and experimental skill to prove that these substances are formed in nerve cells hypothalamus, from where they reach the pituitary gland through the system of portal capillaries and regulate the secretion of pituitary hormones, or rather their release (possibly biosynthesis). These substances were first called neurohormones, and then releasing factors (from the English.
ge1ase-free), or liberins. Substances with the opposite effect, i.e. inhibiting the release (and, possibly, biosynthesis) of pituitary hormones, became known as inhibitory factors, or statins. Thus, the hormones of the hypothalamus play a key role in physiological system hormonal regulation multilateral biological functions of individual organs, tissues and the whole organism.
| CNS
hypothalamus
Hypothalamic hormones (releasing factors)

To date, 7 stimulants (liberins) and 3 inhibitors (statins) of secretion of pituitary hormones have been discovered in the hypothalamus, namely: corticoliberin, thyroliberin, luliberin, follyliberin, somatoliberin, prolactoliberin, melanoliberin, somatostatin, prolactostatin and melanostatin (Table 8.1) . IN pure form 5 hormones were isolated, for which the primary structure was established, confirmed by chemical synthesis.
Great difficulties in obtaining the hormones of the hypothalamus in their pure form are explained by their extremely low content in the original tissue. So, to isolate only 1 mg of thyroliberin, it was necessary to process 7 tons of hypothalamus obtained from 5 million sheep.
It should be noted that not all hypothalamic hormones appear to be strictly specific for one particular pituitary hormone. In particular, thyroliberin has shown the ability to release, in addition to thyrotropin, also prolactin, and for luliberin, in addition to luteinizing hormone, also follicle-stimulating hormone.
Tables:! 8.1. Hypothalamic hormones that control the release of pituitary hormones 1 Old name Accepted Recommended abbreviation Name Corticotropin-releasing factor CRF Corticoliberin Thyrotropin-releasing factor TRF Thyroliberin Gonadotropin-releasing factor GRF Gonadoliberin Releasing factor follicle-stimulating FGF Folliberin hormone FSH-RF releasing -factor SRF Somatoliberin Somatotropin inhibitory factor CIF Somatostatin Prolactin-releasing factor PRF Prolactoliberin Prolactin inhibitory factor PIF Prolactostatin Melanotropin-releasing factor MRF Melanoliberin Melanotropin inhibitory factor MIF Melanostatin
Hypothalamic hormones do not have firmly established names. It is recommended to add the ending "liberin" in the first part of the name of the pituitary hormone; for example, "thyroliberin" means a hypothalamic hormone that stimulates the release (and possibly synthesis) of thyrotropin, the corresponding pituitary hormone. In a similar way, they form the names of hypothalamic factors that inhibit the release (and, possibly, synthesis) of tropic hormones of the pituitary gland - add the ending "statin". For example, "somatostatin" means a hypothalamic peptide that inhibits the release (or synthesis) of the pituitary growth hormone, somatotropin.
It has been established that according to the chemical structure, all hormones of the hypothalamus are low molecular weight peptides, the so-called oligopeptides of an unusual structure, although the exact amino acid composition and primary structure have not been clarified for everyone. We present the data obtained so far on the chemical nature of six of the known 10 hormones of the hypothalamus.
Thyroliberin (Piro-Glu-Gis-Pro-KH2):
H2p-CH-CO-MH-CH-CO^M. O
/\I/\/
N4 I H2C CH-C-MH2
/sn2\/
S n2s-bn2
about NN
Thyroliberin is a tripeptide consisting of pyroglutamic (cyclic) acid, histidine and prolinamide connected by peptide bonds. Unlike classical peptides, it does not contain free KH2 and COOH groups at the K- and C-terminal amino acids.
Gonadoliberin is a decapeptide consisting of 10 amino acids in the sequence:
Piro-Glu-G is-Trp-Ser-Tir-Gpi-Lei-Arg-Pro-Gpi-YN2
The terminal C-amino acid is represented by glycinamide.
Somatostatin is a cyclic tetradecapeptide (consists of 14 amino acid residues):
N-Ala-Gly-Cis-Lys-Asn-Fen-Phen-Trp-Liz-Tre-Phen-Tre-Ser-Cis-OH
This hormone differs from the two previous ones, in addition to the cyclic structure, in that it does not contain pyroglutamic acid at the Window: a disulfide bond is formed between two cysteine ​​residues in the 3rd and 14th positions. It should be noted that the synthetic linear analogue of somatostatin is also endowed with a similar biological activity, which indicates the insignificance of the disulfide bridge of the natural hormone. In addition to the hypothalamus, somatostatin is produced by neurons of the central and peripheral nervous systems, and is also synthesized in 8-cell pancreatic islets (islets of Langerhans) in the pancreas and intestinal cells. It has a wide spectrum of biological action; in particular, an inhibitory effect on the synthesis of growth hormone in the adenohypophysis, as well as its direct inhibitory effect on the biosynthesis of insulin and glucagon in the β- and α-cells of the islets of Langerhans, has been shown.
Somatoliberin has recently been isolated from natural sources. It is represented by 44 amino acid residues with a fully disclosed sequence. The biological activity of somatoliberin is also endowed with a chemically synthesized decapeptide:
N-Val-G is-Lei-Ser-Ala-Glu-Gln-Liz-Glu-Ala-ON.
This decapeptide stimulates the synthesis and secretion of the pituitary growth hormone somatotropin.
Melanoliberin, chemical structure which is similar to the structure of the open ring of the hormone oxytocin (without the tripeptide side chain), has the following structure:
N-Cis-Tir-Ile-Gln-Asn-Cis-OH.
Melanostatin (melanotropin-inhibiting factor) is either a tripeptide: Pyro-Glu-Leu-Gly-MH2, or a pentapeptide with the following sequence:
Pyro-Glu-G is-Phen-Drg-Gly-MN2.
It should be noted that melanoliberin has a stimulating effect, and melanostatin, on the contrary, has an inhibitory effect on the synthesis and secretion of melanotropin in the anterior pituitary gland.
In addition to the listed hypothalamic hormones, the chemical nature of another hormone, corticoliberin, has been intensively studied. Its active preparations have been isolated both from the tissue of the hypothalamus and from the posterior lobe of the pituitary gland; there is an opinion that the latter can serve as a hormone depot for vasopressin and oxytocin. Recently, a 41 amino acid sequence elucidated corticoliberin was isolated from the sheep hypothalamus.
The place of synthesis of hypothalamic hormones, most likely, is the nerve endings-synaptosomes of the hypothalamus, since it is there that the highest concentration of hormones and biogenic amines is noted. The latter are considered along with hormones peripheral glands internal secretion, acting on the principle feedback, as the main regulators of secretion and synthesis of hormones of the hypothalamus. The mechanism of thyroliberin biosynthesis, which is most likely carried out by a nonribosomal pathway, includes the participation of an SH-containing synthetase or a complex of enzymes that catalyze the cyclization of glutamic acid to pyroglutamic acid, the formation of a peptide bond, and the amidation of proline in the presence of glutamine. The existence of a similar mechanism of biosynthesis with the participation of the corresponding synthetases is also assumed in relation to GnRH and somatoliberin.
Ways of inactivation of hormones of the hypothalamus are not well understood. The half-life of thyroliberin in rat blood is 4 minutes. Inactivation occurs both when the peptide bond is broken (under the action of exo- and endopeptidases of the blood serum of rats and humans), and when the amide group in the prolinamide molecule is cleaved off. In the hypothalamus of humans and a number of animals, a specific enzyme, pyroglutamyl peptidase, was discovered, which catalyzes the cleavage of the pyroglutamic acid molecule from thyroliberin or gonadoliberin.
Hypothalamic hormones directly affect the secretion (more precisely, the release) of “ready-made” hormones and the biosynthesis of these hormones by its POUO. It has been proven that cAMP is involved in hormonal signal transduction. The existence of specific adenohypophyseal receptors in the plasma membranes of pituitary cells has been shown, with which the hormones of the hypothalamus bind, after which Ca2+ and cAMP ions are released through the system of adenylate cyclase and membrane complexes Ca2 - ATP and Mg2 + - ATP; the latter acts both on the release and synthesis of the corresponding pituitary hormone by activating protein kinase (see below).
To elucidate the mechanism of action of releasing factors, including their interaction with the corresponding receptors, an important role was played by structural analogues thyroliberin and gonadoliberin. Some of these analogues have even higher hormonal activity and prolonged action than natural hormones hypothalamus. However, there is still a lot of work to be done to elucidate the chemical structure of already discovered releasing factors and decipher the molecular mechanisms of their action.
HYPOPHYSIS HORMONES
The pituitary gland synthesizes a number of biologically active hormones of protein and peptide nature, which have a stimulating effect on various physiological and biochemical processes in target tissues (Table 8.2). Depending on the place of synthesis, the hormones of the anterior, posterior and intermediate lobes of the pituitary gland are distinguished. In the anterior lobe, mainly protein and polypeptide hormones, called tropic hormones, or tropins, are produced due to their stimulating effect on a number of other endocrine glands. In particular, the hormone that stimulates the secretion of thyroid hormones is called thyrotropin.
Table 8.2. Hormones of the pituitary gland and the main clinical syndromes, developing in violation of their secretion Hormone Molecular weight The main clinical syndromes with an excess of the hormone with hormone deficiency Hormones of the anterior pituitary gland Growth hormone 21500 Acromegaly (excessive growth) Dwarfism
(short stature) Corticotropin (ACTH) 4500 Itsenko-Cushing's syndrome Secondary hypofunction of the adrenal cortex Thyrotropin 28000 Hyperthyroidism Secondary hypothyroidism Prolactin 23500 Amenorrhea, infertility, galactorrhea Absence of lactation Follicle-stimulating hormone (follitropin) 34000 Premature puberty Secondary hypofunction of the gonads; infertility Luteinizing hormone (lutropin) 28500 The same The same Lipotropin 11800 Depletion Obesity Posterior pituitary hormones Vasopressin 1070 - Diabetes insipidus Oxytocin 1070 - -
IN last years More than 50 peptides have been isolated from the brain tissue of animals, which are called neuropeptides and determine behavioral responses. It has been shown that these substances affect some forms of behavior, learning and memory processes, regulate sleep and relieve pain, like morphine. Thus, the isolated P-endorphin (31 amino acid residues with an elucidated sequence) turned out to be almost 30 times more active as an anesthetic than morphine. A number of other peptides have a hypnotic effect, and a 16-membered peptide that causes fear of the dark in rats has been named scotophobin. Ameletin polypeptide has been isolated, which, on the contrary, wean rats from being afraid of the sharp sound of an electric bell. Work in this direction is being intensively carried out in many laboratories. It is quite possible that appropriate neuropeptides, including memory peptides, will soon be isolated and correspondingly synthesized artificially for each form of behavior.
The following are data on the structure and functions of the most important hormones of the pituitary gland and other endocrine glands, which have a protein and peptide nature.
Vasopressin and oxytocin
The hormones vasopressin and oxytocin are synthesized by the ribosomal pathway, and simultaneously 3 proteins are synthesized in the hypothalamus: neurophysin I, II and III, the function of which is to non-covalently bind
the formation of oxytocin and vasopressin and the transport of these hormones into the neurosecretory granules of the hypothalamus. Further, in the form of neurophysin-hormone complexes, they migrate along the axon and reach the posterior lobe of the pituitary gland, where they are deposited in reserve; after dissociation of the complex free hormone secreted into the blood. Neurophysins have also been isolated in pure form, and the primary structure of two of them (92 out of 97 amino acids) has been elucidated.
residues, respectively). are cysteine-rich proteins containing
seven disulfide bonds.
The chemical structure of both hormones was deciphered by the classical works of V. du Vignot et al., who were the first to isolate these hormones from the posterior lobe of the pituitary gland and carry out their chemical synthesis. Both hormones are nonapeptides of the following structure:
" ? „
N-Cx-Tyr-Ile -Gln-Asn-Cis-Pro-L * "-Gly-CO-MNg Oxytocin
? ®
N-Cis-Tyr-F*n-Gln-Asn-Cis-Pro-Arg-Gly-CO-YNaVasopressin
Vasopressin differs from oxytocin in two amino acids: it contains phenylalanine instead of isoleucine at position 3 from the window, and arginine instead of leucine at position 8. The indicated sequence of 9 amino acids is characteristic of human, monkey, horse, large vasopressin cattle, sheep and dogs. The molecule of vasopressin from the pituitary gland of the pig contains lysine instead of arginine at position 8, hence the name "lysine-vasopressin". In all vertebrates, with the exception of mammals, vasotocin has also been identified. This hormone, consisting of a ring with an 8-8 oxytocin bridge and a vasopressin side chain, was chemically synthesized by V. du Vignot long before the natural hormone was isolated. It has been suggested that evolutionarily all neurohypophyseal hormones originated from one common precursor, namely arginine-vasotocin, from which modified hormones were formed by single mutations of gene triplets.
The main biological effect of oxytocin in mammals is associated with the stimulation of contraction of the smooth muscles of the uterus during childbirth and the muscle fibers around the alveoli of the mammary glands, which causes the secretion of milk. Vasopressin stimulates the contraction of vascular smooth muscle fibers, exerting a strong vasopressor effect, but its main role in the body is to regulate water metabolism, hence its second name antidiuretic hormone. In small concentrations (0.2 ng per 1 kg of body weight), vasopressin has a powerful antidiuretic effect - it stimulates the reverse flow of water through the membranes. renal tubules. Normally it controls osmotic pressure blood plasma and water balance human body. With pathology, in particular atrophy of the posterior pituitary gland, diabetes insipidus develops - a disease characterized by the release of extremely large quantities urine fluids. At the same time, it violated reverse process absorption of water in the tubules of the kidneys.
Regarding the mechanism of action of neurohypophyseal hormones, it is known that hormonal effects, in particular vasopressin, are realized through the adenylate cyclase system (see below). However, the specific mechanism of action of vasopressin on water transport in the kidneys remains unclear.
Melanocyte-stimulating hormones (MSH, melanotropins)
Melanotropins are synthesized and secreted into the blood by the intermediate lobe of the pituitary gland. The primary structures of two types of hormones, α- and β-melanocyte-stimulating hormones (α-MSH and β-MSH), have been isolated and deciphered. It turned out that in all examined animals, a-MSH consists of 13 amino acid residues arranged in the same sequence:
CH3-CO-YI-Ser-Tyr-Ser-Met-Glu-G is-Phen-Arg-Trp-Gly-Liz-
-Pro-Val-SO-YN2
In a-MSH, the K-terminal serine is acetylated, and the C-terminal amino acid is represented by valinamide.
The composition and structure of s-MSH proved to be more complex. In most animals, the β-MSH molecule consists of 18 amino acid residues; in addition, there are species differences regarding the nature of the amino acid in positions 2, 6 and 16 of the hormone's polypeptide chain. β-MSH isolated from the intermediate lobe of the human pituitary gland turned out to be a 22-mer peptide extended by 4 amino acid residues from the K-terminus:
N-Ala-Glu-Lys-Lys-Asp-Glu-Gly-Pro-Tyr-Arg-Met-Glu-G is-Phen- -Arg-Trp-Gly-Ser-Pro-Pro-Lys-Asp-OH
The physiological role of melanotropins is to stimulate melaninogenesis in mammals and increase the number of pigment cells (melanocytes) in skin amphibians. It is also possible that MSH has an effect on fur color and secretory function. sebaceous glands in animals.
Adrenocorticotropic hormone (ACTH, corticotropin)
Back in 1926, it was found that the pituitary gland has a stimulating effect on the adrenal glands, increasing the secretion of cortical hormones. The data accumulated to date indicate that this property is endowed with ACTH produced by basophilic cells of the adenohypophysis. ACTH, in addition to the main action - stimulation of the synthesis and secretion of hormones of the adrenal cortex, has fat-mobilizing and melanocyte-stimulating activity.
The ACTH molecule in all animal species contains 39 amino acid residues. The primary structure of pig and sheep ACTH was deciphered as early as 1954-1955. Here is the refined structure of human ACTH:
N-Ser-Tyr-Ser-Met-Gpu-G is-Fen-Arg-Trp-Gpi-Liz-Pro-Val-Gpi- -Liz-Liz-Arg-Arg-Pro-Val-Liz-Val-Tyr- Pro-Asp-Ala-Gpi-Glu- -Asp-Gpn-Ser-Ala-Gpu-Ala-Phen-Pro-Leu-Gpu-Fen-ON
Differences in the structure of ACTH in sheep, pigs and bulls concern only the nature of the 31st and 33rd amino acid residues, but they all have almost the same biological activity as human pituitary ACTH. In the molecule of ACTH, as well as other protein hormones, although active centers like the active centers of enzymes are not open, it is assumed that there are two active sites of the peptide chain, one of which is responsible for binding to the corresponding receptor, the other for the hormonal effect.
Data on the mechanism of action of ACTH on the synthesis of steroid hormones indicate a significant role of the adenylate cyclase system. It is assumed that ACTH interacts with specific receptors on the outer surface of the cell membrane (receptors are represented by proteins in combination with other molecules, in particular with sialic acid). The signal is then transmitted to the enzyme adenylate cyclase located on inner surface cell membrane that catalyzes the breakdown of ATP and the formation of cAMP. The latter activates protein kinase, which in turn, with the participation of ATP, phosphorylates cholinesterase, which converts cholesterol esters into free cholesterol, which enters the adrenal mitochondria, which contains all the enzymes that catalyze the conversion of cholesterol into corticosteroids.
Somatotropic hormone (GH, growth hormone, somatotropin)
Growth hormone was discovered in extracts of the anterior pituitary gland as early as 1921, however, it was obtained in a chemically pure form only in 1956-1957. STH is synthesized in acidophilic cells of the anterior pituitary gland; its concentration in the pituitary gland is 5-15 mg per 1 g of tissue, which is 1000 times higher than the concentration of other pituitary hormones. To date, the primary structure of the human, bovine and sheep GH protein molecule has been fully elucidated. Human growth hormone consists of 191 amino acids and contains two disulfide bonds; The K- and C-terminal amino acids are represented by phenylalanine.
STG has a wide range biological action. It affects all cells of the body, determining the intensity of the metabolism of carbohydrates, proteins, lipids and minerals. It enhances the biosynthesis of protein, DNA, RNA and glycogen and at the same time promotes the mobilization of fats from the depot and the breakdown of higher fatty acids and glucose in tissues. In addition to the activation of assimilation processes, accompanied by an increase in body size, growth of the skeleton, GH coordinates and regulates the rate of flow metabolic processes. In addition, human and primate (but not other animal) GH has measurable lactogenic activity. It is believed that many of the biological effects of this hormone are carried out through a special protein factor formed in the liver under the influence of the hormone. This factor has been called sulfating or thymidyl because it stimulates the incorporation of sulfate into cartilage, thymidine into DNA, uridine into RNA, and proline into collagen. By its nature, this factor turned out to be a peptide with a mol. weighing 8000. Given its biological role, he was given the name "somatomedin", i.e. mediator of GH action in the body.
STH regulates the processes of growth and development of the whole organism, which is confirmed clinical observations. So, with pituitary dwarfism (a pathology known in the literature as panhypopituitarism;
associated with congenital underdevelopment of the pituitary gland), there is a proportional underdevelopment of the whole body, including the skeleton, although there are no significant deviations in the development of mental activity. An adult also develops a number of disorders associated with hypo- or hyperfunction of the pituitary gland. Known disease acromegaly (from the Greek. akgoz - limb, nega8 - large), characterized by a disproportionate intensive growth certain parts of the body, such as arms, legs, chin, superciliary arches, nose, tongue, and overgrowth internal organs. The disease is caused, apparently, by a tumor lesion of the anterior lobe of the pituitary gland.
Lactotropic hormone (prolactin, luteotropic hormone)
Prolactin is considered one of the most "ancient" pituitary hormones, since it can be found in the pituitary gland of lower terrestrial animals that do not have mammary glands, and also get a lactogenic effect in mammals. In addition to the main action (stimulation of the development of the mammary glands and lactation), prolactin has an important biological significance- stimulates the growth of internal organs, the secretion of the corpus luteum (hence its second name "luteotropic hormone"), has a renotropic, erythropoietic and hyperglycemic effect, etc. An excess of prolactin, usually formed in the presence of tumors from prolactin-secreting cells, leads to menstruation (amenorrhea) and breast enlargement in women and impotence in men.
The structure of prolactin from the pituitary gland of sheep, bull and man has been deciphered. It is a large protein, represented by a single polypeptide chain with three disulfide bonds, consisting of 199 amino acid residues. Species differences in the amino acid sequence relate essentially to 2-3 amino acid residues. Previously, the opinion about the secretion of lactotropin in the human pituitary gland was disputed, since it was assumed that somatotropin supposedly performs its function. Currently, convincing evidence has been obtained for the existence of human prolactin, although its pituitary gland contains significantly less than growth hormone. In the blood of women, the level of prolactin rises sharply before childbirth: up to 0.2 ng/l against 0.01 ng/l in the norm.
Thyrotropic hormone (TSH, thyrotropin)
Unlike the considered peptide hormones of the pituitary gland, which are mainly represented by one polypeptide chain, thyrotropin is a complex glycoprotein and, in addition, contains two a- and p-subunits, which individually do not have biological activity: they say. its mass is about 30,000.
Thyrotropin controls the development and function of the thyroid gland and regulates the biosynthesis and secretion of thyroid hormones into the blood. The primary structure of the a- and P-subunits of bovine, sheep, and human thyrotropin has been completely deciphered: the a-subunit, containing 96 amino acid residues, has the same amino acid sequence in all studied TSH and in all pituitary luteinizing hormones; The P-subunit of human thyrotropin, containing 112 amino acid residues, differs from the similar polypeptide in bovine TSH by amino acid residues and the absence of C-terminal methionine. Therefore, many authors explain the specific biological and immunological properties of the hormone by the presence of the TSH β-subunit in combination with the α-subunit. It is assumed that the action of thyrotropin is carried out, like the action of other hormones of protein nature, by binding to specific receptors of plasma membranes and activating the adenylate cyclase system (see below).
Gonadotropic hormones (gonadotropins)
Gonadotropins include follicle-stimulating hormone (FSH, follitropin) and luteinizing hormone (LH, lutropin), or a hormone that stimulates interstitial cells. Both hormones are synthesized in the anterior pituitary gland and, like thyrotropin, are complex glycoprotein proteins with a mol. weighing 25,000. They regulate steroidogenesis and gametogenesis in the gonads. Follitropin causes the maturation of follicles in the ovaries in females and spermatogenesis in males. Lutropin in females stimulates the secretion of estrogens and progesterone, as well as the rupture of follicles with the formation of a corpus luteum, and in males - the secretion of testosterone and the development of interstitial tissue. The biosynthesis of gonadotropins, as noted, is regulated by the hypothalamic hormone gonadoliberin.
The chemical structure of the lutropin molecule has been fully deciphered. Lutropin consists of two a- and b-subunits. The structure of the a-subunits of the hormone in most animals is the same. So, in a sheep, it contains 96 amino acid residues and 2 carbohydrate radicals. In humans, the a-subunit of the hormone is shortened by 7 amino acid residues from the K-terminus and differs in the nature of 22 amino acids. The sequence of amino acids in the β-subunits of porcine and human lutropin has also been deciphered. α- and β-subunits are individually devoid of biological activity (by analogy with most enzyme subunits). Only their complex, the formation of which is most likely predetermined by their primary structure, leads to the formation of a biologically active macromolecular structure due to hydrophobic interactions.
Lipotropic hormones (LTH, lipotropins)
Among the hormones of the anterior pituitary gland, the structure and function of which have been elucidated in the last decade, lipotropins, in particular β- and γ-LTH, should be noted. The primary structure of sheep and pig β-lipotropin, whose molecules consist of 91 amino acid residues and have significant species differences in the amino acid sequence, has been studied in most detail. The biological properties of β-lipotropin include fat-mobilizing action, corticotropic, melanocyte-stimulating and hypocalcemic activity, and, in addition, an insulin-like effect, which is expressed in an increase in the rate of glucose utilization in tissues. It is assumed that the lipotropic effect is carried out through the adenylate cyclase-cAMP-protein kinase system, the final stage of which is the phosphorylation of inactive triacylglycerol lipase. This enzyme, after activation, breaks down neutral fats into diacylglycerol and a higher fatty acid (see chapter 11).
The listed biological properties are due not to P-lipotropin, which turned out to be devoid of hormonal activity, but to its decay products formed during limited proteolysis. It turned out that biologically active peptides endowed with an opiate-like effect are synthesized in the brain tissue and in the intermediate lobe of the pituitary gland. Here are the structures of some of them:
N-Tyr-Gly-Gly-Fen-Met-OH N-Tyr-Gly-Gly-Fen-Leu-OH
Methionine enkephalin Leucine enkephalin
N-Tyr-Gli-Gli-Fen-Met-Tre-Ser-Glu-Liz-Ser-Gln-Tre-Pro-Ley-Val-Tre-Ley-Fen-Liz-Asn-Ala-Ile-Val-Liz- Asn-Ala-G is- -Liz-Liz-Gli-Gln-ON
r-Endorphin
The common type of structure for all three compounds is the tetrapeptide sequence at the Window. It has been proven that P-endorphin (31 AMK) is formed by proteolysis from the larger pituitary hormone P-lipotropin (91 AMK); the latter, together with ACTH, is formed from a common precursor - a prohormone called proopiocortin (it is, therefore, a preprohormone), having a molecular weight of 29 kDa and numbering 134 amino acid residues. The biosynthesis and release of proopiocortin in the anterior pituitary is regulated by hypothalamic corticoliberin. In turn, from ACTH and P-lipotropin, through further processing, in particular limited proteolysis, a- and P-melanocyte-stimulating hormones (a- and P-MSH) are formed, respectively. Using the DNA cloning technique, as well as the method of determining the primary structure nucleic acids Sanger in a number of laboratories, the nucleotide sequence of the mRNA precursor of proopiocortin was discovered. These studies can serve as the basis for the targeted production of new biologically active hormonal drugs.
Below are the peptide hormones formed from P-lipotropin by specific proteolysis.
P-lipotropin site Peptide hormone
1-58 y-Lipotropin
41-58 R-MSG
61-65 Met-enkephalin
61-76 a-Endorphin
61-77 y-endorphin
61-79 b-Endorphin
61-91 R-Endorphin
Taking into account the exceptional role of P-lipotropin as a precursor of the listed hormones, we present the primary structure of pig P-lipotropin (91 amino acid residues):
N-Glu-Ley-Ala-Gli-Ala-Pro-Pro-Glu-Pro-Ala-Arg-Asp-Pro-Glu- -Ala-Pro-Ala-G lu-Gli-Ala-Ala-Ala-Arg- Ala-Glu-Lei-G lu-T ir- -Gli-Lei-Val-Ala-Glu-Ala-Glu-Ala-Ala-Glu-Liz-Liz-Asp-Glu- -Gli-Pro-Tyr-Liz- Met-Glu-G is-Fen-Arg-Trp-Gli-Ser-Pro-Pro-
-Liz-Asp-Liz-Arg-Tir-Gli-Gli-Fen-Met-Tre-Ser-Glu-Liz-Ser- -Gln-Tre-Pro-Lay-Val-Tre-Lay-Fen-Liz-Asn- Ala-Ile-Val-Liz- -Asn-Ala-G is-Liz-Liz-Gli-Gln-ON
The increased interest in these peptides, in particular enkephalins and endorphins, is dictated by their extraordinary ability, like morphine, to remove pain. This area of ​​research - the search for new natural peptide hormones and (or) their targeted biosynthesis - is interesting and promising for the development of physiology, neurobiology, neurology, and clinics.
PARATHYROID HORMONES (PARATHORMONES)
Protein hormones also include parathyroid hormone (parathyroid hormone), more precisely, a group of parathyroid hormones that differ in the sequence of amino acids. They are synthesized by the parathyroid glands. As early as 1909, it was shown that the removal of the parathyroid glands causes tetanic convulsions in animals against the background of sharp drop plasma calcium concentrations; the introduction of calcium salts prevented the death of animals. However, only in 1925 an active extract was isolated from the parathyroid glands, causing a hormonal effect - an increase in the calcium content in the blood. Pure hormone was obtained in 1970 from the parathyroid glands of cattle; at the same time its primary structure was determined. It was found that parathyroid hormone is synthesized as a precursor (115 amino acid residues) of the propathic hormone, however, the primary product of the gene turned out to be a hormone preparation containing an additional signal sequence of 25 amino acid residues. The bovine parathyroid hormone molecule contains 84 amino acid residues and consists of one polypeptide chain.
It was found that parathormone is involved in the regulation of the concentration of calcium cations and related phosphoric acid anions in the blood. As you know, the concentration of calcium in the blood serum refers to chemical constants, its daily fluctuations do not exceed 3-5% (normally 2.2-2.6 mmol / l). Biologically active form ionized calcium is considered, its concentration ranges from 1.1-1.3 mmol / l. Calcium ions turned out to be essential factors that are not replaceable by other cations for a number of vital physiological processes: muscle contraction, neuromuscular excitation, blood coagulation, permeability of cell membranes, activity of a number of enzymes, etc. Therefore, any changes in these processes, caused by a long-term lack of calcium in food or a violation of its absorption in the intestine, lead to an increase in the synthesis of parathyroid hormone, which contributes to the leaching of calcium salts (in the form of citrates and phosphates) from bone tissue and, accordingly, to the destruction of the mineral and organic components of the bones.
Another target organ for parathyroid hormone is the kidney. Parathyroid hormone reduces the reabsorption of phosphate in the distal tubules of the kidney and increases the tubular reabsorption of calcium.
It should be pointed out that three hormones play the main role in the regulation of the Ca2+ concentration in the extracellular fluid: parathyroid hormone, calcitonin, synthesized in the thyroid gland (see below), and calcitriol, a B3 derivative (see Chapter 7). All three hormones regulate Ca2+ levels, but their mechanisms of action are different. Thus, the main role of calcitriol is to stimulate the absorption of Ca2+ and phosphate in the intestine, and against the concentration gradient, while parathyroid hormone promotes their release from bone tissue into the blood, calcium absorption in the kidneys and excretion of phosphates in the urine. Less studied is the role of calcitonin in the regulation of Ca2+ homeostasis in the body. It should also be noted that calcitriol is similar in its mechanism of action at the cellular level to the action of steroid hormones (see below).
It is considered proven that the physiological effect of parathyroid hormone on the cells of the kidneys and bone tissue is realized through the adenylate cyclase-cAMP system (see below).
THYROID HORMONES
The thyroid gland plays exclusively important role in metabolism. This is evidenced by a sharp change in the basal metabolism observed in violations of the thyroid gland, as well as a number of indirect data, in particular, its abundant blood supply despite its small mass (20-30 g). The thyroid gland consists of many special cavities - follicles filled with a viscous secret - a colloid. The composition of the colloid includes a special iodine-containing glycoprotein with a high mol. weighing about 650,000 (5000 amino acid residues). This glycoprotein is called iodothyroglobulin. It is a reserve form of thyroxine and triiodothyronine, the main hormones of the follicular part of the thyroid gland.
In addition to these hormones (the biosynthesis and functions of which will be discussed below), in special cells - the so-called parafollicular cells, or C-cells of the thyroid gland, a hormone of a peptide nature is synthesized, which ensures a constant concentration of calcium in the blood. It received the name "calcitonin". For the first time, the existence of calcitonin, which has the ability to maintain a constant level of calcium in the blood, was indicated in 1962 by D. Kopp, who mistakenly believed that this hormone is synthesized by the parathyroid glands. Currently, calcitonin is not only isolated in its pure form from the tissue of the thyroid gland of animals and humans, but also the 32-mer amino acid sequence, confirmed by chemical synthesis, is fully disclosed. The following is the primary structure of calcitonin derived from the human thyroid gland:
N-Cis-Gly-Asn-Ley-Ser-Tre - Cis-Met-Ley - Gly-Tre-Tyr-Tre - Gln- - Asp-Fen-Asn-Liz-Fen - Gis-Tre-Fen - Pro - Gpn -Tre-Ala-Ley - Gli-
Human calcitonin contains a disulfide bridge (between the 1st and 7th amino acid residues) and is characterized by a N-terminal cysteine ​​and a C-terminal prolinamide. Calcitonins of bovine, sheep, pig and salmon fish differ little from each other both in structure and terminal amino acids, and in hypocalcemic activity. The biological effect of calcitonin is directly opposite to the effect of parathyroid hormone: it causes suppression of resorptive processes in the bone tissue and, accordingly, hypocalcemia and hypophosphatemia. Thus, the constancy of the level of calcium in the blood of humans and animals is provided mainly by parathyroid hormone, calcitriol and calcitonin, i.e. hormones of both the thyroid and parathyroid glands, and a hormone-derived vitamin B3. This should be taken into account during surgical therapeutic manipulations on these glands.
The chemical nature of the hormones of the follicular part of the thyroid gland has been clarified in detail for a relatively long time. It is considered established that all iodine-containing hormones that differ from each other in iodine content are derivatives of L-thyronine, which is synthesized in the body from the amino acid L-tyrosine.

b-thyronine b-thyroxine (ZDZ",51-b-3.5.3"-triiodothyronine b-3.3"-diiodothyronine
tetraiodothyronine)
From L-thyronine, the thyroid hormone thyroxin is easily synthesized, containing iodine in 4 positions of the ring structure. It should be noted that 3,5,3"-triiodothyronine and 3,3"-diiodothyronine, also discovered in the thyroid gland, are endowed with hormonal activity. The biosynthesis of thyroid hormones is regulated by thyrotropin, a hormone of the hypothalamus (see earlier).
At present, the enzyme systems that catalyze the intermediate stages of the synthesis of these hormones, and the nature of the enzyme involved in the conversion of iodides into free iodine (2F-NM), necessary for iodination of 115 tyrosine residues in the thyroglobulin molecule, have not yet been fully studied. The sequence of reactions associated with the synthesis of thyroid hormones was deciphered using radioactive iodine. It was shown that the introduced labeled iodine is found first of all in the molecule of monoiodotyrosine, then diiodotyrosine, and only then thyroxine. These data suggested that mono
iodine and diiodotyrosines are precursors of thyroxin. However, it is also known that the incorporation of iodine is not carried out at the level free thyroxine, but at the level of the polypeptide chain of thyroglobulin in the process of its postsynthetic modification in follicular cells. Further hydrolysis of thyroglobulin under the action of proteinases and peptidases leads to the formation of both free amino acids and the release of iodothyronines, in particular thyroxin, the subsequent deposition of which promotes the formation of triiodothyronine. This point of view seems more plausible, given the universality of postsynthetic chemical modification in the biosynthesis of biologically active substances in the body.
The catabolism of thyroid hormones proceeds in two directions: the breakdown of hormones with the release of iodine (in the form of iodides) and deamination (cleavage of the amino group) of the side chain of hormones. Metabolic products or unchanged hormones are excreted by the kidneys or intestines. It is possible that some of the unchanged thyroxin, entering through the liver and bile into the intestine, is reabsorbed, replenishing the reserves of hormones in the body.
The biological action of thyroid hormones extends to many physiological functions of the body. In particular, hormones regulate the rate of basal metabolism, growth and differentiation of tissues, the metabolism of proteins, carbohydrates and lipids, water and electrolyte metabolism, the activity of the central nervous system, digestive tract, hematopoiesis, the function of the cardiovascular system, the need for vitamins, the body's resistance to infections, etc. The point of application of the action of thyroid hormones, like all steroids (see below), is the genetic apparatus. Specific receptors - proteins - provide transport of thyroid hormones to the nucleus and interaction with structural genes, resulting in an increase in the synthesis of enzymes that regulate the rate of redox processes. It is natural, therefore, that insufficient function of the thyroid gland (hypofunction) or, conversely, increased secretion of hormones (hyperfunction) causes profound disorders of the physiological status of the organism.
Hypothyroidism in early childhood leads to the development of the disease known in the literature as cretinism. In addition to growth arrest, specific changes in the skin, hair, muscles, a sharp decrease in the rate of metabolic processes, with cretinism, profound mental disorders are noted; specific hormonal treatment in this case does not give positive results.
Insufficient function of the thyroid gland in adulthood is accompanied by the development of hypothyroid edema, or myxedema (from the Greek tuha - mucus, oeeeto - edema). This disease is more common in women and is characterized by a violation of the water-salt, basic and fat metabolism. Patients have mucous edema, pathological obesity, a sharp decrease in basal metabolism, hair and teeth loss, general brain disorders and mental disorders. The skin becomes dry, the body temperature drops; elevated blood glucose levels. Hypothyroidism is relatively easy to treat with thyroid medications.
One more thyroid lesion should be noted - endemic goiter. The disease usually develops in people living in mountainous areas where the iodine content in water and plants is not enough. Iodine deficiency leads to a compensatory increase in the mass of thyroid tissue due to the predominant growth connective tissue, however, this process is not accompanied by an increase in the secretion of thyroid hormones. The disease does not lead to serious violations of the functions of the body, although increased in size thyroid creates some inconvenience. Treatment is limited to food fortification, in particular table salt, inorganic iodine.
An increased function of the thyroid gland (hyperfunction) causes the development of hyperthyroidism, known in the literature as "diffuse toxic goiter" (Graves' disease, or Graves' disease). A sharp increase in metabolism is accompanied by an increased breakdown of tissue proteins, which leads to the development of a negative nitrogen balance. Most characteristic manifestation The disease is considered a triad of symptoms: a sharp increase in the number of heart contractions (tachycardia), bulging eyes (exophthalmos) and goiter, i.e. enlarged thyroid gland; patients have a general exhaustion of the body, as well as mental disorders.
With hyperfunction of the thyroid gland and, in particular, toxic goiter shown prompt removal the entire gland or the introduction of 1311 (b- and y-radiation partially destroys the tissue of the gland) and thyroxine antagonists that inhibit the synthesis of thyroid hormones. Such substances include, for example, thiourea, thiouracil (or methylthiouracil).
Oh Oh

Thiourea Thiouracil Methylthiouracil
Reduce the function of the thyroid gland thiocyanate and substances containing the aminobenzene group, as well as microdoses of iodine. The mechanism of action of antithyroid substances has not been completely elucidated. It is possible that they have an inhibitory effect on the enzyme systems involved in the biosynthesis of thyroid hormones.
PANCREATIC HORMONES
The pancreas is a mixed secretion gland. Its exocrine function consists in the synthesis of a number of key digestive enzymes, in particular amylase, lipase, trypsin, chymotrypsin, carboxypeptidase, etc., which enter the intestine with pancreatic juice. The intrasecretory function is performed, as was established in 1902 by L.V. Sobolev, pancreatic islets (islets of Langerhans), consisting of cells different type and hormone-producing, as a rule, the opposite action. So, a- (or A-) cells produce glucagon, b- (or B-) cells synthesize insulin, b- (or B-) cells produce somatostatin and P-cells, a little-studied pancreatic polypeptide. Next, insulin and glucagon will be considered as hormones that have exclusively importance for the life of the organism.
Insulin
Insulin, which got its name from the name of the pancreatic islets (lat. tzi1a - island), was the first protein, the primary structure of which was discovered in 1954 by F. Sanger (see Chapter 1). Pure insulin was obtained in 1922 after its discovery in extracts of pancreatic islets by F. Banting and C. Best. The insulin molecule, containing 51 amino acid residues, consists of two polypeptide chains connected to each other at two points by disulfide bridges. The structure of insulin and its precursor, proinsulin, is shown in Chapter 1 (see Figure 1.14). Currently, it is customary to designate a 21-membered peptide as chain A of insulin and a peptide containing 30 amino acid residues as chain B. In addition, chemical synthesis of insulin has been carried out in many laboratories. The closest in structure to human insulin is porcine insulin, in which alanine is present in the B chain instead of threonine at position 30.
There are no significant differences in the amino acid sequence in insulin from different animals. Insulins are different amino acid composition chain A in positions 8-10.
According to modern concepts, the biosynthesis of insulin is carried out in the β-cells of the pancreatic islets from its precursor proinsulin, first isolated by D. Steiner in 1966. At present, not only the primary structure of proinsulin has been elucidated, but also its chemical synthesis has been carried out (see Fig. 1.14) . Proinsulin is represented by one polypeptide chain containing 84 amino acid residues; it is devoid of biological, i.e. hormonal activity. The site of proinsulin synthesis is considered to be the microsome fraction of β-cells of the pancreatic islets; the conversion of inactive proinsulin into active insulin (the most significant part of the synthesis) occurs when proinsulin moves from ribosomes to secretory granules by partial proteolysis (cleavage from the C-terminus of the polypeptide chain of a peptide containing 33 amino acid residues and called a connecting peptide, or C-peptide ). The length and primary structure of the C-peptide is subject to large changes in different types animals than the sequence of insulin A and B chains. It has been established that the initial precursor of insulin is preproinsulin, which contains, in addition to proinsulin, its so-called leader or signal sequence at the Window, consisting of 23 amino acid residues; during the formation of the proinsulin molecule, this signal peptide is cleaved off by a special peptidase. Further, the proinsulin molecule also undergoes partial proteolysis, and under the action of trypsin-like proteinase, two basic amino acids are cleaved from the K- and C-terminus of the C peptide - respectively, the dipeptides Arg-Arg and Lys--Arg (see Fig. 1.14). However, the nature of enzymes and the subtle mechanisms of this important biological process - the formation of an active insulin molecule - have not been fully elucidated.
Insulin synthesized from proinsulin can exist in several forms, differing in biological, immunological and physical and chemical properties. There are two forms of insulin: 1) free, interacting with antibodies obtained to crystalline insulin, and stimulating the uptake of glucose by muscle and adipose tissues; 2) associated, non-reactive with antibodies and active only in relation to adipose tissue. At present, the existence of a bound form of insulin has been proven and its localization in the protein fractions of blood serum, in particular in the area of ​​transferrins and a-globulins, has been established. The molecular weight of bound insulin is from 60,000 to 100,000. In addition, there is the so-called form A of insulin, which differs from the two previous ones in a number of physicochemical and biological properties, occupies an intermediate position and appears in response to a quick, urgent need of the body for insulin.
The concentration of glucose in the blood plays a dominant role in the physiological regulation of insulin synthesis. Thus, an increase in blood glucose causes an increase in insulin secretion in the pancreatic islets, and a decrease in its content, on the contrary, slows down insulin secretion. This phenomenon of feedback control is considered as one of the most important mechanisms for the regulation of blood glucose. Insulin secretion is also influenced by electrolytes (especially calcium ions), amino acids, glucagon and secretin. Evidence of the role of the cyclase system in insulin secretion is given. It is assumed that glucose acts as a signal for the activation of adenylate cyclase, and cAMP formed in this system acts as a signal for insulin secretion.
With insufficient secretion (more precisely, insufficient synthesis) of insulin, a specific disease develops - diabetes mellitus (see Chapter 10). In addition to clinically detectable symptoms (polyuria, polydipsia and polyphagia), diabetes mellitus is characterized by a number of specific metabolic disorders. Thus, patients develop hyperglycemia (an increase in blood glucose levels) and glycosuria (excretion of glucose in the urine, in which it is normally absent). Metabolic disorders also include an increased breakdown of glycogen in the liver and muscles, a slowdown in the biosynthesis of proteins and fats, a decrease in the rate of glucose oxidation in tissues, the development of a negative nitrogen balance, and an increase in cholesterol and other lipids in the blood. In diabetes, the mobilization of fats from the depot, the synthesis of carbohydrates from amino acids (gluconeogenesis) and the excess synthesis of ketone bodies (ketonuria) increase. After the introduction of insulin to patients, all of the above disorders, as a rule, disappear, but the effect of the hormone is limited in time, so it must be administered continuously. Clinical symptoms And metabolic disorders in diabetes mellitus can be explained not only by the lack of insulin synthesis. Evidence has been obtained that in the second form diabetes, the so-called insulin resistance, there are also molecular defects: in particular, a violation of the structure of insulin or a violation of the enzymatic conversion of proinsulin to insulin. The development of this form of diabetes is often based on the loss by target cell receptors of the ability to bind to an insulin molecule, the synthesis of which is impaired, or the synthesis of a mutant receptor (see below).
In experimental animals, the introduction of insulin causes hypoglycemia (decrease in blood glucose levels), an increase in glycogen stores in muscles, an increase in anabolic processes, and an increase in the rate of glucose utilization in tissues. In addition, insulin has an indirect effect on water and mineral metabolism.
The mechanism of action of insulin has not been definitively deciphered, despite the huge amount of evidence indicating the existence of a close and direct relationship between insulin and metabolic processes in the body. In accordance with the "unitary" theory, all the effects of insulin are caused by its influence on glucose metabolism through the enzyme

Rice. 8.1. Insulin receptor (scheme).
Two a-chains on the outer surface of the cell membrane and two transmembrane p-chains. Binding of insulin to a-chains triggers autophosphorylation of tyrosine residues in p-chains; the active tyrosine kinase domain is then involved in the phosphorylation of inactive target proteins in the cytosol.
hexokinase. New experimental data indicate that the enhancement and stimulation by insulin of processes such as ion and amino acid transport, protein translation and synthesis, gene expression, etc., are independent. This was the basis for the assumption of multiple mechanisms of action of insulin.
Membrane localization of the primary action of almost all protein hormones, including insulin, seems to be the most probable at present. Evidence has been obtained for the existence of a specific insulin receptor on the outer plasma membrane of almost all body cells, as well as the formation of an insulin receptor complex. The receptor is synthesized as a precursor, a polypeptide (1382 amino acid residues, molecular weight 190000), which is further cleaved into ai and p subunits, i.e. on a heterodimer (in the formula a2-P2) linked by disulfide bonds. It turned out that if a-subunits (mol. weight 135000) are almost entirely located on outside biomembranes, performing the function of binding insulin to the cell, then p-subunits (mol. mass 95000) are a transmembrane protein that performs the function of signal conversion (Fig. 8.1). The concentration of insulin receptors on the surface reaches 20,000 per cell, and their half-life is 7-12 hours.
by the most interesting property insulin receptor, different from all other hormone receptors of protein and peptide nature, is its ability to autophosphorylate, i.e. when the receptor itself is endowed with protein kinase (tyrosine kinase) activity. When insulin binds to the a-chains of the receptor, the tyrosine kinase activity of the p-chains is activated by phosphorylation of their tyrosine residues. In turn, the active p-chain tyrosine kinase triggers the phosphorylation-dephosphorylation cascade of protein kinases, in particular, membrane or cytosolic serine or threonine kinases; protein kinases and target proteins, in which phosphorylation is carried out due to the OH groups of serine and threonine. Accordingly, changes in cellular activity take place, in particular, activation and inhibition of enzymes, glucose transport, synthesis of polymer molecules of nucleic acids and proteins, etc.
It should be emphasized, however, that the fine molecular mechanisms of signal transduction pathways from the insulin receptor complex to many intracellular processes have not yet been elucidated. It is quite possible that a number of intracellular second messengers, in particular, cyclic nucleotides, derivatives of phosphatidylinositols, etc., may be involved in such processes. In addition, the possibility of the existence of an intracellular mediator or mediator of insulin action (a special intracellular receptor) that controls gene transcription and, accordingly, mRNA synthesis cannot be ruled out. It is assumed that the action of insulin and participation in the regulation of gene expression or in the transcription of specific mRNAs can explain its role in such fundamental life processes as embryogenesis and differentiation of cells of higher organisms.
Glucagon
Glucagon was first discovered in commercial preparations of insulin as early as 1923, but only in 1953 did the Hungarian biochemist F. Straub obtain this hormone in a homogeneous state. Glucagon is synthesized mainly in the a-cells of the pancreatic islets of the pancreas, as well as in a number of intestinal cells (see below). It is represented by one linearly located polypeptide chain, which includes 29 amino acid residues in the following sequence:
N-G is-Ser-Gln-Gli-Tre-Fen-Tre-Ser-Asp-Tir-Ser-Liz-Tir-Ley- -Asp-Ser-Arg-Arg-Ala-Gln-Asp-Fen-Val- Gln-Trp-Ley-Met-Asn-
-Tre-OH
The primary structure of human and animal glucagons was found to be identical; the only exception is turkey glucagon, which has serine instead of asparagine at position 28. A feature of the structure of glucagon is the absence of disulfide bonds and cysteine. Glucagon is formed from its precursor proglucagon, which contains an additional octapeptide (8 residues) at the C-terminus of the polypeptide, which is cleaved off during postsynthetic proteolysis. There is evidence that proglucagon, like proinsulin, has a precursor - preproglucagon (molecular weight 9000), whose structure has not yet been deciphered.
According to the biological effect, glucagon, like adrenaline, is a hyperglycemic factor that causes an increase in the concentration of glucose in the blood, mainly due to the breakdown of glycogen in the liver. The target organs for glucagon are the liver, myocardium, adipose tissue but not skeletal muscles. The biosynthesis and secretion of glucagon are controlled mainly by the concentration of glucose on the feedback principle. The same property is possessed by amino acids and free fatty acid. Glucagon secretion is also influenced by insulin and insulin-like growth factors.
In the mechanism of action of glucagon, binding to specific receptors of the cell membrane is primary, the resulting glucagon receptor complex activates adenylate cyclase and, accordingly, the formation of cAMP. The latter, being a universal effector of intracellular enzymes, activates protein kinase, which in turn phosphorylates phosphorylase kinase and glycogen synthase. Phosphorylation of the first enzyme promotes the formation of active glycogen phosphorylase and, accordingly, the breakdown of glycogen with the formation of glucose--1-phosphate (see Chapter 10), while phosphorylation of glycogen synthase is accompanied by its transition to an inactive form and, accordingly, blocking of glycogen synthesis. The overall result of the action of glucagon is the acceleration of the breakdown of glycogen and the inhibition of its synthesis in the liver, which leads to an increase in the concentration of glucose in the blood.
The hyperglycemic effect of glucagon is due, however, not only to the breakdown of glycogen. There is indisputable evidence for the existence of a gluconeogenetic mechanism for glucagon-induced hyperglycemia. It has been established that glucagon promotes the formation of glucose from the intermediate products of protein and fat metabolism. Glucagon stimulates the formation of glucose from amino acids by inducing the synthesis of gluconeogenesis enzymes with the participation of cAMP, in particular phosphoenolpyruvate carboxykinase, the key enzyme of this process. Glucagon, unlike adrenaline, inhibits the glycolytic breakdown of glucose to lactic acid, thereby contributing to hyperglycemia. It activates tissue lipase indirectly through cAMP, providing a powerful lipolytic effect. There are also differences in physiological action: unlike adrenaline, glucagon does not increase blood pressure and does not increase heart rate. It should be noted that, in addition to pancreatic glucagon, the existence of intestinal glucagon, which is synthesized throughout the digestive tract and enters the blood, has recently been proven. The primary structure of intestinal glucagon has not yet been accurately deciphered, however, amino acid sequences identical to the K-terminal and middle sections of pancreatic glucagon, but a different C-terminal amino acid sequence, have been discovered in its molecule.
Thus, pancreatic islets, synthesizing two opposite hormone actions - insulin and glucagon, play a key role in the regulation of metabolism at the molecular level.
ADRENAL HORMONES
The adrenal glands consist of two morphologically and functionally individual parts - the medulla and the cortical substance. The medulla belongs to the chromaffin, or adrenal, system and is expressed
It contains hormones that, according to the previous classification, are considered derivatives of amino acids. The cortex is composed of epithelial tissue and secretes steroid hormones.
Adrenal medulla hormones
The ability of extracts from the adrenal glands to increase blood pressure was known as early as the 19th century, but it was not until 1901 that J. Takamine et al. isolated from the adrenal medulla an active principle identified with adrenaline. It was the first hormone obtained in pure crystalline form. More than 40 years later, in 1946, another hormone, norepinephrine, was isolated from the medulla, which had previously been synthesized chemically. In addition to these two main hormones, another hormone is synthesized in the adrenal glands in trace amounts - isopropyradrenaline. All these hormones have a similar structure.

These hormones are similar in structure to the amino acid tyrosine, from which they differ in the presence of additional OH groups in the ring and at the P-carbon atom of the side chain and the absence of a carboxyl group. Indeed, experimental evidence has been obtained that the precursor of the hormones of the adrenal medulla is tyrosine, which undergoes hydroxylation, decarboxylation and methylation reactions with the participation of the corresponding enzymes during the exchange process (see Chapter 12). The biosynthesis of catecholamines (adrenaline and norepinephrine) can be represented as the following simplified scheme:

BUT
Tyrosine
Dihydroxyphenylalanine
(DOPA)

Norepinephrine
Dihydroxyphenylethylamine
(dopamine)

Adrenalin
The adrenal medulla of a 10 g human contains about 5 mg of epinephrine and 0.5 mg of norepinephrine. Their content in the blood is 1.9 and 5.2 nmol/l, respectively. In the blood plasma, both hormones are present both in the free state and in the bound state, in particular, with albumin. Small amounts of both hormones are deposited as a salt with ATP in nerve endings, releasing in response to their irritation. Adrenaline and norepinephrine, like dopamine (see structure), are catecholamines, i.e. to the class of organic substances that have a strong biological effect. In addition, they all have a powerful vasoconstrictor effect, causing an increase blood pressure, and in this respect their action is similar to that of the sympathetic nervous system. The powerful regulating effect of these hormones on the metabolism of carbohydrates in the body is known. So, in particular, adrenaline causes a sharp increase in the level of glucose in the blood, which is due to the acceleration of the breakdown of glycogen in the liver under the action of the enzyme phosphorylase (see Chapter 10). Adrenaline, like glucagon, does not activate phosphorylase directly, but through the adenylate cyclase-cAMP-protein kinase system (see below). The hyperglycemic effect of norepinephrine is much lower - about 5% of the action of adrenaline. In parallel, there is an accumulation of hexose phosphates in tissues, in particular in muscles, a decrease in the concentration of inorganic phosphate and an increase in the level of unsaturated fatty acids in the blood plasma. There is evidence of inhibition of glucose oxidation in tissues under the influence of adrenaline. Some authors attribute this action to a decrease in the rate of penetration (transport) of glucose into the cell. The mechanism of action of catecholamines, including a- and p-adrenergic receptors, the adenylate cyclase system, and other factors, is discussed at the end of this chapter.
It is known that both epinephrine and norepinephrine are rapidly destroyed in the body; inactive products of their metabolism are excreted in the urine, mainly in the form of 3-methoxy-4-hydroxymandelic acid, oxoadrenochrome, methoxynorepinephrine and methoxyadrenaline. These metabolites are found in the urine mainly in the form associated with glucuronic acid. The enzymes that catalyze the indicated transformations of catecholamines have been isolated from many tissues and are fairly well studied, in particular, monoamine oxidase (MAO), which determines the rate of biosynthesis and degradation of catecholamines, and catechol methyltransferase, which catalyzes Main way conversion of adrenaline, i.e. o-methylation due to 8-adenosylmethionine. We give the structure of two final products breakdown of catecholamines:

3-Methoxy-4-hydroxyalmond
acid
Hormones of the adrenal cortex
From the second half of XIX V. a disease called bronze disease, or Addison's disease, is known, after the name of the author who first described it. The disease is characterized by increased pigmentation of the skin, muscle
weakness, dysfunction of the digestive tract, a sharp violation water-salt metabolism and metabolism of proteins and carbohydrates. As established, the disease is based on tuberculous lesion of the adrenal glands, which leads to insufficiency or lack of synthesis of hormones in the cortical substance.
In Addison's disease, metabolic disorders are expressed by a sharp decrease in the concentration of sodium and chlorine ions and an increase in the level of potassium ions in the blood and muscles, loss of water by the body and a decrease in blood glucose levels. Protein metabolism disorders are manifested by a decrease in the synthesis of proteins from amino acids and an increase in the level of residual nitrogen in the blood.
Previously, the disease was considered incurable and patients, as a rule, died. After establishing the etiology of the disease and introducing antibiotics into medical practice and specific means tuberculosis therapy the disease is treatable.
Chemical structure, biosynthesis and biological action of corticosteroids
To date, about 50 different compounds have been isolated from the adrenal cortex of humans, pigs, and bulls. common name"corticoids", or "corticosteroids". The total number of all steroids that are synthesized in the adrenal glands of many animals approaches 100, but not all corticosteroids are endowed with biological activity.
Depending on the nature of the biological effect, the hormones of the adrenal cortex are conditionally divided into glucocorticoids (corticosteroids that affect the metabolism of carbohydrates, proteins, fats and nucleic acids) and mineralocorticoids (corticosteroids that have a predominant effect on the metabolism of salts and water). The former include corticosterone, cortisone, hydrocortisone (cortisol), 11-deoxycortisol and 11-dehydrocorticosterone, while the latter include deoxycorticosterone and aldosterone.
Their structure, as well as the basis of the structure of cholesterol, ergosterol, bile acids, B vitamins, sex hormones and a number of other substances, is based on the condensed ring system of cyclopentanperhydrophenanthrene (see Chapter 7).
For hormones of the adrenal cortex endowed with biological activity, the presence of 21 carbon atoms was common in the structure; consequently, they are all derivatives of pregnane. In addition, the following structural features are characteristic of all bioactive hormones of the adrenal cortex: the presence of a double bond between the 4th and 5th carbon atoms, a ketone group (C=O) at the 3rd carbon atom, a side chain (-CO-CH2 -OH) at the 17th carbon atom.
In humans and most animals, the 5 hormones of the adrenal cortex are most common.

Pregnane Corticosterone Hydrocortisone (cortisol)

Cortisone Desoxynorthinosterone Aldosterone
It has been established that the precursor of corticosteroids is cholesterol(ol) and the process of steroidogenesis, like normal histological structure and adrenal mass, is regulated by pituitary ACTH. In turn, the synthesis of ACTH in the pituitary gland, and hence corticosteroids in the adrenal cortex, is regulated by the hypothalamus, which, in response to stressful situations secretes corticoliberin. There is undeniable evidence of a fast (short-term) and slow (chronic) effect of ACTH on the adrenal glands, and in the acute case, the gland tissue responds with a short-term increase in the synthesis of corticosteroids, while with chronic exposure to ACTH, its trophic effect is noted, which boils down to stimulating all metabolic processes, providing growth and reproduction of gland cells, as well as a prolonged increase in the secretion of steroid hormones. It should be noted that the action of ACTH is also mediated through a specific receptor and the adenylate cyclase-cAMP-protein kinase system.
Experimental evidence of the inducing effect of corticosteroids on the synthesis of specific mRNA and, accordingly, protein synthesis has been obtained.
It is assumed that the mechanisms of this action of steroids include the penetration of the hormone due to its easy solubility in fats through the lipid bilayer of the cell membrane, the formation of a steroid receptor complex in the cytoplasm of the cell, the subsequent transformation of this complex in the cytoplasm, rapid transport to the nucleus and its binding to chromatin. It is believed that both acidic chromatin proteins and DNA itself are involved in this process. The concept has been developed
about the existence in the body of a certain sequence of the mechanism of corticosteroid regulation of metabolism:
HORMONE -> GENE -> PROTEIN (ENZYME).
The main biosynthetic pathway for corticosteroids involves the sequential enzymatic conversion of cholesterol(ol) to pregnenolone, which is the precursor of all steroid hormones (Fig. 8.2).

Isocaproaldehyde
Rice. 8.2. Biosynthesis of pregnenolone, a precursor of steroid hormones. K denotes the ring structures (A, B, C) of cholesterol.
Enzymes catalyze at least two successive hydroxylation reactions and the reaction of cleavage of the side chain of cholesterol (in the form of isocaproic acid aldehyde). Cytochrome P-450 is involved as an electron carrier in a complex oxygenase system, in which electron transport proteins, in particular adrenodoxin and adrenodoxin reductase, also take part.
Further stages of steroidogenesis are also catalyzed by a complex hydroxylation system, which is open in the mitochondria of the cells of the adrenal cortex; the sequence of all these reactions in the synthesis of steroid hormones is summarized in general scheme according to N.A. Yudaev and S.A. Afinogenova.
Glucocorticoids have a versatile effect on the metabolism in different tissues. In muscle, lymphatic, connective and adipose tissues, glucocorticoids, showing a catabolic effect, cause a decrease in the permeability of cell membranes and, accordingly, inhibition of the absorption of glucose and amino acids; while in the liver they have the opposite effect. The end result of exposure to glucocorticoids is the development of hyperglycemia, mainly due to gluconeogenesis.
The mechanism for the development of hyperglycemia after the administration of glucocorticoids also includes a decrease in glycogen synthesis in muscles, inhibition of glucose oxidation in tissues, and increased fat breakdown (respectively, the preservation of glucose reserves, since free fatty acids are used as an energy source).
The inducing effect of cortisone and hydrocortisone on the synthesis of certain enzyme proteins in the liver tissue has been proven: tryptophan pyrrolase, tyrosine transaminase, serine and threonine dehydratases, etc.
Mineralocorticoids (deoxycorticosterone and aldosterone) regulate mainly the exchange of sodium, potassium, chlorine and water; they contribute to the retention of sodium and chloride ions in the body and the excretion of potassium ions in the urine. Apparently, there is a reverse absorption of sodium and chlorine ions in the tubules of the kidneys in exchange for the excretion of other metabolic products,

in particular urea. Aldosterone got its name based on the presence of an aldehyde group at the 13th carbon atom in its molecule instead of a methyl group, like all other corticosteroids. Aldosterone is the most active mineralocorticoid among other corticosteroids; in particular, it is 50-100 times more active than deoxycorticosterone in terms of its effect on mineral metabolism.
It is known that the half-life of corticosteroids is only 70-90 minutes. Corticosteroids undergo either reduction due to the breaking of double bonds (and the addition of hydrogen atoms), or oxidation, which is accompanied by the elimination of the side chain at the 17th carbon atom, in both cases the biological activity of hormones is reduced. The resulting products of oxidation of the hormones of the adrenal cortex are called 17-ketosteroids; they are excreted in the urine as metabolic end products, and in men they are also the end products of male sex hormone metabolism. Determination of the level of 17-ketosteroids in the urine has a large clinical significance. Normal daily urine contains 10 to 25 mg of 17-ketosteroids in men and 5 to 15 mg in women. Increased excretion is observed, for example, in tumors of the interstitial tissue of the testes, while in other testicular tumors it is normal. In tumors of the adrenal cortex, the excretion of 17-ketosteroids in the urine sharply increases, up to 600 mg per day. Simple hyperplasia of the cortical substance is accompanied by a moderate increase in the level of ketosteroids in the urine. For differential diagnosis tumors or simple hyperplasia, a separate definition of α- and β-17-ketosteroids is commonly used. Reduced excretion of 17-ketosteroids in the urine is noted with eunuchoidism, hypofunction of the anterior pituitary gland. At Addison's disease in men, the excretion of 17-ketosteroids is sharply reduced (from 1 to 4 mg / day), and in women with this disease, it is practically not observed. This fact confirms the previously noted position that 17-ketosteroids are formed not only from the hormones of the adrenal cortex, but also from male sex hormones. With myxedema (hypofunction of the thyroid gland), the daily amount of excreted 17-ketosteroids is close to the minimum level (2-4 mg). It should be pointed out, however, that the use of thyroid hormones, although effective in the treatment of the underlying disease, has little effect on the amount of 17-ketosteroids excreted in the urine.
The hormones of the adrenal cortex are currently widely used in clinical practice as medicines. The use of cortisone therapeutic purpose was the result of a random observation. It has been observed that during pregnancy, the severity of symptoms of rheumatoid arthritis decreases dramatically, however, all these symptoms reappear after childbirth. It turned out that during pregnancy there is an acceleration of the secretion of hormones of the adrenal cortex and their entry into the blood. Parallel histological examination of the adrenal glands showed a sharp increase in the growth and proliferation of cortical cells. These observations suggested the use of adrenal cortex hormones, in particular cortisone, in the treatment of rheumatoid arthritis. The results of the treatment were so effective that in the first years of cortisone use, some authors observed an almost 100% cure for arthritis of rheumatic origin. With anti-inflammatory, anti-allergic and anti-immune activity, glucocorticoids have been found wide application during treatment
diseases such as bronchial asthma, rheumatoid arthritis, lupus erythematosus, pemphigus, hay fever, various autoimmune diseases, dermatoses, etc. However, long-term use corticosteroid drugs can lead to serious metabolic disorders in the body.
SEX HORMONES
Sex hormones are synthesized mainly in the sex glands of women (ovaries) and men (testes); a certain amount of sex hormones is formed, in addition, in the placenta and the adrenal cortex. It should be noted that a small amount of female hormones and, conversely, a small amount of male sex hormones is synthesized in the ovaries. This position is confirmed by studies of the chemical nature of hormones with some pathological conditions when there are sharp shifts in the ratio of the synthesis of male and female sex hormones.
female sex hormones
The main place for the synthesis of female sex hormones - estrogens (from the Greek. 0181G08 - passionate attraction) - are the ovaries and corpus luteum; the formation of these hormones in the adrenal glands, testes and placenta has also been proven. Estrogens were first discovered in 1927 in the urine of pregnant women, and in 1929 A. Butenandt and at the same time E. Doisy isolated estrone from urine, which turned out to be the first steroid hormone obtained in crystalline form.
Currently, 2 groups of female sex hormones have been discovered, differing in their chemical structure and biological function: estrogens (the main representative is estradiol) and progestins (the main representative is progesterone). We give the chemical structure of the main female sex hormones:

The most active estrogen - estradiol, is synthesized mainly in the follicles; the other two estrogens are derivatives of estradiol and are also synthesized in the adrenal glands and placenta. All estrogens are made up of 18 carbon atoms. The secretion of estrogens and progesterone by the ovary is cyclical, depending on the phase of the sexual cycle: in the first phase of the cycle, mainly estrogens are synthesized, and in the second, mainly progesterone.
The precursor of these hormones, like corticosteroids, in the body is cholesterol, which undergoes successive reactions of hydroxylation, oxidation, and side chain cleavage to form pregnenolone. The synthesis of estrogens is completed by a unique aromatization reaction of the first ring, catalyzed by the aromatase microsomal enzyme complex. It is believed that the aromatization process involves at least three oxidase reactions, all of which depend on cytochrome P-450.
It should be noted that during pregnancy in female body there is another endocrine organ that produces estrogen and progesterone, the placenta. It has been established that one placenta cannot synthesize steroid hormones and is functionally complete. endocrine organ, most likely, is a complex of the placenta and the fetus - the fetoplacental complex (from lat. Goeshz - fetus). A feature of the synthesis of estrogens is also that the starting material - cholesterol - is supplied by the mother's body; in the placenta, sequential conversions of cholesterol into pregnenolone and progesterone are carried out. Further synthesis is carried out only in the tissues of the fetus.
The leading role in the regulation of estrogen and progesterone synthesis is played by the pituitary gonadotropic hormones (follitropin and lutropin), which indirectly, through ovarian cell receptors and the adenylate cyclase-cAMP system and, most likely, through the synthesis of a specific protein, control hormone synthesis. Main biological role estrogen and progesterone, the synthesis of which begins after puberty, is to ensure the reproductive function of the woman's body. During this period, they cause the development of secondary sexual characteristics and create optimal conditions, providing the possibility of fertilization of the egg after ovulation. Progesterone performs a number of specific functions in the body: it prepares the uterine mucosa for successful egg implantation in the event of its fertilization, and when pregnancy occurs, the main role is to maintain pregnancy; It has an inhibitory effect on ovulation and stimulates the development of breast tissue. Estrogens have anabolic action on the body by stimulating protein synthesis.
The breakdown of estrogens seems to occur in the liver, although the nature of the bulk of their metabolic products excreted in the urine has not yet been elucidated. They are excreted in the urine as esters with sulfuric or glucuronic acid, with estriol excreted predominantly as a glucuronide and estrone ester with sulfuric acid. Progesterone is first converted in the liver to the inactive pregnanediol, which is excreted in the urine as an ester of glucuronic acid.
IN medical practice natural hormones and synthetic drugs with estrogenic activity, which, unlike the former, are not destroyed in the digestive tract, have been widely used. Synthetic estrogens include diethylstilbestrol and sinestrol, which are derivatives of the hydrocarbon stilbene.

Diethylstilbestrol
Sinestrol
Both of these drugs and a number of other stilbene derivatives have also found application in oncological practice: they inhibit the growth of prostate tumors.
male sex hormones
The intrasecretory function of the male gonads was established in 1849, but only in 1931 A. Butenandt isolated a hormone in crystalline form from the urine of men, which had a stimulating effect on the growth of the cock's comb of capons. This hormone was named androsterone (from the Greek apegos-male, and its proposed chemical structure was confirmed by a chemical synthesis carried out in 1934 simultaneously by A. Butenandt and L. Ruzicka. Later, another hormone, dehydroepiandrosterone, was isolated from the urine of men, which possessed less biological activity.Further on, the group of C19-steroids (consisting of 19 carbon atoms), which have the ability to accelerate the growth of the cockscomb, was called androgens.At the same time, the hormone isolated from the testicular tissue turned out to be almost 10 times more active than androsterone and was identified in the form of testosterone (from lat. 1e8118-testis).The structure of all three androgens can be represented as follows:

Testosterone
Androgens, unlike estrogens, have two angular methyl groups (at C10 and C13 atoms); in contrast to the aromatic nature of the A ring of estrogens, testosterone also contains a ketone group (as do corticosteroids).
The biosynthesis of androgens is carried out mainly in the testes and partly in the ovaries and adrenal glands. The main sources and precursors of androgens, in particular testosterone, are acetic acid and cholesterol. There is experimental evidence that the testosterone biosynthetic pathway from the cholesterol stage involves several successive enzymatic reactions via pregnenolone and 17-a-hydroxypregnenolone (see earlier). The regulation of androgen biosynthesis in the testes is carried out by pituitary gonadotropic hormones (LH and FSH), although the mechanism of their primary effect has not yet been elucidated; in turn, androgens regulate the secretion of gonadotropins by a negative feedback mechanism, blocking the corresponding centers in the hypothalamus.
The biological role of androgens in male body mainly related to differentiation and function reproductive system, and, unlike estrogens, androgenic hormones already in the embryonic period have a significant effect on the differentiation of the male gonads, as well as other tissues, determining the nature of the secretion of gonadotropic hormones in adults. In the adult body, androgens regulate the development of male secondary sexual characteristics, spermatogenesis in the testes, etc. It should be noted that androgens have a significant anabolic effect, expressed in the stimulation of protein synthesis in all tissues, but to a greater extent in muscles. To realize the anabolic effect of androgens necessary condition is the presence of somatotropin. There is evidence of the participation of androgens in the regulation of the biosynthesis of macromolecules in female reproductive organs, in particular mRNA synthesis in the uterus.
The breakdown of male sex hormones in the body is carried out mainly in the liver along the path of formation of 17-ketosteroids (see earlier). The half-life of testosterone does not exceed several tens of minutes. In adult men, no more than 1% of unchanged testosterone is excreted in the urine, which indicates its splitting mainly in the liver to the final metabolic products. Dehydroepiandrosterone is mainly excreted in the urine unchanged. In some diseases, urinary excretion of hydroxylated forms of androgens increases with an equivalent decrease in the excretion of classical forms of 17-ketosteroids. The possibility of the formation of 17-ketosteroids from testosterone in women should also be pointed out. Featured high level incidence of breast cancer in women with reduced excretion of 17-ketosteroids. Testosterone and its synthetic analogues (testosterone-propionate) have found application in medical practice as drugs in the treatment of cancerous tumor mammary gland.
PROSTAGLANDINS
The term "prostaglandins" was introduced by W. Euler, who first showed that human sperm and extracts from ram seminal vesicles contain substances that have a pronounced vasopressor effect and cause contraction of the smooth muscles of the uterus. W. Euler's suggestion that these substances are a specific secretion of the prostate gland (programla) has not been confirmed, since, as has now been established, they are found in all organs and tissues. Nevertheless, this term has been preserved in the literature (synonyms: prostaglandins, prostaglandins).
In the last decade, prostaglandins and related biologically active compounds (leukotrienes, prostacyclins, thromboxanes) have been the subject of close attention of researchers. This is explained by the fact that, in addition to being widely distributed in tissues, they have a strong pharmachologic effect on many physiological functions of the body, regulating the hemodynamics of the kidneys, the contractile function of smooth muscles, the secretory function of the stomach, fat, water-salt metabolism, etc. There is evidence that prostaglandins are probably not "true" hormones, although some authors consider them "local , local hormones", however, they have been shown to modulate the action of hormones. The biological effects of prostaglandins appear to be mediated through cyclic nucleotides (see below).
Recently, the ideas of S. Bergström et al. have been confirmed that the precursors of all prostaglandins are polyunsaturated fatty acids, in particular arachidonic acid (and a number of its derivatives, dihomo-y-linolenic and pentanoic acids, which in turn are formed in the body from linoleic and linolenic acids) (see chapter 11). Arachidonic acid, after being released from phosphoglycerols (phospholipids) of biomembranes under the action of specific phospholipases A (or C), depending on the enzymatic pathway of transformation, gives rise to prostaglandins and leukotrienes according to the scheme:

Prostanoids
Leukotrienes (LT)
Prostaglandins
Prostacyclins
Thromboxanes (Tx)
LTA
LTV
LTS
LTE
The first pathway is called the cyclooxygenase pathway. arachidonic acid, since the first stages of prostaglandin synthesis are catalyzed by cyclooxygenase, more precisely prostaglandin synthase (EC 1.14.99.1). Biosyn data are currently known

soon
Thromboxane B2 (Tx B2)

BUT" about
6,15-Diketoprostaglandin P1a
Rice. 8.3. Cyclooxygenase pathway for the conversion of arachidonic acid.
K1 and K2 are side chains that are identical for all three prostaglandins. The sign 0 denotes the blocking effect of these substances.
thesis of the main prostanoids (Fig. 8.3). The central chemical process of biosynthesis is the incorporation of molecular oxygen (two molecules) into the structure of arachidonic acid, carried out by specific oxygenases, which, in addition to oxidation, catalyze cyclization with the formation of intermediate products - prostaglandin endoperoxides ROD], denoted P002 and ROH2; the latter, under the action of prostaglandin isomerases, are converted into primary prostaglandins. Distinguish
class of primary prostaglandins: ether-soluble POE prostaglandins and POE-soluble prostaglandins in phosphate buffer. Each of the classes is divided into subclasses: POE1, POE2, POE1, POE2, etc. Prostacyclins and thromboxanes are synthesized from these intermediates with the participation of enzymes other than isomerases. The details of the mechanism of biosynthesis of prostanoids have not yet been fully elucidated, as well as the ways of their oxidation to the final products of metabolism.
Primary prostaglandins are synthesized in all cells (with the exception of erythrocytes), act on the smooth muscles of the digestive tract, reproductive and respiratory tissues, on vascular tone, modulate the activity of other hormones, autonomously regulate nervous excitement, inflammation processes (mediators), the rate of renal blood flow; their biological action is mediated by regulation of cAMP synthesis (see below).
Thromboxane A, in particular thromboxane Az (TxA^), is synthesized mainly in the tissues of the brain, spleen, lungs, kidneys, as well as in platelets and inflammatory granuloma from ROI2 under the action of thromboxane synthase (see Fig. 8.3); from TxA2, other thromboxanes, which cause platelet aggregation, thereby promoting thrombus formation, and, in addition, have the most powerful vasoconstrictive effect of all prostaglandins.
Prostacyclin (PC12) is synthesized predominantly in the vascular endothelium, cardiac muscle, uterine tissue, and gastric mucosa. It relaxes as opposed to thromboxane smooth muscle fibers vessels and causes platelet disaggregation, promoting fibrinolysis.
We should also point out the special significance of the blood thromboxane/prostacycline ratio, in particular TxA2/P012, for the physiological status of the organism. It turned out that in patients predisposed to thrombosis, there is a tendency to shift the balance towards aggregation; in patients suffering from uremia, on the contrary, platelet disaggregation is observed. It has been suggested that the balance of TxA2/P012 is important for the regulation of platelet function in vivo, cardiovascular homeostasis, thrombotic disease, etc.
On fig. 8.3 also presents the catabolism pathways of prostanoids. initial stage The catabolism of "classical" prostaglandins is the stereospecific oxidation of the OH group at the 15th carbon atom with the formation of the corresponding 15-keto derivative. The enzyme catalyzing this reaction, 15-hydroxyprostaglandin dehydrogenase, is open in the cytoplasm and requires the presence of NAD or NADP. Thromboxane is inactivated by y1yo either by chemical cleavage to thromboxane B2 or by oxidation by dehydrogenase or reductase. Similarly, P012 (prostacyclin) rapidly decomposes to 6-keto-POP1a with VyGO, and t V1VO is inactivated by oxidation by 15-hydroxyprostaglandin dehydrogenase to form 6,15-diketo-POP1a.
The second pathway for the conversion of arachidonic acid, the lipoxygenase pathway (Fig. 8.4), differs in that it gives rise to the synthesis of another class of biologically active substances, leukotrienes. Feature structure of leukotrienes lies in the fact that it does not contain a cyclic structure, although leukotrienes, like prostanoids, are built from 20 carbon atoms. The structure of leukotrienes contains four double bonds, some of them form peptidolipid complexes with glutathione or with its constituent parts(leukotriene B can be further converted to leukotriene E, losing a glycine residue). The main biological effects of leukotrienes are associated with inflammatory processes, allergic and immune reactions, anaphylaxis and smooth muscle activity. In particular, leukotrienes promote smooth muscle contraction. respiratory tract, digestive tract, regulate vascular tone (have a vasoconstrictive effect) and stimulate contraction coronary arteries. The catabolic pathways of leukotrienes have not been definitively established.
/=H/=h^/C00n \-
Arachidonic acid
°2^ Lipoxygenase Vitamin E -I.
Vitamin E -C- / "h
/^/-\^soono[o1n
/ \u003d hh ^ \u003d H / ^ C00n
L/"H/
He
He
/=week^soon
N A ^y\y*
, ^ hvhh y\ y-COOH
¦ 5H11 3-CH2-CH-CO-MH-CH2-COOH
mn-so-sng-sn2-sn-soon
1
N1-1,

Leukotriene C
y-Glutamyltransferase
UNSD
"5 11 5-CH2“CH-CO-MH-CH2-COOH
N42 Leukotriene R
Rice. 8.4. Lipoxygenase pathway for the conversion of arachidonic acid.
K is a glutamic acid residue acceptor. The © symbol indicates the blocking effect of vitamin E.
Thus, thanks to its widespread in tissues and high and versatile biological activity, prostaglandins (and prostanoids in general) and leukotrienes are increasingly used in medical practice as drugs. These circumstances stimulate further research both in the search for new prostanoids and in the chemical synthesis of their analogs with protected functional groups that are more stable when introduced into the body.
HORMONES OF THE THYMUS GLAND (THYMUS)
The role of the thymus as an endocrine gland has long been known. It is also known that the thymus, shortly after the birth of a child, supplies lymphoid cells to The lymph nodes and spleen and carries out the formation and secretion of specific hormones that affect the development and maturation of certain cells lymphoid tissue. However, the chemical nature of hormone-active preparations remained unknown, although it was clearly shown in animal experiments that the cell-free thymus extract affects both the growth of the whole organism and the development and maintenance of immunological competence, providing normal functioning cellular and humoral immunity.
To date, several hormones have been isolated and characterized from thymus gland extracts, mainly represented by low molecular weight polypeptides. They influence Various types lymphoid cells performing specific functions. Here is the primary structure of thymopoietin II, isolated from the calf thymus, which seems to be the main hormone that stimulates the formation of T-lymphocytes.
N-Ser-Gln-Fen-Ley-G lu-Asp-Pro-Ser-Val-Ley-Tre-Liz-G li-Liz-Ley-Liz-
-Ser-Glu-Ley-Val-Ala-Asn-Asn-Val-Tre-Ley-Pro-Ala-Gli-Glu-Gln-Arg-.Liz-
-Asp-Val-Tyr-Val-Gln-Ley-Tyr-Ley-Glu-Tre-Ley-Tre-Ala-Val-Liz-Arg-ON
Thymopoietin II consists of 49 amino acid residues. It is assumed that the active center of the hormone is a pentapeptide (it is highlighted in red and occupies the 32-36th position from the K-terminus). Recently, this short five-membered peptide was synthesized chemically and received the name "timopentin-5"; when introduced into the body, it enhances non-specific factors protection.
Another hormone isolated by A. Goldstein et al. from the thymus gland of a calf, is thymosin a1 (28 amino acid residues) of the following structure:
N-Ser-Asp-Ala-Ala-Val-Asp-T re-Ser-Ser-Glu-Ile-T re-T re-Liz- -Asp-Ley-Liz-Glu-Liz-Liz-Glu-Val- Val-Glu-Glu-Ala-Glu-Asn-ON
It is assumed that thymosin a1 in the body performs a regulatory function on late stages differentiation of T cells. It is also shown that it has a pronounced pharmacological effect in the treatment of leukemia and immune deficiency.
Recently, a new thymus hormone (nonapeptide) has been obtained that induces T-cell differentiation. For the manifestation of its biological activity, the presence of divalent zinc ions is required. The zinc-containing hormone has a peculiar configuration.
In addition to hormones of a peptide nature, an active non-polar fraction has been isolated from the thymus, similar in biological properties to steroid hormones, called thymosterol; its nature has not yet been deciphered.
Not all currently known hormonal substances are described in this chapter. Yes, in pineal gland(pineal gland) from the amino acid tryptophan, an interesting, but little studied hormone melatonin is synthesized. More than 20 biologically active hormones are isolated from the digestive tract. The most studied of them are gastrin
and gastrin II (17 and 14 amino acid residues, respectively), regulating secretion gastric juice; progastrin (34 BAM), considered the circulating form of the prohormone in the blood and converted to active gastrin I in the cells of the target organ, as well as glucagon and secretin (27 BAM) (the latter was the first substance identified as a hormone). In addition, somatostatin is synthesized in the intestinal mucosa. It has been suggested that interstitial somatostatin and glucagon regulate the secretion of hormones synthesized in the hypothalamus and pancreas, respectively. Information about other hormones, including plant hormones, can be partially found in chapters 12, 17 or in the specialized literature.
MOLECULAR MECHANISMS OF HORMONAL SIGNAL TRANSMISSION
In this chapter, the chemical structure of most known hormones and other biologically active hormone-like substances was considered, as well as clinical picture deficiency or overproduction. In some cases, the biological effects of hormones are given without a detailed consideration of the mechanisms of metabolism regulation. Despite the huge variety of hormones and hormone-like substances, the biological action of most hormones is based on surprisingly similar, almost identical fundamental mechanisms that transmit information from one cell to another. Below, examples of the mechanisms of action of hormones of a peptide (including amino acid derivatives) and steroid nature will be presented. E. Sutherland's research and the discovery of cyclic adenosine monophosphate (see below) have played a huge role in modern ideas about the fine molecular mechanisms of the biological action of most hormones.
It is known that the direction and fine regulation of the process of information transmission are provided primarily by the presence on the surface of cells of receptor molecules (most often proteins) that recognize the hormonal signal (see Insulin receptors). The receptors transform this signal into a change in the concentrations of intracellular mediators, called second messengers, the level of which is determined by the activity of enzymes that catalyze their biosynthesis and decay.
By their chemical nature, the receptors of almost all biologically active substances turned out to be glycoproteins, and the “recognizing” domain (site) of the receptor is directed towards the intercellular space, while the site responsible for the coupling of the receptor with the effector system (with an enzyme, in particular) is located inside (in the thickness) of the plasma membrane. common property of all receptors is their high specificity for one particular hormone (with an affinity constant of 0.1 to 10 nM). It is also known that the coupling of the receptor with effector systems is carried out through the so-called O-protein, the function of which is to ensure the repeated conduction of the hormonal signal at the level of the plasma membrane.
wounds. O-protein in an activated form stimulates the synthesis of cyclic AMP through adenylate cyclase, which triggers a cascade mechanism for activating intracellular proteins.
The general fundamental mechanism through which the biological effects of "secondary" messengers inside the cell are realized is the process of phosphorylation - dephosphorylation of proteins with the participation of a wide variety of protein kinases that catalyze the transport of the end group from ATP to the OH groups of serine and threonine, and in some cases, protein tyrosine - targets. The process of phosphorylation is the most important post-translational chemical modification of protein molecules, radically changing both their structure and functions. In particular, it causes a change in structural properties (association or dissociation of constituent subunits), activation or inhibition of their catalytic properties, ultimately determining the rate of chemical reactions and, in general, the functional activity of cells.
Adenylate cyclase messenger system
The most studied is the adenylate cyclase pathway of hormonal signal transmission. It involves at least five well-studied proteins: 1) the hormone receptor; 2) the enzyme adenylate cyclase, which performs the function of synthesis of cyclic AMP (cAMP); 3) O-protein, carrying out the connection between adenylate cyclase and the receptor; 4) cAMP-dependent protein kinase, catalyzing the phosphorylation of intracellular enzymes or target proteins, respectively changing their activity; 5) phosphodiesterase, which causes the breakdown of cAMP and thereby terminates (breaks) the action of the signal (Fig. 8.5).
α- and β-adrenergic receptors were obtained in pure form from the plasma membranes of liver cells, muscles and adipose tissue. It has been shown that the binding of the hormone to the β-adrenergic receptor leads to structural changes the intracellular domain of the receptor, which in turn ensures the interaction of the receptor with the second protein of the signaling pathway, GTP-binding.
GTP-binding protein-O-protein is a mixture
types of proteins: active O8 (from the English. 8Ishi1a1ogu O) and inhibitory O4 with a mol. weighing 80000-90000. Each of them has three different subunits (a-, b- and y-), i.e. they are heterotrimers. It was shown that the O8 and O4 β-subunits are identical (molecular weight 35000); at the same time, a-subunits, which are products of different genes (molecular weight 45,000 and 41,000), turned out to be responsible for the manifestation of activator and inhibitory activity by the O-protein.
Rice. 8.5. Adenylate cyclase pathway of hormonal signal transduction.
Rets - receptor; O - O-protein; AC - adenylate cyclase.
noah activity, respectively. The hormone receptor complex gives the O-protein the ability not only to easily exchange endogenous bound GDP for GTP, but also to transfer the O8-protein to an activated state, while the active O-protein dissociates in the presence of Mg2+ ions into β-, γ-subunits and a complex a-subunits O8 in the GTP form; this active complex then moves to the adenylate cyclase molecule and activates it. The complex itself then undergoes self-inactivation due to the decay energy of GTP and reassociation of the β- and γ-subunits with the formation of the initial GDP form O8.
Adenylate cyclase is an integral protein of plasma membranes, its active center is oriented towards the cytoplasm and catalyzes the reaction of cAMP synthesis from ATP:

ATP 3",5"-cAMP
The catalytic component of adenylate cyclase, isolated from different tissues of animals, is represented by one polypeptide with a mol. weighing 120000-150000; in the absence of O-proteins, it is practically inactive; contains two SH groups, one of which is involved in conjugation with the O8 protein, and the second is necessary for the manifestation of catalytic activity. There are several allosteric centers in the enzyme molecule, through which the activity is regulated by low molecular weight compounds: Mg2+, Mn2+ and Ca2+ ions, adenosine and forskolin. Under the action of phosphodiesterase, cAMP is hydrolyzed to form inactive 5'-AMP.
Protein kinase is an intracellular enzyme through which cAMP realizes its effect. Protein kinase can exist in 2 forms. In the absence of cAMP, protein kinase is presented as a tetrameric complex consisting of two catalytic (C2) and two regulatory (K,) subunits with a mol. masses 49000 and 38000 respectively; in this form, the enzyme is inactive. In the presence of cAMP, the protein kinase complex reversibly dissociates into one K, subunit and two free catalytic C subunits; the latter have enzymatic activity, catalyzing the phosphorylation of proteins and enzymes, thus changing the cellular activity.
Inactive
protein kinase

Rice. 8.6. Covalent regulation of glycogen phosphorylase.
It should be noted that a large class of cAMP-dependent protein kinases, called protein kinases A, has been discovered in cells; they catalyze the transfer of a phosphate group to the OH groups of serine and threonine (the so-called serine-threonine kinases). Another class of protein kinases, in particular those activated by the insulin receptor (see above), acts only on the OH group of tyrosine. However, in all cases, the addition of a highly charged and bulky phosphate group causes not only conformational changes in phosphorylated proteins, but also changes their activity or kinetic properties.
The activity of many enzymes is regulated by cAMP-dependent phosphorylation; accordingly, most hormones of a protein-peptide nature activate this process. However, a number of hormones have an inhibitory effect on adenylate cyclase, respectively, reducing the level of cAMP and protein phosphorylation. In particular, the hormone somatostatin, by combining with its specific receptor-inhibitory O-protein (O4, which is a structural homologue of the O8-protein (see earlier), inhibits adenylate cyclase and cAMP synthesis, i.e. causes an effect that is directly opposite to that caused by adrenaline and glucagon In a number of organs, prostaglandins (in particular, POE1) also have an inhibitory effect on adenylate cyclase, although in the same organ (depending on the cell type) the same POE1 can activate cAMP synthesis.
The mechanism of activation and regulation of muscle glycogen phosphorylase, which activates the breakdown of glycogen, has been studied in more detail. There are 2 forms: catalytically active - phosphorylase and inactive - phosphorylase. Both phosphorylases are built from two identical subunits (mol. weight 94500), in each the serine residue in position 14 undergoes the process of phosphorylation-dephosphorylation, respectively, activation and inactivation (Fig. 8.6).
Under the action of phosphorylase b kinase, whose activity is regulated by cAMP-dependent protein kinase, both subunits of the molecule of the inactive form of phosphorylase b undergo covalent phosphorylation and are converted into active phosphorylase a. Dephosphorylation of the latter under the action of a specific phosphatase phosphorylase a leads to enzyme inactivation and a return to its original state.
IN muscle tissue 3 types of glycogen phosphorylase regulation have been discovered. The first type is covalent regulation based on hormone-dependent phosphorylation-dephosphorylation of phosphorylase subunits (see Fig. 8.6).

Rice. 8.7. Allosteric regulation of glycogen phosphorylase.
The second type is allosteric regulation. It is based on adenylation-deadenylation reactions of glycogen phosphorylase b subunits (activation-inactivation, respectively). The direction of the reactions is determined by the ratio of the concentrations of AMP and ATP, which do not attach to active center, but to the allosteric center of each subunit (Fig. 8.7).
In a working muscle, the accumulation of AMP, due to the consumption of ATP, causes adenylation and activation of phosphorylase B. At rest, on the contrary, high concentrations ATP, displacing AMP, leads to allosteric inhibition of this enzyme by deadenylation.
cAMP and protein kinase play a central role in the hormonal regulation of the synthesis and breakdown of glycogen in the liver (Fig. 8.8). See chapter 10 for details on the chemical transformations of glycogen.
The third type is calcium regulation, based on the allosteric activation of phosphorylase kinase b by Ca2+ ions, the concentration of which increases with muscle contraction, thereby contributing to the formation of active phosphorylase a.
Guanylate cyclase messenger system
Enough for a long time cyclic guanosine monophosphate (cGMP) was considered as the antipode of cAMP. He was credited with functions opposite to cAMP. To date, a lot of evidence has been obtained that cGMP plays an independent role in the regulation of cell function. In particular, in the kidneys and intestines, it controls ion transport and water exchange, in the heart muscle it serves as a signal of relaxation, etc.
The biosynthesis of cGMP from GTP is carried out under the action of specific guanylate cyclase, by analogy with the synthesis of cAMP:
Guanylate cyclase
GTP * cGMP + PP;

short extracellular peptides (18-20 amino acid residues), in particular, the hormone atrial natriuretic peptide (ANF), a thermostable toxin of gram-negative bacteria, etc. ANF, as is known, is synthesized in the atrium in response to an increase in blood volume, enters with blood to the kidneys, activates guanylate cyclase (correspondingly increases the level of cGMP), contributing to the excretion of Na and water. Vascular smooth muscle cells also contain a similar receptor, the guanylate cyclase system, through which receptor-bound ANF exerts a vasodilating effect, helping to lower blood pressure. In the epithelial cells of the intestine, bacterial endotoxin can act as an activator of the receptor-guanylate cyclase system, which leads to a slowdown in the absorption of water in the intestine and the development of diarrhea.
The soluble form of guanylate cyclase (mol. wt. 152,000) is a heme-containing enzyme consisting of 2 subunits. This form of guanylate cyclase is regulated by nitrovazodilators, free radicals, products of lipid peroxidation. One well-known activator is endothelial factor (EBF.R), which causes vascular relaxation. The active component, natural ligand, of this factor is nitric oxide NO. This form of the enzyme is also activated by some nitrosovasodilators (nitroglycerin, nitroprusside, etc.) used for heart disease; the breakdown of these drugs also releases NO.
Nitric oxide is formed from the amino acid arginine with the participation of a complex Ca2+-dependent enzyme system with a mixed function called NO-synthase:

citrulline
Nitric oxide, when interacting with the heme of guanylate cyclase, promotes the rapid formation of cGMP, which reduces the strength of heart contractions by stimulating ion pumps that function at low concentrations of Ca2+. However, the action of NO is short-term, a few seconds, localized near the site of its synthesis. A similar effect, but longer lasting, has nitroglycerin, which releases NO more slowly.
Evidence has been obtained that most of the effects of cGMP are mediated through a cGMP-dependent protein kinase called protein kinase O. This enzyme, which is widespread in eukaryotic cells, was obtained in pure form (molecular weight 80,000). It consists of 2 subunits - a catalytic domain with a sequence similar to that of the C-subunit of protein kinase A (cAMP-dependent), and a regulatory domain similar to the K-subunit of protein kinase A (see earlier). However, protein kinases A and O recognize different protein sequences, regulating the phosphorylation of the OH group of serine and threon, respectively.
on different intracellular proteins and thereby exerting different biological effects.
The level of cyclic nucleotides cAMP and cGMP in the cell is controlled by the corresponding phosphodiesterases, which catalyze their hydrolysis to 5'-nucleotide monophosphates and differ in their affinity for cAMP and cGMP. A soluble calmodulin-dependent phosphodiesterase and a membrane-bound isoform not regulated by Ca2+ and calmodulin have been isolated and characterized.
Ca2+ messenger system
Ca2+ ions play a central role in the regulation of many cellular functions. A change in the concentration of intracellular free Ca2+ is a signal for the activation or inhibition of enzymes, which in turn regulate metabolism, contractile and secretory activity, adhesion and cell growth. Sources of Ca2+ can be intra- and extracellular. Normally, the concentration of Ca2+ in the cytosol does not exceed 10-7 M, and its main sources are the endoplasmic reticulum and mitochondria. Neurohormonal signals lead to sharp increase concentrations of Ca2+ (up to 10-6 M), coming both from the outside through the plasma membrane (more precisely, through voltage-dependent and receptor-dependent calcium channels), and from intracellular sources. One of the most important mechanisms of hormonal signal transmission in the calcium-messenger system is the triggering of cellular reactions (responses) by activating a specific Ca2+-calmodulin-dependent protein kinase. The regulatory subunit of this enzyme turned out to be Ca2+-binding protein calmodulin (molecular weight 17000). With an increase in the concentration of Ca2+ in the cell in response to incoming signals, a specific protein kinase catalyzes the phosphorylation of many intracellular target enzymes, thereby regulating their activity. Phosphorylase b kinase, activated by Ca2+ ions, as well as NO-synthase, was shown to contain calmodulin as a subunit. Calmodulin is part of many other Ca2+ binding proteins. With an increase in calcium concentration, the binding of Ca2+ to calmodulin is accompanied by its conformational changes, and in this Ca2+-bound form, calmodulin modulates the activity of many intracellular proteins (hence its name).
The intracellular system of messengers also includes derivatives of phospholipids of eukaryotic cell membranes, in particular, phosphorylated derivatives of phosphatidylinositol. These derivatives are released in response to a hormonal signal (for example, from vasopressin or thyrotropin) under the action of a specific membrane-bound phospholipase C. As a result of successive reactions, two potential second messengers are formed - diacylglycerol and inositol-1,4,5-triphosphate.
The biological effects of these second messengers are realized in different ways. The action of diacylglycerol, as well as free Ca2+ ions, is mediated through the membrane-bound Ca-dependent enzyme protein kinaseC, which catalyzes the phosphorylation of intracellular enzymes, changing their activity. Inositol-1,4,5-triphosphate binds to a specific receptor on the endoplasmic reticulum, facilitating the release of Ca2+ ions from it into the cytosol.

Sno-O-CO-R,
I
sn-o-co-i2
I
CH2-he
diacylglycerol
Thus, the presented data on second messengers indicate that each of these systems of intermediaries hormonal effect corresponds to a certain class of protein kinases, although the possibility of a close relationship between these systems cannot be ruled out. The activity of type A protein kinases is regulated by cAMP, protein kinase O - by cGMP; Ca2+-calmodulin-dependent protein kinases are under the control of intracellular [Ca2+], while protein kinase type C is regulated by diacylglycerol in synergy with free Ca2+ and acidic phospholipids. An increase in the level of any second messenger leads to the activation of the corresponding class of protein kinases and subsequent phosphorylation of their protein substrates. As a result, not only the activity changes, but also the regulatory and catalytic properties of many cell enzyme systems: ion channels, intracellular structural elements, and the genetic apparatus.
It is known that the effect of steroid hormones is realized through the genetic apparatus by changing gene expression. The hormone, after delivery with blood proteins into the cell, penetrates (by diffusion) through the plasma membrane and then through the nuclear membrane and binds to the intranuclear protein receptor. The steroid-protein complex then binds to a DNA regulatory region, the so-called hormone-sensitive elements, promoting the transcription of the relevant structural genes, induction of de-POA protein synthesis (see Chapter 14), and alteration of the cell's metabolism in response to a hormonal signal.
It should be emphasized that the main distinctive feature The molecular mechanisms of action of the two main classes of hormones is that the action of peptide hormones is realized mainly through post-translational (post-synthetic) modifications of proteins in cells, while steroid hormones (as well as thyroid hormones, retinoids, vitamin B3-hormones) act as regulators gene expression. This generalization, however, is not absolute, and modifications are possible here, considered when describing individual hormones.