In the synthesis of proteins on the ribosomes of microorganisms (30S and 50S), the following stages are distinguished:

1) initiation (attachment of amino acids to mRNA);

2) elongation (attachment of a new amino acid using tRNA);

3) transpeptidation (attachment of an already formed peptide to a new amino acid);

4) translocation (movement of the resulting peptide from place A to place P) (Fig. 65).

Antibiotics that interfere with protein synthesis include aminoglycosides, tetracyclines, chloramphenicol, macrolides, and lincosamides.

Aminoglycosides

Aminoglycosides are broad-spectrum antibiotics. Polar connections. They are practically not absorbed from the gastrointestinal tract, so they are administered parenterally.

Aminoglycosides do not penetrate the bacterial cell wall well. They penetrate the cytoplasmic membrane of bacteria by oxygen-dependent active transport (therefore, they are ineffective against anaerobic bacteria).

Aminoglycosides act on the 30S ribosomal subunit. They disrupt the initial stages of protein synthesis on bacterial ribosomes: the formation of polysomes and the correct reading of mRNA. As a result, other amino acids are added to place A and “incorrect” (non-functional) proteins are formed. In addition, the action of aminoglycosides disrupts the permeability of the cytoplasmic membrane of bacteria. The action of aminoglycosides is bactericidal.

There are 3 generations of aminoglycosides: I generation - streptomycin, kanamycin, neomycin; II generation - gentamicin, tobramycin;

III generation - amikacin, netilmicin.

Streptomycin- broad-spectrum antibiotic. Effective against Mycobacterium tuberculosis. For the discovery of streptomycin, the first antibiotic effective against tuberculosis, S.A. Waksman (USA) in 1952 received Nobel Prize. Streptomycin is effective against cocci, Haemophilus influenzae, Klebsiella, causative agents of tularemia, plague, brucellosis, Shigella, and Salmonella.

Streptomycin is used for tuberculosis, tularemia, plague (together with doxycycline), and brucellosis. Administered intramuscularly.

Kanamycin used when Mycobacterium tuberculosis is resistant to streptomycin.

Neomycin more toxic; applied only topically. The drug is not absorbed from the gastrointestinal tract; it can be administered orally for enteritis, as well as to suppress intestinal microbial flora before surgery.

Of the second generation aminoglycosides, the most commonly used gentamicin, effective against staphylococci, Escherichia coli, Shigella, Salmonella, Klebsiella, Protea, Brucella, etc. Unlike first generation drugs, gentamicin acts on Pseudomonas aeruginosa. The drug is administered intramuscularly or intravenously (slowly or drip-wise).

Gentamicin is used for pneumonia, septicemia, meningitis, peritonitis, endocarditis, cholecystitis, acute pyelonephritis, cystitis, prostatitis, purulent infections of the skin, soft tissues, bones, joints, and burn infections caused by microorganisms sensitive to aminoglycosides. The drug is also used for brucellosis (together with doxycycline), plague, and tularemia.

Gentamicin is used externally in the form of an ointment for pyoderma and infected wounds; in eye practice (in the form of eye drops, ointments) - for blepharitis, conjunctivitis, keratitis.

Second generation aminoglycosides also include tobramycin, similar in properties and use to gentamicin.

Aminoglycosides III generation amikacin, netilmicin similar in spectrum of action to gentamicin and tobramycin; are effective against bacteria resistant to aminoglycosides of the first and second generations. Administered intramuscularly or intravenously.

Aminoglycosides are used mainly for severe infections caused by microorganisms sensitive to aminoglycosides (sepsis, peritonitis, urinary tract infections, pneumonia, wound and burn infections).

Side effects aminoglycosides: ototoxic effect - hearing loss (periodic audiometry is required), vestibular disorders. Possible renal dysfunction and allergic reactions. Aminoglycosides may impair neuromuscular transmission and enhance the effect of antidepolarizing muscle relaxants. Contraindicated in myasthenia gravis.

Similar in structure to aminoglycosides aminocyclitol Spectinomycin. The drug is used mainly in the treatment of gonorrhea. Uncomplicated gonorrhea is cured after 1 intramuscular injection spectinomycin; disseminated gonorrhea is treated for 7 days.

Tetracyclines

Tetracyclines are broad-spectrum antibiotics. They disrupt protein synthesis on bacterial ribosomes. Act on the 30S ribosomal subunit; prevent elongation - the joining of transfer RNA (tRNA) with the next amino acid at place A. The action of tetracyclines is bacteriostatic.

Tetracyclines penetrate well into cells and act on intracellular microorganisms - chlamydia, legionella, mycoplasma, rickettsia.

Tetracyclines (most often doxycycline) are the drugs of choice for typhus, brucellosis (together with gentamicin or rifampicin), cholera, chlamydia of the lungs and genitourinary system, infections caused by mycoplasma or ureaplasma. Effective against cocci, Haemophilus influenzae, Klebsiella, Legionella, Borrelia, Treponema pallidum, Escherichia coli, Shigella, Salmonella, plague bacilli, tularemia, anthrax.

They do not act on Pseudomonas aeruginosa, Bacteroides, Proteus.

Doxycycline (vibramycin) is prescribed orally for rickettsiosis (typhoid fever, etc.), brucellosis (together with rifampicin), plague, cholera, chlamydia, respiratory tract infections (acute bronchitis, pneumonia), urinary tract infections, prostatitis, as well as anthrax, syphilis (with allergies to benzylpenicillins), Lyme disease, malaria.

Absorbed almost completely in the intestines (about 90%). Duration of action is 12 hours (prescribed 2 times a day).

Metacycline (Rondomycin) has similar properties to doxycycline.

Tetracycline is not completely absorbed in the intestine (about 60%). Duration of action 6 hours.

The drug is prescribed orally for the same indications as doxycycline. In eye practice, eye ointment with tetracycline is used for conjunctivitis, keratitis, and blepharitis.

Side effects of tetracyclines: nausea, vomiting, glossitis, intestinal candidiasis (associated with suppression of normal intestinal microflora), diarrhea, liver dysfunction, anemia, neutropenia, skin rashes, allergic reactions. Tetracyclins are deposited in bone tissue, therefore early age possible disturbances in the development of bone tissue and teeth; Tetracyclines are not recommended for use in children under 8 years of age or in pregnant and nursing mothers.

2. What are the names of the nuclear structures that store information about the body’s proteins?
3. Which molecule is the matrix (template) for the synthesis of mRNA?
4. What is the name of the process of synthesis of a polypeptide chain of a protein on a ribosome?
5. On which molecule is there a triplet called a codon?
6. On which molecule is there a triplet called an anticodon?
7. By what principle does an anticodon recognize a codon?
8. Where in the cell does the t-RNA+amino acid complex form?
9. What is the name of the first stage of protein biosynthesis?
10. Given a polypeptide chain: -VAL - ARG - ASP - Determine the structure of the corresponding DNA chains.

1.what type of RNA transfers hereditary information from DNA to the site of protein synthesis?

2.what type of RNA transports amino acids to the site of protein synthesis?
3.what type of RNA transfers hereditary information from the nucleus to the cytoplasm?
4. In which organisms are the processes of transcription and translation not separated in time and space?
5. How many nucleotides of mRNA does the “functional center” of the ribosome include?
6. How many amino acids should be present in the large subunit of the ribosome at the same time?
7. How many genes can prokaryotic mRNA include?
8.How many genes can eukaryotic mRNA include?
9. when the ribosome reaches the STOP codon, it adds a molecule to the last amino acid
10. if there are many ribosomes on one mRNA at the same time, this structure is called
11. energy is used for protein biosynthesis, as for other processes in the cell

energy for reaction

E. Protein monomer

F Group of nucleotides coding for one amino acid

connections

2. DNA triplets

3. Ribosome

4. RNA polymerase

5. Amino acid

it is necessary to correlate the substances and structures involved in protein synthesis with their functions

Where is hereditary information stored? The name of the protein shell of the virus. The second name of nuclear organisms. The second name of viruses - eaters

bacteria. What does the cell wall of plants consist of? What cellular structure can be smooth and rough? The name of the main substance of the cytoplasm. Which organelle is the center of protein synthesis in the cell? The general name for the processes of phago- and pinocytosis. Name of colorless plastids.

1. The reactions of plastic metabolism in the human body include the process

1) transport nutrients along the alimentary canal
2) secretion of sebum by the sebaceous glands
3) protein synthesis in liver cells
4) filtration of blood plasma in the nephron
2. Establish the level organization of the structure of the human auditory analyzer
century, starting from its peripheral part - the ear. In response, write down the corresponding
the corresponding sequence of numbers.
1) receptor hair cells
2) snail
3) inner ear
4) membranous labyrinth
5) organ of Corti
3. Insert into the text “Processes occurring in the human large intestine”
missing terms from the proposed list, using
digital symbols. Write down the numbers of the selected answers in the text, and then
enter the resulting sequence of numbers (according to the text) in the given
Below is the table.
Processes occurring in the human large intestine
In the large intestine, a large amount of ________ is absorbed into the blood (A).
The glands of the large intestine produce a lot of ________ (B) and facilitate,
thus promoting and eliminating undigested food debris.
Bacteria in the large intestine synthesize some ________ (B). Not over-
cooked food remains enter the ________ (D) and are removed from the body.
List of terms
1) mucus
2) water
3) glucose
4) enzyme
5) vitamin
6) rectum
7) cecum
8) pancreas
4. The reactions of energy metabolism in the human body include the process
1) protein synthesis in muscle fibers
2) blood transport of nutrients throughout the body
3) glucose oxidation in brain neurons
4) reabsorption of primary urine in the convoluted tubules of the kidneys
5. Why do doctors recommend including foods containing
What iodine?
1) iodine affects changes in the composition of blood plasma
2) iodine normalizes activity thyroid gland
3) iodine prevents sore throat
4) iodine promotes the synthesis of vitamin C in the body
6. During an athlete’s training, reserves are the first to be used up.
1) vitamins 2) proteins 3) fats 4) carbohydrates
7. The danger of tanning is that
1) skin darkens
2) melanoma may occur
3) excess vitamin D is produced
4) a large amount of blood flows into the expanding vessels of the skin
8. In which part of the digestive canal does absorption mainly occur?
tion organic matter food?
1) in the oral cavity 3) in the large intestine
2) in the stomach 4) in the small intestine
9. Establish the level organization of the structure of the human visual analyzer
century, starting from its peripheral section. In response, write down the corresponding
particular sequence of numbers.
1) eye
2) retina
3) eyeball
4) cones
5) photoreceptors

There are also toxic effects associated with the direct effect of xenobiotics on microsomal monooxygenases. Typical here is the mechanism of the toxic effect of carbon tetrachloride, which dissolves in all membrane elements of liver cells with a predominant accumulation in the microsomal fraction. Here it binds to cytochrome P-450, and a rapidly occurring reduction reaction leads to the formation of the CCl3 radical, which is the trigger in the mechanism of the damaging effect of this xenobiotic.

The radical stimulates sharply lipid peroxidation, causing damage to biomembranes and leads to the destruction of cytochrome P-450. As a result, these mechanisms, coupled with other, less significant ones, cause cell death. For the toxicity mechanism briefly described here, A.I. Archakov introduced the term “lethal decay.”

When interacting xenobiotics with microsomal monooxygenases, not radicals can be formed, but stable, highly toxic products leading to intoxication. This version of the toxic effect is called "lethal synthesis". For example, the formation of toxic fluorocitric acid from fluoroacetate, the accumulation of formaldehyde and formic acid during the oxidative transformation of methanol, etc.

All chemicals, damaging protein synthesis, can be divided into 2 groups. The first of them includes xenobiotics that have an indirect effect on protein synthesis through changes in bioenergy processes, hormonal status, biomembrane permeability, etc. Violation of protein synthesis in the mechanism of their toxic action is a secondary phenomenon that complicates, but does not determine the development of intoxication. An example would be chlorinated hydrocarbons. Thus, tetrachloroalkanes inhibit the incorporation of methionine and lysine into serum and liver proteins.

There is also another mechanism: in the process of metabolism of xenobiotics, active radicals and peroxides are formed, affecting the phospholipids of the membranes of the endoplasmic reticulum and damaging them, which contributes to the disruption of protein synthesis. In particular, inhalation of dichloroethane leads to inhibition of the incorporation of leucine into the liver proteins of mice and causes damage to the polyribosomal structures of hepatocytes. In silicosis, macrophage protein synthesis is inhibited in the lungs; in chronic berylliosis, the processes of incorporation of amino acids into lung proteins are disrupted. Under the influence of lead, the use of methionine for protein synthesis is inhibited; This process is also suppressed by organomercury compounds.

Second group xenobiotics includes compounds that directly inhibit protein synthesis either by interfering with transcription or translation processes. A significant part of xenobiotics disrupts transcription processes, damaging the matrix, i.e. DNA. Under their influence, covalent bonds between nucleotides are disrupted and their functional groups are modified due to the formation of complexes, loss or destruction of sections of the DNA chain. This is exactly how alkylating compounds work. A large group of antibiotics blocks DNA. The template properties of DNA are damaged by a large class of xenobiotics of the acridine series, intercalating between nucleic acid bases.

As a result mRNA synthesis decreases(matrix ribonucleic acid) and protein biosynthesis is inhibited. Amanitins, products poisonous mushrooms genus Amanita, disrupt transcription by inhibiting the activity of RNA polymerase, which also leads to suppression of protein synthesis.

Xenobiotics, which disrupt translation, can be divided into groups depending on the stage of translation at which they act. For example, at the stage of initiation of the translation process, dihydroxybutyraldehyde and methylglyoxal, synthetic anions - polyvinyl sulfate, polydextran sulfate, etc., and trichothecene fungal toxins act. However, their mechanism of action may be different: aliphatic aldehydes block the attachment of mRNA to ribosomes; polyvinyl sulfate binds to ribosomes at the site where the mRNA attaches; other polyanions block the interaction of ribosomal subunits. Xenobiotics that disrupt translation at the elongation stage may also have different mechanisms of action. For example, the formation of a peptide bond at the elongation stage is blocked by erythromycin and oleandomycin. Diphtheria toxin disrupts translocation. Cycloheximide and its derivatives disrupt translocation in a slightly different way. At the stage of termination of the translation process, tenuazonic acid acts, suppressing the separation of newly formed proteins from ribosomes.

At the conclusion of the consideration protein synthesis disorders xenobiotics indicate the possibility of suppressing the processes of activation of amino acids and inhibiting the activity of aminoacyl-tRNA synthetases. Substances that act in this way primarily include synthetic analogues of natural amino acids, for example 5-methyltryptophan, 2-methylhistidine, methylhomocysteine, cisfluoroproline, fluorophenylalanine, ethionine, canavanine, etc. These xenobiotics inhibit the incorporation of natural amino acids into proteins due to competitive inhibition corresponding aminoacyl synthetases.

General biological mechanism implementation of toxic effects is also a disorder of bioenergetic processes, usually associated with the mitochondrial structural-metabolic complex.

Hydrolysis and absorption of food proteins in the gastrointestinal tract.

Disturbance of the first stage of protein metabolism

In the stomach and intestines, hydrolytic breakdown of food proteins into peptides and amino acids occurs under the influence of enzymes from gastric juice (pepsin), pancreatic (trypsin, chymotrypsin, aminopeptidase and carboxypeptidase) and intestinal (aminopeptidase, dipeptidase) juices. Amino acids formed during the breakdown of proteins are absorbed by the wall of the small intestine into the blood and consumed by the cells of various organs. Disruption of these processes occurs in diseases of the stomach (inflammatory and ulcerative processes, tumors), pancreas (pancreatitis, blockage of ducts, cancer), small intestine (enteritis, diarrhea, atrophy). Extensive surgical interventions, such as removal of the stomach or a significant part of the small intestine, are accompanied by violation of the breakdown and absorption of food proteins. The absorption of food proteins is impaired during fever due to a decrease in the secretion of digestive enzymes.

With a decrease in the secretion of hydrochloric acid in the stomach, the swelling of proteins in the stomach and the conversion of pepsinogen to pepsin decrease. Due to the rapid evacuation of food from the stomach, proteins are not sufficiently hydrolyzed into peptides, i.e. Some proteins enter the duodenum unchanged. It also interferes with the hydrolysis of proteins in the intestines.

Insufficient absorption of food proteins is accompanied by a deficiency of amino acids and impaired synthesis of its own proteins. The lack of dietary proteins cannot be fully compensated by the excessive administration and absorption of any other substances, since proteins are the main source of nitrogen for the body.

Protein synthesis occurs in the body continuously throughout life, but occurs most intensively during intrauterine development, in childhood and adolescence.

The causes of protein synthesis disorders are:

Lack of sufficient amino acids;

Energy deficiency in cells;

Disorders of neuroendocrine regulation;

Disruption of the processes of transcription or translation of information about the structure of a particular protein encoded in the cell genome.

The most common cause of protein synthesis disorder is lack of amino acids in the body due to:

1) digestive and absorption disorders;

2) low protein content in food;

3) nutrition with incomplete proteins, which lack or contain insignificant amounts of essential amino acids that are not synthesized in the body.

A complete set of essential amino acids is found in most animal proteins, while plant proteins may lack or contain some of them (for example, corn proteins are low in tryptophan). Flaw in the body at least one of essential amino acids leads to a decrease in the synthesis of one or another protein, even with an abundance of others. Essential amino acids include tryptophan, lysine, methionine, isoleucine, leucine, valine, phenylalanine, threonine, histidine, arginine.

Deficiency of essential amino acids in food less often leads to a decrease in protein synthesis, since they can be formed in the body from keto acids, which are products of the metabolism of carbohydrates, fats and proteins.

Lack of keto acids occurs when diabetes mellitus, disruption of the processes of deamination and transamination of amino acids (hypovitaminosis B 6).

Lack of energy sources occurs with hypoxia, the action of uncoupling factors, diabetes mellitus, hypovitaminosis B1, deficiency nicotinic acid etc. Protein synthesis is an energy-dependent process.

Disorders of neuroendocrine regulation of protein synthesis and breakdown. The nervous system has a direct and indirect effect on protein metabolism. When nerve influences are lost, cell trophic disorder occurs. Tissue denervation causes: cessation of their stimulation due to disruption of the release of neurotransmitters; impaired secretion or action of comediators that provide regulation of receptor, membrane and metabolic processes; disruption of the release and action of trophogens.

The action of hormones can be anabolic(increasing protein synthesis) and catabolic(increasing protein breakdown in tissues).

Protein synthesis increases under the influence of:

Insulin (provides active transport of many amino acids into cells - especially valine, leucine, isoleucine; increases the rate of DNA transcription in the nucleus; stimulates ribosome assembly and translation; inhibits the use of amino acids in gluconeogenesis, enhances the mitotic activity of insulin-dependent tissues, increasing the synthesis of DNA and RNA);

Somatotropic hormone (GH; the growth effect is mediated by somatomedins produced under its influence in the liver). The main one is somatomedin C, which increases the rate of protein synthesis in all cells of the body. This stimulates the formation of cartilage and muscle tissue. Chondrocytes also have receptors for growth hormone itself, which proves its direct effect on cartilage and bone tissue;

Thyroid hormones in physiological doses: triiodothyronine, binding to receptors in the cell nucleus, acts on the genome and causes increased transcription and translation. As a result, protein synthesis is stimulated in all cells of the body. In addition, thyroid hormones stimulate the action of GH;

Sex hormones that have a growth hormone-dependent anabolic effect on protein synthesis; androgens stimulate the formation of proteins in the male genital organs, muscles, skeleton, skin and its derivatives, and to a lesser extent in the kidneys and brain; The action of estrogens is directed mainly to the mammary glands and female genital organs. It should be noted that the anabolic effect of sex hormones does not affect protein synthesis in the liver.

Protein breakdown increases under the influence of:

Thyroid hormones with increased production (hyperthyroidism);

Glucagon (reduces the absorption of amino acids and increases the breakdown of proteins in muscles; activates proteolysis in the liver, and also stimulates gluconeogenesis and ketogenesis from amino acids; inhibits the anabolic effect of growth hormone);

Catecholamines (promote the breakdown of muscle proteins with the mobilization of amino acids and their use by the liver);

Glucocorticoids (increase the synthesis of proteins and nucleic acids in the liver and increase the breakdown of proteins in muscles, skin, bones, lymphoid and adipose tissue with the release of amino acids and their involvement in gluconeogenesis. In addition, they inhibit the transport of amino acids into muscle cells, reducing protein synthesis).

The anabolic effect of hormones is carried out mainly through the activation of certain genes and increased formation various types RNA (messenger, transport, ribosomal), which accelerates protein synthesis; the mechanism of the catabolic action of hormones is associated with an increase in the activity of tissue proteinases.

A long-term and significant decrease in protein synthesis leads to the development of dystrophic and atrophic disorders in various organs and tissues due to insufficient renewal structural proteins. Regeneration processes slow down. In childhood, growth, physical and mental development are inhibited. The synthesis of various enzymes and hormones (GH, antidiuretic and thyroid hormones, insulin, etc.) decreases, which leads to endocrinopathies and disruption of other types of metabolism (carbohydrate, water-salt, basal). The content of proteins in the blood serum decreases due to a decrease in their synthesis in hepatocytes. The production of antibodies and other protective proteins decreases and, as a result, the immunological reactivity of the body decreases.

Causes and mechanism of disruption of the synthesis of individual proteins. In most cases, these disorders are hereditary. They are based on the absence in cells of messenger RNA (mRNA), a specific matrix for the synthesis of any particular protein, or a violation of its structure due to a change in the structure of the gene on which it is synthesized. Genetic disorders, for example, the replacement or loss of one nucleotide in a structural gene, lead to the synthesis of an altered protein, often devoid of biological activity.

The formation of abnormal proteins can be caused by deviations from the norm in the structure of mRNA, mutations of transfer RNA (tRNA), as a result of which an inappropriate amino acid is added to it, which will be included in the polypeptide chain during its assembly (for example, during the formation of hemoglobin).

Causes, mechanism and consequences of increased breakdown of tissue proteins. Along with synthesis in the cells of the body, protein degradation constantly occurs under the action of proteinases. The renewal of proteins per day in an adult is 1-2% of the total amount of protein in the body and is associated mainly with the degradation of muscle proteins, while 75-80% of the released amino acids are again used for synthesis.

A general idea of ​​protein metabolism disorders can be obtained by studying nitrogen balance organism and environment.

Nitrogen imbalance

Nitrogen imbalance manifests itself in the form of a positive or negative nitrogen balance.

Positive nitrogen balance - a condition when less nitrogen is excreted from the body than is supplied with food. It is observed during the growth of the body, during pregnancy, as well as after fasting, with excessive secretion of anabolic hormones (somatotropic hormone, androgens, etc.) and when they are prescribed for therapeutic purposes.

The anabolic effect of hormones is to enhance the processes of protein synthesis compared to its breakdown. The following hormones have this effect.

Somatotropic hormone enhances fat oxidation and mobilization of neutral fat and thus leads to a sufficient release of energy necessary for protein synthesis processes.

Sex hormones enhance protein synthesis processes.

Insulin facilitates the passage of amino acids across cell membranes into cells and, thus, promotes protein synthesis and weakens gluconeogenesis. Lack of insulin leads to decreased protein synthesis and increased gluconeogenesis.

Negative nitrogen balance - a condition when more nitrogen is excreted from the body than is taken in with food. Negative nitrogen balance develops during fasting, proteinuria, infectious diseases, injuries, thermal burns, surgery, excessive secretion or administration of catabolic hormones (cortisol, thyroxine, etc.).

The catabolic effect of hormones is to enhance the processes of protein breakdown compared to the processes of synthesis. The following hormones have this effect.

Thyroxine increases the number of active sulfhydryl groups in the structure of some enzymes - tissue cathepsins are activated and their proteolytic effect is enhanced. Thyroxine increases the activity of amino oxidases - the deamination of some amino acids increases. With hyperthyroidism, patients develop a negative nitrogen balance and creatinuria.

When there is a deficiency of thyroid hormones, such as hypothyroidism, the insufficiency of the catabolic effect of the hormone manifests itself in the form of a positive nitrogen balance and accumulation of creatine.

Glucocorticoid hormones (cortisol, etc.) increase the breakdown of proteins. Protein consumption increases for the needs of gluconeogenesis; this also slows down protein synthesis.

Protein metabolism can be disrupted at different stages of transformation of protein substances taken with food. The following violations can be distinguished:

• 1) upon receipt, digestion and absorption of proteins in the gastrointestinal tract;
• 2) during the synthesis and breakdown of proteins in the cells and tissues of the body;
• 3) during interstitial amino acid metabolism;
• 4) at the final stages of protein metabolism;
• 5) in the protein composition of blood plasma.

Disturbances in the supply, digestion and absorption of proteins in the gastrointestinal tract

Disorders of the secretion of certain proteolytic enzymes gastric tract, as a rule, do not cause serious disturbances in protein metabolism. Thus, the complete cessation of the secretion of pepsin with gastric juice does not affect the degree of protein breakdown in the intestine, but significantly affects the rate of its breakdown and the appearance of individual free amino acids.

The elimination of individual amino acids in the gastrointestinal tract occurs unevenly. Thus, tyrosine and tryptophan are normally cleaved from proteins already in the stomach, and other amino acids are only cleaved under the action of proteolytic enzymes of intestinal juice. The composition of amino acids in the intestinal contents at the beginning and end of intestinal digestion is different.

Amino acids can enter the portal vein system in different ratios. A relative deficiency of even one essential amino acid complicates the entire process of protein biosynthesis and creates a relative excess of other amino acids with the accumulation of intermediate metabolic products of these amino acids in the body.

Similar metabolic disorders associated with a delay in the elimination of tyrosine and tryptophan occur with achylia and subtotal resection of the stomach.

Malabsorption of amino acids can occur due to pathological changes in the wall of the small intestine, for example, with inflammation and edema.

Disorders of protein synthesis and breakdown

Protein synthesis occurs inside cells. The nature of the synthesis depends on the genetic makeup on the chromosomes in the cell nucleus. Under the influence of genes specific to each type of protein in each organism, enzymes are activated, and messenger ribonucleic acid (RNA) is synthesized in the cell nucleus. mRNA is a mirror copy of deoxyribonucleic acid (DNA) found in the cell nucleus.

Protein synthesis occurs in the cytoplasm of the cell on ribosomes. Under the influence of mRNA, messenger RNA (m-RNA) is synthesized on ribosomes, which is a copy of mRNA and contains encoded information about the type and sequence of amino acids in the molecule of the protein being synthesized.

To incorporate amino acids into a protein molecule in accordance with the matrix (m-RNA), their activation is necessary. The function of activating amino acids is performed by a fraction of RNA called soluble or transport (t-RNA). Activation of amino acids is accompanied by their phosphorylation. The attachment of amino acids by means of t-RNA to certain groups of m-RNA nucleotides occurs when they are dephosphorylated due to the energy of guanine triphosphate. The synthesized protein performs a specific function in the cell or is transported from the cell and performs its function as a blood protein, antibody, hormone, enzyme.

The regulation of protein synthesis in a cell is genetically determined by the presence of not only structural genes that control the sequence of nucleotide bases during mRNA synthesis, but also additional regulatory genes. At least two more genes take part in the regulation of protein synthesis in the cell - the operator gene and the regulatory gene.

The regulatory gene is responsible for the synthesis of the repressor, which is an enzyme and ultimately inhibits the activity of structural genes and the formation of mRNA.

The operator gene, or operating gene, is directly subject to the action of a repressor, causing in one case repression, and in the other - derepression: the appearance of the synthesis of a number of enzymes that synthesize mRNA. The operating gene forms a single whole with structural genes, forming a so-called operon.

A repressive substance can be in two states: active and inactive. In the active state, the repressor acts on the operating gene, stops its effects on structural genes, and ultimately stops the synthesis of mRNA and protein synthesis.

Repressor activators are called corepressors. They can be either a certain concentration of the regulated protein or factors formed as a result of the action of this protein.

Protein synthesis is regulated as follows. If there is a lack of protein in the cell, the effect of the repressor on the operon stops. The synthesis of mRNA and m-RNA increases. and the synthesis of protein molecules begins on ribosomes. Protein concentration increases. If the synthesized protein is not metabolized quickly enough, its amount continues to increase. A certain concentration of this protein, or factors formed under its action, can serve as a corepressor of synthesis, activating the repressor. The influence of the operating gene on structural genes stops and protein synthesis ultimately stops. Its concentration decreases, etc.

When the regulation of protein synthesis is disturbed, pathological conditions associated with both excessive synthesis and insufficient protein synthesis can occur.

Protein synthesis can be disrupted under the influence of various external and internal pathogenic factors:

• a) in case of deficiency of the amino acid composition of proteins;
• b) with pathological gene mutations associated with both the appearance of pathogenic structural genes and the absence of normal regulatory and structural genes;
• c) when humoral factors block enzymes responsible for the processes of repression and derepression of protein synthesis in cells;
• d) in case of violation of the ratio of anabolic and catabolic factors regulating protein synthesis.

The absence of even one essential amino acid in cells stops protein synthesis.

Protein biosynthesis can be disrupted not only in the absence of individual essential amino acids, but also in the event of a violation of the ratio between the amount of essential amino acids entering the body. The need for individual essential amino acids is associated with their participation in the synthesis of hormones, mediators, and biologically active substances.

Insufficient intake of essential amino acids into the body causes not only general disturbances in protein synthesis, but also selectively disrupts the synthesis of individual proteins. A deficiency of an essential amino acid may be accompanied by its characteristic disorders.

Tryptophan . With prolonged exclusion from the diet, rats develop corneal vascularization and cataracts. In children, restriction of tryptophan in food is accompanied by a decrease in the concentration of plasma proteins.

Lysine . Lack of food is accompanied in people by the appearance of nausea, dizziness, headache and hypersensitivity to noise.

Arginine . Lack of food can lead to inhibition of spermatogenesis.

Leucine . A relative excess of it compared to other essential amino acids in rats inhibits growth due to a corresponding impairment in the absorption of isoleucine.

Histidine . Its deficiency is accompanied by a decrease in hemoglobin concentration.

Methionine . Excluding it from food is accompanied by fatty degeneration of the liver, caused by a lack of labile methyl groups for the synthesis of lecithin.

Valin . Its deficiency leads to growth retardation, weight loss, and the development of keratoses.

Nonessential amino acids significantly affect the need for essential amino acids. For example, the need for methionine is determined by the cystine content of the diet. The more cystine in food, the less methionine is consumed for the biological synthesis of cystine. If the body's rate of synthesis of a non-essential amino acid becomes insufficient, an increased need for it appears.

Some non-essential amino acids become essential if they are not supplied with food, as the body cannot cope with their rapid synthesis. Thus, a lack of cystine leads to inhibition of cell growth even in the presence of all other amino acids in the medium.

Dysregulation of protein synthesis - antibodies - may be observed in some allergic diseases. Thus, in immunocompetent cells (lymphoid cells) that produce antibodies, the production of autoantibodies is usually repressed. During embryonic development, when phases change (stage of the neural tube, mesenchyme sheets), derepression of the synthesis of autoantibodies occurs. Autoantibodies are detected in tissues, which are involved in the resorption of tissues from previous phases of embryo development. This change in repressor activity occurs several times. In the adult body, the synthesis of autoantibodies is repressed. For example, the synthesis of autoantibodies to antigens of one’s own red blood cells is repressed. If, depending on the blood group, there is agglutininogen A in the erythrocytes, then there are no α-agglutinins in the blood plasma, the production of which is reliably repressed. On this basis, transplantation of blood and hematopoietic tissue (bone marrow) is possible.

To some tissues (lens of the eye, nerve tissue, testicles) the production of autoantibodies is not repressed, but these tissues, due to their anatomical and functional characteristics, are isolated from immunocompetent cells and normally the production of autoantibodies does not occur. When anatomical isolation is disrupted (damage), the production of autoantibodies begins and autoallergic diseases occur.

Amino acid metabolism disorders

Deamination disorders. Oxidative deamination occurs as a result of sequential transformations of amino acids in transamination and deamination reactions:

Amino acids, with the participation of specific transaminases, are first transaminated with α-ketoglutaric acid. A ketoacid and glutamate are formed. Glutamate, under the action of dehydrogenase, undergoes oxidative deamination with the release of ammonia and the formation of α-ketoglutarate. The reactions are reversible. This way new amino acids are formed. The inclusion of α-ketoglutaric acid in the Krebs cycle ensures the inclusion of amino acids in energy metabolism. Oxidative deamination also determines the formation of final products of protein metabolism.

Transamination is associated with the formation of amino sugars, porphyrins, creatine and deamination of amino acids. A violation of transamination occurs with a lack of vitamin B6, since its form - phosphopyridoxal - is an active group of transaminases.

The ratio of transamination substrates determines the direction of the reaction. When urea formation is impaired, transamination accelerates.

Weakening of deamination occurs when the activity of enzymes - amino oxidases - decreases and when oxidative processes are disrupted (hypoxia, hypovitaminosis C, PP, B 2).

If the deamination of amino acids is impaired, the excretion of amino acids in the urine increases (aminoaciduria), and urea formation decreases.

Decarboxylation disorders. Decarboxylation of amino acids is accompanied by the release of CO 2 and the formation of biogenic amines:

In the animal body, only some amino acids undergo decarboxylation to form biogenic amines: histidine (histamine), tyrosine (tyramine), 5-hydroxytryptophan (serotonin), glutamic acid (γ-aminobutyric acid) and the products of further transformations of tyrosine and cystine: 3,4- dioxyphenylalanine (DOPA, hydroxytyramine) and cysteic acid (taurine) (Fig. 47).

Biogenic amines exhibit their effects even at low concentrations. The accumulation of amines in high concentrations poses a serious danger to the body. Under normal conditions, amines are quickly eliminated by amine oxidase, which oxidizes them to aldehydes:

This reaction produces free ammonia. Inactivation of amines is also achieved by binding them to proteins.

The accumulation of biogenic amines in tissues and blood and the manifestation of their toxic effect occurs; by increasing the activity of decarboxylases, inhibiting the activity of oxidases and disrupting their binding to proteins.

In pathological processes accompanied by inhibition of oxidative deamination, the conversion of amino acids occurs to a greater extent by decarboxylation with the accumulation of biogenic amines.

Metabolism disorders of individual amino acids. There are a number of hereditary human diseases associated with congenital defects in the metabolism of individual amino acids. These disorders of amino acid metabolism are associated with a genetically determined disorder in the synthesis of protein groups of enzymes that carry out the transformation of amino acids (Table 24).

Disorders of phenylalanine metabolism (phenylketonuria) . The cause of the disease is a deficiency of the enzyme phenylalanine hydroxylase in the liver, as a result of which the conversion of phenylalanine to tyrosine is blocked (Fig. 48). The concentration of phenylalanine in the blood reaches 20-60 mg% (normally about 1.5 mg%). Its metabolic products, in particular the ketoacid phenylpyruvate, have a toxic effect on the nervous system. Nerve cells of the cerebral cortex are destroyed and replaced by the proliferation of microglial elements. Phenylpyruvic oligophrenia develops. Phenylpyruvate appears in urine and gives a green color with iron trichloride. This reaction is carried out in newborns and serves for the early diagnosis of phenylketonuria.

With the development of the disease, already at 6 months of age, the child shows signs of insufficient mental development, clearing of skin and hair color, general agitation, increased reflexes, increased muscle tone and basal metabolism, epilepsy, microcephaly, etc.

Lightening of skin and hair color develops due to insufficient production of melanin, since the accumulation of phenylalanine blocks the metabolism of tyrosine.

Insufficiency of catecholamine synthesis develops, and the level of other free amino acids in the blood plasma decreases. The excretion of ketone bodies in urine increases.

Excluding phenylalanine from the diet leads to a decrease in the content of phenylalanine and its derivatives in the blood and prevents the development of phenylketonuria.

Disorders of homogentisic acid metabolism (a product of tyrosine metabolism) - alkaptonuria - occurs when there is a deficiency of the enzyme - homogentisic acid oxidase (Fig. 49).

In this case, homogentisic acid does not transform into maleylacetoacetic acid (the hydroquinone ring does not break). Under normal conditions, homogentisic acid is not detected in the blood. If the enzyme is deficient, homogentisic acid appears in the blood and is excreted from the body in the urine. There is a characteristic darkening of urine, especially in an alkaline environment.

Deposition of homogentisic acid derivatives in tissues causes pigmentation connective tissue- ochronosis. The pigment is deposited in articular cartilage, in the cartilage of the nose, ears, endocardium, large blood vessels, kidneys, lungs, and epidermis. Alkaptonuria is often accompanied by kidney stones.

Tyrosine metabolism disorder - albinism . The cause of the disease is a lack of the enzyme tyrosinase in melanocytes - cells that synthesize the pigment melanin (Fig. 50).

In the absence of melanin, the skin acquires a milky white color with whitish hair growth (albinism), photophobia, nystagmus, translucency of the iris, and decreased visual acuity are observed. Sun exposure causes inflammatory changes in the skin - erythema.

Albinism may be accompanied by deafness, muteness, epilepsy, polydactyly and mental retardation. The intelligence of such patients is often normal.

Disorders of histidine metabolism . Mastocytosis - hereditary disease, accompanied by increased proliferation of mast cells. The cause of the disease is considered to be an increase in the activity of histidine decarboxylase, an enzyme that catalyzes the synthesis of histamine. Histamine accumulates in the liver, spleen and other organs. The disease is characterized by skin lesions, disturbances of cardiac activity and gastrointestinal tract function. There is increased urinary excretion of histamine.

Hyperaminaciduria . Occur when the reabsorption of amino acids in the renal tubules is impaired (renal hyperaminoaciduria, for example cystinosis, cystinuria) or when the concentration of amino acids in the blood increases (extrarenal hyperaminoaciduria, for example phenylketonuria, cystathionuria).

Cystinosis . It is observed with a congenital defect in the reabsorption of cystine, cysteine ​​and other non-cyclic amino acids in the renal tubules. Excretion of amino acids in urine can increase 10 times. Excretion of cystine and cysteine ​​increases 20-30 times. Cystine is deposited in the kidneys, spleen, skin, and liver. Cystinosis is accompanied by glucosuria, hyperkaliuria, proteinuria and polyuria.

With cystinuria, cystine excretion can increase up to 50 times compared to normal, accompanied by inhibition of reabsorption of lysine, arginine and ornithine in the renal tubules. The level of cystine in the blood does not exceed the norm. No disturbances were found in the interstitial metabolism of these amino acids. Increased excretion of amino acids can lead to disturbances in protein synthesis and protein malnutrition.

Disorders of the final stages of protein metabolism

Urea formation disorders. The end products of amino acid breakdown are ammonia, urea, CO 2 and H 2 O. Ammonia is formed in all tissues as a result of deamination of amino acids. Ammonia is toxic; when it accumulates, the protoplasm of cells is damaged. There are two mechanisms to bind ammonia and neutralize it: urea is formed in the liver, and in other tissues ammonia joins glutamic acid (amidation) - glutamine is formed. Subsequently, glutamine releases ammonia for the synthesis of new amino acids, the transformations of which are completed by the formation of urea, excreted in the urine. Of the total urine nitrogen, urea accounts for 90% (ammonia about 6%).

Urea synthesis occurs in the liver in the citrulline nargininornithine cycle (Fig. 51). There are diseases associated with hereditary defects in urea formation enzymes.

Arginine succinaturia . It consists of hyperaminoaciduria (argininosuccinic acid) and mental retardation. The reason is a defect in the enzyme argininosuccinate lyase.

Ammoniemia . The concentration of ammonia in the blood is increased. Increased excretion of glutamine in urine. The cause of the disease is blocking of carbamyl phosphate synthetase and ornithine carbamoyltransferase, which catalyze the binding of ammonia and the formation of ornithine in the urea cycle.

Citrullinuria . The concentration of citrulline in the blood can increase above normal by 50 times. Up to 15 g of citrulline per day is excreted in the urine. The cause is a hereditary defect in arginine succinate synthetase.

The activity of urea synthesis enzymes is also impaired in liver diseases (hepatitis, congestive cirrhosis), hypoproteinemia, and inhibition of oxidative phosphorylation. Ammonia accumulates in the blood and tissues - ammonium intoxication develops.

Cells are most sensitive to excess ammonia nervous system. In addition to the direct damaging effect of ammonia on nerve cells, ammonia is bound by glutamate, as a result of which it is switched off from metabolism. By accelerating the transamination of amino acids with α-keto-glutaric acid, it is not included in the Krebs cycle, the oxidation of pyruvic and acetic acids is limited and they are converted into ketone bodies. Oxygen consumption decreases. A comatose state develops.

Disorders of uric acid metabolism. Gout. Uric acid is the end product of the metabolism of aminopurines (adenine and guanine) in humans. In reptiles and birds, uric acid is the end product of the metabolism of all nitrogenous compounds. Human blood usually contains 4 mg% uric acid. With excessive consumption of foods rich in purine nucleotides and amino acids, from which purine bases are synthesized in the body (liver, kidneys), the amount of uric acid in the body increases. Its concentration also increases with nephritis and leukemia. Hyperurecemia occurs.

Sometimes hyperurecemia is accompanied by the deposition of uric acid salts in cartilage, tendon sheaths, legs, skin and muscles, since uric acid is poorly soluble. Inflammation occurs around deposits of crystalline urates - a granulation shaft is created surrounding dead tissue, and gouty nodes are formed. Urecemia may be accompanied by the precipitation of uric acid salts in the urinary tract with the formation of stones.

The pathogenesis of gout is not clear. It is believed that the disease is hereditary in nature and is associated with a violation of the factors that maintain uric acid in a soluble state. These factors are associated with the exchange of mucopolysaccharides and mucoproteins, which form the center of crystallization. When liver function is impaired (intoxication), the deposition of urates in tissues and the excretion of urates in the urine increases.

Blood protein disorders

Hypoproteinemia- a decrease in the total amount of protein in the blood, occurring mainly due to a decrease in albumin.

In the mechanism of occurrence of hypoproteinemia, the main pathogenetic factors are acquired hereditary disorders in the synthesis of blood proteins, the release of serum proteins from the bloodstream without subsequent return to the vessels and blood thinning.

Disorders of blood protein synthesis depend on the weakening of synthetic processes in the body (fasting, impaired absorption of food proteins, vitamin deficiencies, exhaustion of the body due to prolonged infectious intoxication or malignant neoplasms, etc.).

The synthesis of blood proteins can also decrease if the function of the organs and tissues that produce these proteins is impaired. In case of liver diseases (hepatitis, cirrhosis), the content of albumin, fibrinogen, and prothrombin in the blood plasma decreases. There are hereditary defects in the synthesis of certain protein fractions of the blood, for example hereditary forms: afibrinogenemia and agammaglobulinemia. Severe insufficiency of gamma globulin synthesis is associated with the complete absence of plasma cells in all tissues in such patients and a significant decrease in the number of lymphocytes in the lymph nodes.

Release of proteins from the bloodstream observed when:

• a) blood loss, wounds, major hemorrhages;
• b) plasma losses, in particular burns;
• c) increasing the permeability of the capillary wall, for example, during inflammation and venous stagnation.

With extensive inflammatory processes The content of albumin in the blood decreases due to their release from the vessels into the interstitial space (Fig. 52). A large amount of albumin is also found in ascitic fluid in portal hypertension and heart failure.

Hypoalbuminemia can occur when protein reabsorption processes in the kidneys are impaired, for example, with nephrosis.

With hypoproteinemia, due to a decrease in albumin content, the oncotic pressure of the blood decreases, which leads to edema.

With an absolute decrease in the amount of albumin in the blood, the binding and transport of cations (calcium, magnesium), hormones (thyroxine), bilirubin and other substances is disrupted, which is accompanied by a number of functional disorders.

With a deficiency of haptoglobin, a protein from the α 2 -globulin fraction, the binding and transport of hemoglobin, released during physiological hemolysis of erythrocytes, is impaired, and hemoglobin is lost in the urine.

A decrease in the synthesis of antihemophilic globulin from the β 2 -globulin fraction leads to bleeding.

With a lack of transferrin, which belongs to β 1 -globulins, iron transfer is impaired.

The main consequence of hypo- or agammaglobulinemia is a decrease in immunity due to impaired production of antibodies (γ-globulins). At the same time, there is no reaction to homologous transplants (antibodies to foreign tissue are not formed and engraftment is possible).

Hyperproteinemia. More often, relative hyperproteinemia develops with an increase in the concentration of proteins in the blood, although their absolute number does not increase. This condition occurs when the blood thickens due to the body losing water.

Absolute hyperproteinemia is usually associated with hyperglobulinemia. For example, an increase in the content of γ-globulins is characteristic of infectious diseases when intense antibody production occurs. Hypergammaglobulinemia can occur as a compensatory reaction to a lack of albumin in the blood. For example, in chronic liver diseases (cirrhosis), albumin synthesis is disrupted; the amount of proteins in the blood does not decrease, but increases due to the intensive synthesis of γ-globulins. In this case, nonspecific γ-globulins can be formed.

The predominance of globulins over albumins changes the albumin-globulin coefficient of blood towards its decrease (normally it is 2-2.5).

In some pathological processes and diseases, the percentage of individual protein fractions in the blood changes, although the total protein content does not change significantly. For example, during inflammation, the concentration of the protective protein properdin increases (from the Latin perdere - to destroy). Properdin, in combination with complement, has bactericidal properties. In its presence, bacteria and some viruses undergo lysis. The content of properdin in the blood decreases with ionizing radiation.

Paraproteinemia . Significant hyperproteinemia (up to 12-15% or more protein in the blood) is observed when a large number of abnormal globulins appear. A typical example of changes in globulin synthesis is myeloma (plasmacytoma). Myeloma is a type of leukemia (paraproteinemic reticulosis).

In γ-myeloma, abnormal globulins are synthesized by tumor clones of plasma cells that enter the peripheral blood, accounting for 60% or more of the total number of leukocytes. Pathological myeloma protein does not have the properties of antibodies. It has a low molecular weight, passes through the kidney filter, and is deposited in the kidneys, contributing to the development of kidney failure in 80% of cases. In myeloma, ROE sharply accelerates (60-80 mm per hour) due to the predominance of globulins over albumins.

There is a disease called Waldenström's macroglobulinemia, characterized by tumor-like proliferation of lymphoid cells and increased production of macroglobulins with a molecular weight above 1,000,000. Macroglobulins are close to group M globulins (JqM); Normally there are no more than 0.12%. With the disease described, their content reaches 80% of the total amount of protein in the plasma, blood viscosity increases 10-12 times, which makes it difficult for the heart to function.

Metabolic disorders in a variety of diseases can be accompanied by the appearance of completely new proteins in the blood. For example, in the acute phase of rheumatism, with streptococcal, pneumococcal infections, myocardial infarction, C-reactive protein was found in the blood serum (it is called C-reactive because it gives a precipitation reaction with the C-polysaccharide of pneumococci). C-reactive protein moves between α- and β-globulins during electrophoresis; does not apply to antibodies. Apparently, its appearance reflects the reaction of the reticuloendothelial system to tissue breakdown products.

An unusual blood protein also includes cryoglobulin, which electric field moves with γ-globulins. Cryoglobulin can precipitate at temperatures below 37°. It appears in myeloma, nephrosis, liver cirrhosis, leukocytes and other diseases. The presence of cryoglobulin in the blood of patients is dangerous, since with strong local cooling the protein precipitates, which contributes to the formation of blood clots and tissue necrosis.