Inhibition of the enzyme that breaks down the mediator. irreversible inhibition
Enzyme inhibition
Drugs often inhibit enzyme activity
Covalent (chemical) modification
Activation of protein kinase A by cAMP
Covalent modification consists in the reversible addition or elimination of a certain group, due to which the activity of the enzyme changes. Most often, such a group is phosphoric acid, less often methyl and acetyl groups. Phosphorylation of the enzyme occurs at the residues of serine and tyrosine. The addition of phosphoric acid to protein is carried out by enzymes. protein kinases, splitting - protein phosphatase.
Change in enzyme activity
during phosphorylation-dephosphorylation
Enzymes can be active in either the phosphorylated or dephosphorylated state.. For example, the enzymes glycogen phosphorylase and glycogen synthase are phosphorylated when the body needs glucose, while glycogen phosphorylase becomes active and begins the breakdown of glycogen, and glycogen synthase inactive. When glycogen synthesis is required, both enzymes are dephosphorylated, synthase becomes active, and phosphorylase becomes inactive.
Dependence of the activity of metabolic enzymes
glycogen from the presence of phosphoric acid in the structure
In medicine, compounds are being actively developed and used that change the activity of enzymes in order to regulate the rate of metabolic reactions and reduce the synthesis of certain substances in the body.
Inhibition of enzyme activity is commonly referred to as inhibition, however, this is not always correct. Inhibitor a substance that causes a specific decrease in the activity of an enzyme is called. Thus, inorganic acids and heavy metals are not inhibitors, but are inactivators, since they reduce the activity of any enzymes, i.e. operate non-specific.
There are two main directions of inhibition
According to the strength of the binding of the enzyme to the inhibitor, inhibition can be reversible And irreversible.
In relation to the inhibitor to the active site of the enzyme, inhibition is divided into competitive And non-competitive.
With irreversible inhibition, the binding or destruction of the functional groups of the enzyme necessary for the manifestation of its activity occurs.
For example, substance diisopropylfluorophosphate binds strongly and irreversibly to the hydroxy group of serine in the active site of the enzyme acetylcholinesterase hydrolyzing acetylcholine at nerve synapses. Inhibition of this enzyme prevents the breakdown of acetylcholine in the synaptic cleft, as a result of which the mediator continues to act on its receptors, which uncontrollably enhances cholinergic regulation. Combat works in the same way. organophosphates(sarin, soman) and insecticides(karbofos, dichlorvos).
With irreversible inhibition, the binding or destruction of the functional groups of the enzyme necessary for the manifestation of its activity occurs.
For example, substance diisopropylfluorophosphate binds strongly and irreversibly to the hydroxy group of serine in the active site of the enzyme acetylcholinesterase hydrolyzing acetylcholine at nerve synapses. Inhibition of this enzyme prevents the breakdown of acetylcholine in the synaptic cleft, as a result of which the mediator continues to act on its receptors, which uncontrollably enhances cholinergic regulation. Combat works in the same way. organophosphates(sarin, soman) and insecticides(karbofos, dichlorvos).
Mechanism of irreversible inhibition of acetylcholinesterase
Another example is related to the inhibition acetylsalicylic acid(aspirin) a key enzyme in the synthesis of prostaglandins - cyclooxygenases. This acid is part of anti-inflammatory drugs and is used in inflammatory diseases and feverish conditions. Attachment of the acetyl group to the amino group in the active site of the enzyme causes inactivation of the latter and cessation of prostaglandin synthesis.
Mechanism of irreversible inhibition of cyclooxygenase
Reversible inhibition
With reversible inhibition, the inhibitor is not firmly bound to the functional groups of the enzyme, as a result of which the activity of the enzyme is gradually restored.
An example of a reversible inhibitor is prozerin that binds to an enzyme acetylcholinesterase in its active center. A group of cholinesterase inhibitors (prozerin, distigmine, galantamine) is used for myasthenia gravis, after encephalitis, meningitis, and CNS injuries.
Competitive inhibition
In this type of inhibition, the inhibitor is structurally similar to the substrate of the enzyme. Therefore, it competes with the substrate for the active site, which leads to a decrease in the binding of the substrate to the enzyme and disruption of catalysis. This is the feature of competitive inhibition, i.e., the ability to enhance or weaken inhibition through a change in the concentration of the substrate.
For example:
1. Competitive interaction ethanol And methanol for the active center alcohol dehydrogenase.
2. Inhibition succinate dehydrogenase malonic acid, the structure of which is similar to the structure of the substrate of this enzyme - succinic acid (succinate).
In medicine, compounds are being actively developed and used that change the activity of enzymes in order to regulate the rate of metabolic reactions and reduce the synthesis of certain substances in the body.
Inhibition of enzyme activity is commonly referred to as inhibition, however, this is not always correct. An inhibitor is a substance that causes specific decrease in enzyme activity. Thus, inorganic acids and heavy metals are not inhibitors, but are inactivators, as they reduce the activity of many enzymes, i.e. operate non-specific.
In scientific activity, for a more accurate description of the inhibition processes, the Michaelis-Menten kinetics and its terms - the maximum speed (Vmax) and the Michaelis constant (Km) are used.
Enzyme inhibition
There are two main directions of inhibition
- according to the binding strength of the enzyme to the inhibitor, inhibition is reversible and irreversible.
- In relation to the inhibitor to the active site of the enzyme, inhibition is divided into competitive and non-competitive.
irreversible inhibition
With irreversible inhibition, the binding or destruction of the functional groups of the enzyme necessary for the manifestation of its activity occurs.
For example, substance diisopropylfluorophosphate binds strongly and irreversibly to the hydroxy group of serine in the active site of the enzyme acetylcholinesterase hydrolyzing acetylcholine at nerve synapses. Inhibition of this enzyme prevents the breakdown of acetylcholine in the synaptic cleft, as a result of which the mediator continues to act on its receptors, which uncontrollably enhances cholinergic regulation.
Similarly, diisopropylfluorophosphate inhibits chymotrypsin and other proteases that have serine in the active center (serine proteases).
Diisopropylfluorophosphate refers to nerve poisons, combat organophosphorus substances (sarin, soman) act in a similar way. This also includes the substance "malathion", which is included in insecticides (karbofos, dichlorvos) and turns into an acetylcholinesterase inhibitor in the body of insects, and decomposes to harmless products in the body of animals and humans.
Mechanism of irreversible inhibition of acetylcholinesterase
Another example is related to the inhibition acetylsalicylic acid(aspirin) a key enzyme in the synthesis of prostaglandins - cyclooxygenases. This acid is part of anti-inflammatory drugs and is used in inflammatory diseases and feverish conditions. Attachment of an acetyl group to the hydroxyl group of serine in the active site of the enzyme causes inactivation of the latter and cessation of prostaglandin synthesis.
Mechanism of irreversible inhibition of cyclooxygenase
A third illustrative example of irreversible inhibition is the effect of an antibiotic penicillin for enzyme transpeptidase, which cross-links peptidoglycan chains as the last step in the synthesis of the bacterial cell wall.
Reversible inhibition
With reversible inhibition, the inhibitor is not firmly bound to the functional groups of the enzyme, as a result of which the activity of the enzyme is gradually restored.
An example of a reversible inhibitor is prozerin that binds to an enzyme acetylcholinesterase in its active center. A group of cholinesterase inhibitors (prozerin, distigmine, galantamine) is used for myasthenia gravis, after encephalitis, meningitis, and CNS injuries.
Competitive inhibition
In this type of inhibition, the inhibitor is structurally similar to the substrate of the enzyme. Therefore, it competes with the substrate for the active center (for the contact site), which leads to a decrease in the binding of the substrate to the enzyme and disruption of catalysis. This is the feature of competitive inhibition, i.e., the ability to enhance or weaken inhibition through a change in the concentration of the substrate. With this inhibition the maximum reaction rate remains quite achievable when creating high concentrations of the substrate.
For example:
1. Inhibition of the tricarboxylic acid cycle enzyme succinate dehydrogenase malonic acid, the structure of which is similar to the structure of the substrate of this enzyme - succinic acid (succinate).
Competitive inhibition of succinate dehydrogenase
2. Antimetabolites or pseudosubstrates e.g. antibacterial agents sulfonamides, similar in structure to para-aminobenzoic acid, a component of folic acid. When treated with sulfonamides in a bacterial cell, competition occurs between sulfonamide and para-aminobenzoic acid in the synthesis of dihydrofolic acid, which causes a therapeutic effect.
3. Other examples of drug competitive inhibitors include
- cholesterol synthesis inhibitor lovastatin, reversibly inhibiting HMG-S-CoA reductase,
- anticancer drug methotrexate, which irreversibly inhibits dihydrofolate reductase,
- indirect anticoagulant dicoumarol, a competitor of vitamin K,
- antihypertensive drug methyl-DOPA, which inhibits the activity of DOPA decarboxylase,
- remedy for gout allopurinol, which inhibits xanthine oxidase.
An example of competition but not inhibition (!), is the interaction ethanol And methanol for the active site of alcohol dehydrogenase. In this case, there is no inhibition, as such, but the alcohol with a higher concentration binds to the active center of the enzyme. This effect is used in patients with methanol poisoning, for which ethyl alcohol is an antidote.
Noncompetitive inhibition
This type of inhibition is associated with the attachment of the inhibitor not in the active center, but in another place of the molecule. However, the structure of the active center changes and the connection with the substrate becomes impossible. This can be allosteric inhibition, when the activity of the enzyme is reduced by natural modulators, or the binding of any substances to the enzyme outside the active and allosteric center. For example:
- hydrocyanic acid(cyanides) binds to the heme iron of respiratory chain enzymes and blocks cellular respiration,
- ion binding heavy metals(Cu 2+ , Hg 2+ , Ag +) with SH-groups of proteins.
Another example is fructose-1,6-diphosphate, which, by inhibiting adenylosuccinate synthetase (synthesis of purine nucleotides), synchronizes the functioning of the purine nucleotide cycle and glycolysis in the muscle, which supplies energy for muscle contraction.
A feature of a non-competitive inhibitor is its ability to bind to the enzyme regardless of the substrate, i.e. change in substrate concentration does not affect to the formation of an enzyme-inhibitor complex.
Uncompetitive inhibition
In this case, the inhibitor binds in the active site to enzyme-substrate complex. Increasing the concentration of the substrate, increasing the amount of the enzyme-substrate complex, enhances the binding of the inhibitor to it. Thus, uncompetitive inhibition is more complex than other types of inhibition.
An example of uncompetitive inhibition is usually called the binding penicillin and enzyme transpeptidase, which provides cross-linking of peptidoglycan chains during the synthesis of the bacterial cell wall.
Penicillin is integrated into the active site of the enzyme and its lactam ring mimics under transitional the state of the enzyme is enzyme-substrate. Although the situation is similar to competitive inhibition, due to the simultaneous decrease Vmax And km this case is classified as uncompetitive.
On the example of penicillin, the so-called. suicidal inhibition. With it, the substrate initially binds to the enzyme reversibly, and then forms a stable covalent bond with the active center, which leads to inhibition of the enzyme activity.
Mixed inhibition
With such inhibition, the inhibitor is able to bind everywhere, not only in the active site, but also in other parts of the molecule. But after that, the enzyme is still able to partially retain its activity. An example is the influence merthiolate(mercury organic matter) on sucrase fungi micromycetes to suppress their growth.
Non-specific inhibitors. Inhibitors to influenza viruses in normal human and animal blood sera were discovered in 1942 by Hurst.
The cells of the body produce special virotropic substances - inhibitors that can interact with viruses and suppress their activity. Thus, serum inhibitors have a wide range of action: some suppress the hemagglutinating properties of viruses, others - their infectious activity. Serum inhibitors are divided into: heat-labile (Chu-inhibitors, β-inhibitors), which are inactivated at a temperature of 60-62 °C. They are able to neutralize the infectious and hemagglutinating activity of influenza viruses, measles, Newcastle disease, etc.; thermostable (Francis, α- and γ-inhibitors). They block the hemagglutinating activity of the virus.
Different viruses (even of the same species) differ in their sensitivity to inhibitors. There are inhibitor-sensitive and inhibitor-resistant strains.
Profound differences in the biochemical nature of inhibitors and their quantitative content in the blood sera of animals of various species have been established.
There is a difference between inhibitors and antibodies in their interaction with the virus. Thus, unlike antibodies, the inhibitor-virus complex does not fix complement; the virus combines with antibodies in the presence of antibodies and inhibitors; the virus with antibodies forms a stronger bond.
In addition to serum inhibitors, inhibitors are described in tissues, secrets and excretions of animals, including birds, as well as in cell cultures.
Interferon system (IFN). In 1957 English virologists A. Isaacs and J. Lindeman discovered that cells infected with a virus produce a special substance that inhibits the reproduction of both homologous and heterologous viruses, which they called interferon. It has been established that there is not one interferon, but a whole system of them, in which three main types are distinguished.
The nomenclature of interferons was developed by a special commission of WHO in 1980.
Within each type there are subtypes, for example, α-interferon has about 20 of them. By nature, interferons are glycoproteins. They are encoded in the genetic apparatus of the cell. In humans, interferon genes are localized on chromosomes 2, 5, 9 and 11.
The interferon system does not have a central organ, since all cells of the body of vertebrates have the ability to produce interferon, although white blood cells (leukocytes, T-lymphocytes, NK, macrophages, etc.) produce it most actively.
Interferon is not spontaneously produced by cells. For its formation, an inductor is needed (viruses, bacterial toxins, synthetic substances, double-stranded viral RNA).
Induction of interferon occurs due to derepression of its gene (the operon for α-interferon has 12 structural genes). Transcription of mRNA for interferon and its translation on the ribosomes of the cell occur.
The time interval between the interaction of the inductor and the cell and the appearance of interferon (lag period) usually lasts 4-8 hours. Interferon does not interact directly with the virus, does not prevent the adsorption of the virus on the cell and its penetration into it.
The antiviral effect of interferon is not associated with the synthesis of any new protein, but is manifested in an increase in the activity of a number of key enzymes of cellular metabolism (protein kinases and synthetase). As a result, the stages of initiation and translation are blocked and the destruction of viral mRNAs occurs - this determines the universal mechanism of action of interferon in infections caused by different viruses. The most characteristic properties of interferon: tissue specificity. It is active in homologous systems and sharply reduces activity in heterogeneous organisms (therefore, interferons of human origin are used for human treatment);
universality against a wide range of viruses, that is, it does not have specificity for viruses, although different viruses have unequal sensitivity to interferon;
high efficiency. Small doses of it have antiviral activity.
The study of the properties of interferons showed that they also have antibacterial properties (especially against gram-positive bacteria), antitumor activity and immunomodulatory properties. Interferons stimulate the activity of natural killer cells and cytotoxic T-lymphocytes, increase the sensitivity of target cells to them, stimulate phagocytosis, antibody formation, complement fixation, etc.
The biological activity of different interferons can be expressed to varying degrees, for example, α- and β-interferons have a higher antiviral activity than γ-interferons, which have many times greater immunomodulatory activity.
One of the factors that determine the body's resistance is the ability of its tissues to produce interferon. In different animals, it is not the same and is determined by the innate characteristics of the organism, age (interferon of newborns exhibits a lower antiviral effect compared to interferon of adult animals). In addition, the production of interferon by body tissues is also affected by external conditions, for example, weather, air temperature (in winter and autumn, the body produces less interferons than in the warm season), ionizing radiation of animals leads to a decrease in the production of endogenous interferon.
In practice, there are two ways to use interferon: the use of ready-made exogenous homologous interferon for the prevention and treatment of a number of viral infections (influenza, hepatitis B, herpes and malignant neoplasms). The drug is more effective in the early stages of the disease; induction of endogenous interferon in the body. Its manifestation is well known when vaccine strains of the Newcastle disease virus, as well as lapinized strain L3 and LT of the rinderpest virus are administered to birds.
Currently, interferons are produced by a genetic engineering method.
killer cells. In 1976, natural killers were found in lymphoid tissue - NK cells (from the English. Natural killer - natural killer), they are also referred to as natural killers (NK cells). They are derived from progenitor cells in the bone marrow. The content of NK cells in the blood is 5-20% of the total number of lymphocytes, in the liver - 42%, in the spleen - 36, in the lymph nodes - 3, in the lungs - 5, in the small intestine - 3 and in the bone marrow - 2%. Unlike T-cytotoxic lymphocytes, the killer activity of NK cells does not depend on the presentation of foreign antigens by MHC class I molecules.
Recognition and destruction of target cells by NK cells does not require prior sensitization (immunization) and is not accompanied by the formation of memory cells. However, NK cells play an important role in protecting the body against tumor growth, tumor metastases and viral infections - in the elimination of mutated and virus-infected cells, transplant rejection. Essentially, natural killers are involved in the body's first defense response before other, specific, immune mechanisms are activated. NK cells cause lysis of target cells that are independent of antibodies and complement, and at the same time do not have the ability to phagocytosis. The cytotoxic factor of NK cells is a special protein, which in its physicochemical and immunological properties is similar to the protein perforin, which causes the formation of pores in the membrane of target cells. NK cells also contain granzymes that cause the induction of apoptosis (programmed cell death) upon penetration into target cells.
After lysis of target cells, NK cells remain viable, are released from targets and can interact with a new target cell (recycled NK cells). NK cells kill target cells quickly (1-2 hours) without preparation in the form of an immune response, which distinguishes them from T-lymphocytes.
In addition to NK cells, antibody-dependent K-cells (antibody-dependent cell-mediated cytotoxicity - ADCC) have natural cytotoxicity not caused by previous immunization.
Thanks to the well-coordinated interaction of the systems of macrophages, interferons, complement, the main histocompatibility complex, T-lymphocytes and natural killers, even before the acquisition of specific immunity, timely recognition and destruction of all genetically alien substances (microorganisms and mutant cells) is ensured. As a result, the structural and functional integrity of the body is preserved.
At the same time, these systems serve as the basis for the formation of acquired (specific) immunity, and at their level, specific and acquired immunity merge, forming a single and most effective system of self-defense of the body.
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Ticket 9.
1. Enzyme inhibitors: reversible and irreversible. Drugs as enzyme inhibitors Inhibitors should include substances that cause a decrease in enzyme activity.
Inhibitors are able to interact with enzymes with varying degrees of strength. Based on this, a distinction is made between reversible and irreversible inhibition. According to the mechanism of action, inhibitors are divided into competitive and non-competitive.
Reversible inhibition. Reversible inhibitors bind to the enzyme by weak non-covalent bonds and, under certain conditions, are easily separated from the enzyme. Reversible inhibitors are either competitive or non-competitive.
competitive inhibition. Competitive inhibition refers to a reversible decrease in the rate of an enzymatic reaction caused by an inhibitor that binds to the active site of the enzyme and prevents the formation of the enzyme-substrate complex. This type of inhibition is observed when the inhibitor is a structural analogue of the substrate, resulting in competition between the substrate and inhibitor molecules for a place in the active site of the enzyme (inhibition of the succinate dehydrogenase reaction by malonic acid). Drugs as competitive inhibitors Many drugs exert their therapeutic effect through the mechanism of competitive inhibition .(drugs - prozerin, endrophonium, etc.)
Non-competitive inhibition Non-competitive inhibition of an enzymatic reaction is called such inhibition of an enzymatic reaction, in which the inhibitor interacts with the enzyme at a site other than the active site. Non-competitive inhibitors are not structural analogues of the substrate. A non-competitive inhibitor can bind to either the enzyme or the enzyme-substrate complex to form an inactive complex. The addition of a non-competitive inhibitor causes a change in the conformation of the enzyme molecule in such a way that the interaction of the substrate with the active site of the enzyme is disrupted, which leads to a decrease in the rate of the enzymatic reaction.
Irreversible inhibition. Irreversible inhibition is observed in the case of the formation of covalent stable bonds between the inhibitor molecule and the enzyme. Most often, the active center of the enzyme undergoes modification. As a result, the enzyme cannot perform a catalytic function. Irreversible inhibitors include heavy metal ions, such as mercury (Hg2+), silver (Ag+), and arsenic (As3+), which block the sulfhydryl groups of the active center at low concentrations. In this case, the substrate cannot undergo chemical transformation. Irreversible enzyme inhibitors as drugs An example of a drug whose action is based on irreversible enzyme inhibition is the widely used drug aspirin. The anti-inflammatory non-steroidal drug aspirin provides a pharmacological effect by inhibiting the cyclooxygenase enzyme, which catalyzes the formation of prostaglandins from arachidonic acid. As a result of a chemical reaction, the acetyl residue of aspirin is attached to the free terminal NH2 group of one of the cyclooxygenase subunits. This causes a decrease in the formation of prostaglandin reaction products (see Section 8), which have a wide range of biological functions, including mediators of inflammation.
2. Gluconeogenesis, key enzymes, significance for the body. Regulation of glycolysis and gluconeogenesis in the liver. Corey cycle. Glucose-alanine cycle.
Gluconeogenesis - synth of glucose from non-carbohydrate products (lactic acid, PVC, the so-called glycogenic amino acids, glycerol. In other words, glucose precursors in gluconeogenesis can be pyruvate or any compound that turns into pyruvate or one of the intermediate products of the tricarboxylic acid cycle during catabolism .In vertebrates, gluconeogenesis occurs most intensively in the cells of the liver and kidneys (in the cortex).
As is known, there are three irreversible reactions in glycolysis: pyruvate kinase (tenth), phosphofructokinase (third), and hexokinase (first). These reactions release energy for ATP synthesis. Therefore, in the reverse process, energy barriers arise, which the cell bypasses with the help of additional reactions.
Bypassing the tenth reaction of glycolysis. At this stage of gluconeogenesis, two key enzymes work - pyruvate carboxylase in the mitochondria and phosphoenolpyruvate carboxykinase in the cytosol. Bypassing the third glycolysis reaction. The second obstacle to glucose synthesis, the phosphofructokinase reaction, is overcome by the enzyme fructose-1,6-diphosphatase. This enzyme is found in the kidneys, liver, and striated muscles. Thus, these tissues are able to synthesize fructose-6-phosphate and glucose-6-phosphate. Bypass of the first glycolysis reaction. The last reaction is catalyzed by glucose-6-phosphatase. It is present only in the liver and kidneys, therefore, only these tissues can produce free glucose.
The glucose-lactate cycle (Cori) is a combination of gluconeogenesis and anaerobic glycolysis.
The purpose of the glucose-alanine cycle is to remove excess nitrogen from the muscle. During muscular work and at rest, proteins break down in the myocyte and the amino acids formed are transaminated with α-ketoglutarate. The resulting glutamate interacts with pyruvate. The resulting alanine is the transport form of nitrogen and pyruvate from the muscle to the liver. In the hepatocyte, a reverse transamination reaction occurs, the amino group is transferred to the synthesis of urea, pyruvate is used to synthesize glucose. In addition to muscle work, the glucose-alanine cycle is activated during starvation, when muscle proteins break down and many amino acids are used as an energy source, and their nitrogen must be delivered into the liver.
Regulation of glycolysis and gluconeogenesis in the liver There are three main areas where these processes are regulated: the first reaction of glycolysis, the third reaction of glycolysis and its reversibility, the tenth reaction of glycolysis and its reversibility.
Regulation of gluconeogenesis. Hormonal activation of gluconeogenesis is carried out by glucocorticoids, which increase the synthesis of pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-diphosphatase. Glucagon stimulates the same enzymes through the adenylate cyclase mechanism by phosphorylation.
There is also metabolic regulation, in which pyruvate carboxylase is allosterically activated with the help of acetyl-SCoA, fructose-1,6-diphosphatase with the participation of ATP.
regulation of glycolysis. Glycolysis is stimulated by insulin, which increases the number of molecules of hexokinase, phosphofructokinase, pyruvate kinase.
In the liver, glucokinase activity is regulated by hormones: insulin and androgens cause activation, and glucocorticoids and estrogens suppress its activity.
Phosphofructokinase is sensitive for metabolic regulation. It is activated by AMP and its own substrate, inhibited by ATP, citric acid, fatty acids. Pyruvate kinase is activated by fructose-1,6-diphosphate. Non-hepatic cell hexokinase is inhibited by its own reaction product, glucose-6-phosphate.
3. hemolytic jaundice. Total bilirubin concentration 75% indirect belirubin. erythrocyte membrane defect = increased fragility and reduced elasticity of the membrane = accelerated destruction in the vascular bed and spleen = increased production of free hemoglobin = increased production of bilirubin, exceeding the ability of the liver to remove it = accumulation in the bloodstream, tissues = yellowness of the skin and mucous membranes.
Ticket 10
1. Differences in the enzymatic composition of organs and tissues. Enzymodiagnostics and enzyme therapy. Cofactors of enzymes - metal ions. Organ specificity. The enzyme composition of different cells is not the same. Enzymes that perform the function of cell life support are found in all cells of the body. In the process of cell differentiation, a change in the enzymatic composition of cells occurs. If we talk about highly specialized cells, then there are more enzymes that perform functions in these cells than in other cells. For example, in cardiac muscle cells there is an increased amount of creatine kinase and aspartate aminotransferase enzymes, in liver cells - alanine aminotransferase and aspartate aminotransferase, in osteoblasts - alkaline phosphatase, etc. Compartmentalization. A cell is a complex functional system that regulates its life support .. So, in the nucleus there are enzymes associated with the synthesis of DNA and RNA molecules, in the cytoplasm - glycolysis enzymes, in lysosomes - hydrolytic enzymes, etc. basis for determining the activity of enzymes in human biological fluids. The principles of enzymodiagnostics are based on the following positions:
when cells are damaged in the blood or other biological fluids (for example, in urine), the concentration of intracellular enzymes of damaged cells increases;
the amount of released enzyme is sufficient for its detection;
the activity of enzymes in biological fluids detected when cells are damaged is stable for a sufficiently long time AND differs from normal values;
a number of enzymes have a predominant or absolute localization in certain organs (organ specificity);
there are differences in the intracellular localization of a number of enzymes.
In many diseases, cell damage occurs, and their contents, including enzymes, are released into the blood. The reasons causing the release of intracellular contents into the blood include a violation of the permeability of the cell membrane (in inflammatory processes) or a violation of the integrity of cells (with necrosis). However, an increase in the concentration of enzymes is not always associated with tissue damage. With excessive cell proliferation, for example, with oncoproliferative processes, with an increased rate of synthesis of certain enzymes in cells or with impaired clearance, an increase in the concentration of certain enzymes in the blood is observed. Enzyme therapy. Enzyme replacement therapy is effective in gastrointestinal diseases associated with insufficient secretion of digestive juices. As additional therapeutic agents, enzymes are used in a number of diseases. Proteolytic enzymes (trypsin, chymotrypsin) are used locally to treat purulent wounds in order to break down the proteins of dead cells, to remove blood clots or viscous secrets in inflammatory diseases of the respiratory tract. Enzyme preparations ribonuclease and deoxyribonuclease are used as antiviral drugs in the treatment of adenoviral conjunctivitis, herpetic keratitis.
Cofactors. Metal ions perform the function of stabilizers of the substrate molecule, the active center of the enzyme and the conformation of the protein molecule of the enzyme, namely the tertiary and quaternary structures. For some enzymes, the substrate is a complex of the converted substance with a metal ion. For example, for most kinases, one of the substrates is not the ATP molecule, but the Mg2+-ATP complex.
In some cases, metal ions serve as a "bridge" between the enzyme and the substrate. They act as active site stabilizers, facilitating the attachment of a substrate to it and the occurrence of a chemical reaction. In some cases, the metal ion can contribute to the addition of the coenzyme. The functions listed above are performed by such metals as Mg2+, Mn2+, Zn2+, Co2+, Mo2+. Metal ions ensure the preservation of the secondary, tertiary, quaternary structure of the enzyme molecule. Such enzymes in the absence of metal ions are capable of chemical catalysis, but they are unstable. Their activity decreases and even completely disappears with small changes in pH, temperature, and other minor changes in the external environment.
2. Metabolism of fructose and galactose. Hereditary disorders of their metabolism.
Fructose metabolism begins with a phosphorylation reaction catalyzed by fructokinase with arr fructose-1-phosphate. The enzyme is found in the liver, as well as in the kidneys and intestines. This enzyme is absolutely specific, therefore, unlike glucokinase, insulin does not affect its activity. Fructose-1-phosphate is further cleaved by fructose-1-phosphate aldolase (aldolase B) into glyceraldehyde and dihydroxyacetone-3-phosphate. The latter is an intermediate product. Glyceraldehyde can be included in glycolysis after its phosphorylation with the participation of ATP. Two molecules of triose phosphates either break down along the glycolytic pathway or condense to form fructose-1,6-bisphosphate and then participate in gluconeogenesis. Fructose in the liver is mainly in the second way. Part of dihydroxyacetone-3-phosphate can be reduced to glycerol-3-phosphate and participate in the synthesis of triacylglycerols. It should be noted that the incorporation of fructose into metabolism via fructose-1-phosphate bypasses the step catalyzed by phosphofructokinase, which is the point of metabolic control of the rate of glucose catabolism. This circumstance can explain why an increase in the amount of fructose accelerates the processes in the liver leading to the synthesis of fatty acids, as well as their esterification with the formation of triacylglycerols. Deficiency of fructokinase. Fructose accumulates in the blood and is excreted in the urine, where it can be detected by laboratory methods. It is very important not to confuse this harmless anomaly with diabetes mellitus. Hereditary fructose intolerance, which occurs with a genetically determined defect in fructose-1-phosphate aldolase, does not appear while the child is breastfeeding, i.e. as long as the food does not contain fructose. Symptoms occur when fruits, juices, sucrose are added to the diet. Vomiting, abdominal pain, diarrhea, hypoglycemia, and even coma and convulsions occur 30 minutes after ingestion of food containing fructose. Young children and adolescents who continue to take fructose develop chronic liver and kidney dysfunction.
Metabolism of galactose. To convert galactose into glucose, it is necessary to change the optical configuration of the H- and OH-groups of the C4 atom in galactose, i.e. carry out the epimerization reaction. This reaction in the cell is possible only with the UDP-derivative of galactose. However, the inclusion of galactose in the described epimerization reaction is preceded by its phosphorylation with the formation of galactose-1-phosphate. Further, galactose-1-phosphate replaces the glucose residue in UDP-glucose with the formation of UDP-galactose, i.e. no direct reaction of phosphorylated galactose with UTP occurs. Reaction 2 can be considered as the transfer of a uridyl residue from UDP-glucose to galactose, therefore the enzyme is named galactose-1-phosphate uridyltransferase (GALT). Then, galactose as part of the nucleotide is included in the epimerization reaction, in which epimerase, a NAD-dependent enzyme that catalyzes the oxidation and reduction of galactose at the C4 carbon atom, participates. Glucose-1-phosphate formed in reaction 2 can be involved in different metabolic pathways: 1) glycogen synthesis after reaction with UDP and formation of UDP-glucose; 2) conversion in the liver into free glucose and maintaining its concentration in the blood; 3) catabolism associated with the synthesis of ATP, etc.
3. Obstructive jaundice, caused by blockage of the bile duct by a gallbladder stone. Bilirubin does not enter the intestines, the product of its catabolism, urobelin, is not in the urine and feces, feces are provided. There is a leak of bilirubin into the blood, so the patient has an increased content of conjugated bilirubin. Dissolved bilirubin is excreted in the urine giving it a rich color. Total bilirubin 8.5-20.5 µmol/l.
Ticket 11
1. Coenzyme functions of water-soluble vitamins (on the example of transaminases and dehydrogenases, vitamins B6, PP, B2, etc.).
Water solution vitamins are enzyme vitamins, that is, they perform coenzyme functions as part of enzymes. The manifestations and mechanisms of hypovitaminosis for various enzymes are interrelated and overlap, although specific avitaminosis has been described for most of them.
Vitamin B2, riboflavin. is part of two coenzymes FMN and FAD, which are components of such enzymes as succinate dehydrogenase, fatty acid dehydrogenase, amino acid oxidase, MAO, cytochrome reductase. Vitamin B5, PP is part of the coenzymes NAD and NADP, which are coenzymes of more than a hundred dehydrogenases involved in tissue respiration , oxidation of lactic, malic, ketoglutaric, isocitric acids, phosphoglyceraldehyde, fatty acids, etc. Vitamin B6, pyridoxine This vitamin in the form of coenzymes PALF (pyridoxal phosphate) and PAMF (pyridoxamine phosphate) is part of the enzymes of transamination, deamination and decarboxylation of amino acids. In reactions involving pyridoxine, absorption and transport of amino acids is carried out, the amino acid composition of the body is balanced. Vitamin H, biotin serves as a coenzyme for carboxylase, such as pyruvate carboxylase, acetyl-CoA carboxylase, propionyl-CoA carboxylase. Biotin binds a carbon dioxide molecule and incorporates it into organic matter. As a coenzyme, vitamin H is involved in the synthesis of fatty acids, sterols, purine bases, urea, the conversion of piovic acid into oxaloacetic acid. Vitamin B3, pantothenic acid is part of the acetylation coenzyme (CoA), which activates acetate and acyl groups necessary for the synthesis of fatty acids. acids, sterols, acetylcholine. Pantothenic acid is involved in the biosynthesis of fatty acids
2. Classification of lipids. Neutral fats, their biological role. Essential fatty acids, vitamin F.
Lipids are a large group of substances of biological origin, highly soluble in organic solvents such as methanol, acetone, chloroform and benzene. At the same time, these substances are insoluble or slightly soluble in water. Weak solubility is associated with an insufficient content in lipid molecules of atoms with a polarizable electron shell, such as O, N, S or P. The classification of lipids is difficult, since the class of lipids includes substances very diverse in structure. They are united by only one property - hydrophobicity. In relation to hydrolysis in an alkaline environment, all lipids are divided into two large groups: saponifiable and unsaponifiable.
Triacylglycerols (TAGs, triglycerides, triacylglycerols, neutral fats) are the most abundant lipids in the human body. On average, their share is 16-23% of the body weight of an adult.
The functions of triacylglycerols are reserve-energy - the average person has enough subcutaneous fat reserves to maintain life for 40 days of complete starvation, heat-saving - due to the thickness of subcutaneous fat, mechanical protection of the body and internal organs in the subcutaneous and mesenteric adipose tissue.
TAG contains trihydric alcohol glycerol and three fatty acids. Fatty acids can be saturated (palmitic, stearic) and monounsaturated (palmitoleic, oleic). By structure, simple and complex TAGs can be distinguished. In simple TAGs, all fatty acids are the same, for example, tripalmitate, tristearate. In complex TAGs, fatty acids differ, for example, dipalmitoyl stearate, palmitoyl oleyl stearate.
The daily requirement for neutral fats is taken at the level of 80-100 g, vegetable oils should be at least 30% of the total amount of fat. However, due to lifestyle changes in developed countries (overeating, physical inactivity), in recent years there has been a tendency to revise the recommended values downward to 30-40 g / day.
Essential fatty acids (vitamin F). Under this name - vitamin F - combine unsaturated fatty acids, primarily linoleic, linolenic and arachidonic, which are not synthesized in the body and therefore are indispensable. Unsaturated fatty acids, like other fatty acids, are absorbed in the small intestine and transported by the blood to the organs. In body tissues, they are used to form lipids that are part of biological membranes and are involved in the regulation of metabolism. Unsaturated fatty acids are necessary for the normal growth and regeneration of the skin epithelium, as well as for the production of prostaglandins - hormones that are essential for our body. Vitamin F helps to reduce the level of cholesterol in the blood, prevents its deposition in the blood vessels.
Vitamin F deficiency is rare in humans. Hypovitaminosis F causes follicular hyperkeratosis, that is, excessive keratinization of the skin epithelium around the hair follicles. In experimental animals with a significant lack of vitamin F, cases of infertility were observed. The main source of unsaturated fatty acids is vegetable oils, primarily sunflower, soybean, peanut, as well as almonds, avocados, and fish oils.
3. 1. This is a classic case of gout. In this case, all signs of inflammation were present, and hyperuricemia was laboratory confirmed. Renal colic could be due to renal urate stone. Gout is more common in obese men than in women, and is more common with hypertriglyceridemia, hypertension, overeating, and alcohol abuse.
2. In humans, uric acid is the end product of purine nucleotide metabolism and is excreted from the body in the urine. Polymorphism of enzymes involved in the synthesis of purine nucleotides (phosphoribosyl pyrophosphate synthetase - FRPP synthetase), accompanying a sample of proteins with low enzymatic activity or insensitive to the action of allosteric effectors. At the same time, the regulation of the synthesis of purine nucleotides was disrupted by the negative feedback mechanism. Over-synthesized nucleotides are catabolized, and the rate of uric acid rises. The same result is obtained with a decrease in the activity of purine recycling pathways (the enzyme hypoxanthine-guanine-phosphoribosiptransferase). Adenine, guanine, and hypoxanthine are not reused but are converted to uric acid, resulting in hyperuricemia. The consequence of hyperuricemia (a state of the body in which the content of uric acid in the blood serum exceeds the level of solubility) is the crystallization of urates in soft tissues and ligaments. Sodium urate crystals that form in the joints are taken up by neutrophils but damage the membranes of their lysosomes, causing cell destruction. The formation of free superoxide radicals and the release of lysosomal enzymes into the joint cavity cause an acute inflammatory reaction. The release of interleukin-1 from monocytes and tissue macrophages provides an additional inflammatory stimulus. The deposition of urates in the kidney tissue leads to the development of renal failure, a common complication of gout. Urates can also be deposited in the renal pelvis, forming kidney stones (in about half of patients with gout).
3. It is required to prescribe allopurinol to the patient. Allopurinol is a structural analog of hypoxanthine. Xanthine oxidase oxidizes allopurinol to oxypurinol (an analogue of xanthine), but this reaction product remains firmly bound to the active center of the enzyme: thus, the enzyme is inactivated (suicidal catalysis): In this case, hypoxanthine becomes the end product of purine catabolism, the solubility of which in urine and other fluids the body is about 10 times greater than the solubility of uric acid, and therefore hypoxanthine is more easily excreted from the body.
Ticket number 12
1. Metabolism: nutrition, metabolism and excretion of metabolic products. The composition of human food. organic and mineral components. Major and minor components.
Basic nutrients: carbohydrates, fats, proteins; daily requirement, digestion; partial interchangeability in nutrition. Essential components of essential nutrients. Essential amino acids; nutritional value of different proteins. Essential fatty acids.
Metabolism: nutrition, metabolism and excretion of metabolic products. The composition of human food.
Proteins: total daily requirement 80-100g of which half should be of animal origin. Any food proteins are compared according to the composition of amino acids with a standard (as a standard - chicken egg protein, which best meets the physiological needs of the body). Carbohydrates: polysaccharides (starch glycogen), disaccharides (sucrose, lactose, maltose) have biological value. The main function of carbohydrates is energy, but they perform structural and other functions. Daily requirement 400-500 gr. of these, 400 are starch. Fats: daily requirement 80-100 gr. of which 20-25 gr. vegetable. Fat-soluble vitamins and vitamin-like compounds that are irreplaceable for the body come with food fats. Water is one of the essential components of food, although small amounts of water are formed from proteins, fats and carbohydrates when they are exchanged with tissues. Daily requirement 1750-2200 gr.
Nutrients may or may not be interchangeable. The essential ones include all mineral compounds, vitamins, some amino acids (Valine, leucine, isoleucine, threonine, methionine, argenine, lysine, phenylalanine, tryptophan, histidine) and polyunsaturated fatty acids.
Metabolism consists of 3 stages: the intake of substances into the body, interstitial metabolism (tissue transformation of substances), the formation and excretion of end products. Human food contains many chemical compounds, both organic and mineral, they are divided into major nutrients (proteins, fats, carbohydrates) and minor (vitamins and mineral compounds). The main nutrients - polymers in the gastrointestinal tract are hydrolyzed with the participation of enzymes to monomers that penetrate the cell membranes of the intestinal epithelium. Polymers are practically not absorbed. With blood, monomers are transported to all organs and tissues and used by cells. Nutrients may or may not be interchangeable. The essential ones include all mineral compounds, vitamins, some amino acids (Valine, leucine, isoleucine, threonine, methionine, argenine, lysine, phenylalanine, tryptophan, histidine) and polyunsaturated fatty acids (lenoleic, linolenic). Metabolism: there are 2 directions of the transformation of substances: catabolism and anabolism. During catabolism, organic substances decompose to CO2 and H2O, the process is exerganic (energy release). In an adult, 8-12 thousand kJ are released per day. Anabolism is the transformation of simple substances into more complex ones. Many reactions of anabolism are endergonic (absorption of energy), the source of which is the process of catabolism.
2 Sterols and sterides. Cholesterol, structure, content in blood serum, biological role. Sterols and sterides. Cholesterol, structure, content in blood serum, biological role.
Steroids are isoprenoids. Most steroids are alcohols, which are referred to as sterols or sterols. Animal sterols are zoosterols, and plant sterols are phytosterols. The ancestor of this group, cholesterol, is an important component of the cell membranes of animal cells. The daily requirement for cholesterol (1 g) can, in principle, be covered by biosynthesis. With a mixed diet, approximately half of the daily requirement of cholesterol is synthesized in the intestines, skin and mainly in the liver (about 50%), and the rest of the cholesterol comes from food. A significant part of cholesterol is included in the lipid layer of plasma membranes. A large amount of cholesterol is consumed in the biosynthesis of bile acids (see p. 306), some is excreted in the bile. Approximately 1 g of cholesterol is excreted from the body every day. A very small portion of cholesterol is used for the biosynthesis of steroid hormones, including cortisol, cortisone, aldosterone, the female sex hormones estrogen and progesterone, the male sex hormone testosterone, and, according to recent data, plays an important role in the transmission of nerve impulses in the brain. In tissues, it is in free form or in the form of esters (sterides). Cholesterol is rich in animal tissues, in large quantities it is found in the nervous tissue, the adrenal glands of the liver. Cholesterol is classified as a str-lipid. Sterides are esters of sterols and fatty acids. Cholesterol esters are more common. They are found in animal products. Plant sterides such as fatty acid esters of stigmasterol, ergosterol, beta-sitosterol make up a significant part of the total plant sterols.
3 A hereditary disease is described, in which in childhood, patients are characterized by a lag in
.This disease is primary hereditary orotic aciduria. The disease is associated with the loss in all tested cell types of the function of the enzyme that catalyzes the last two reactions of UMP synthesis, the formation and decarboxylation of orotidylic acid. As a result, there is a deficiency of pyrimidine nucleotides necessary for the synthesis of nucleic acids, and orotic acid, on the contrary, accumulates. The accumulation of orotic acid is also facilitated by the absence of the regulatory action of UTP (an allosteric inhibitor of the enzyme that promotes the formation of orotic acid) under these conditions, since the concentration in cells of UTP, like other pyrimidine nucleotides, is constantly low. As a result, the synthesis of orotic acid occurs at a higher rate than normal. If left untreated, hereditary orotaciduria leads to the development of an irreversible sharp lag in mental and physical development; usually patients die in the first years of life. Orotic acid is not toxic, developmental disorders are the result of "pyrimidine hunger". Therefore, uridine (nucleoside) is used to treat this disease in doses of 0.5-1.0 g per day. This ensures the formation of UMF and other pyrimidine nucleotides, bypassing the disturbed reactions:
Uridine + ATP UMF + ADP This treatment eliminates "pyrimidine hunger" and, in addition, reduces the release of orotic acid, since the mechanism of inhibition of the first reaction of the metabolic pathway is turned on. Treatment should continue without interruption throughout life, uridine for such patients is an indispensable nutritional factor along with vitamins and essential amino acids.
The cause of orotaciduria can also be the introduction of allopurinol in the treatment of gout. Allopurinol in the body is partially converted into an analogue of a natural mononucleotide (oxypurinol mononucleotide), which is a strong inhibitor of the decarboxylation reaction of orotidylic acid, as a result of which it causes the accumulation of orotic acid in tissues.
Ticket 13
1. Vitamins. Classification, functions of vitamins. Alimentary and secondary avitaminosis and hypovitaminosis. Hypervitaminosis
hypovitaminosis, is a consequence of the relative lack of vitamins.
avitaminosis, or an extreme degree of vitamin deficiency. Currently, in socio-economically developed countries, it is rarely diagnosed.
Hypo- and beriberi are divided into:
1) exogenous (primary, alimentary) associated with a deficiency of vitamins in food;
2) endogenous (secondary), caused by impaired absorption, transport, metabolism of vitamins in the body. Endogenous hypovitaminosis often accompanies: chronic diseases of the gastrointestinal tract (chronic enteritis, dysbacteriosis, helminthiases, chronic pancreatitis), cancer, protracted infectious process, systemic connective tissue diseases.
2. Eicosanoids (prostacyclins, prostaglandins, thromboxanes and leukotrienes), enzymes involved in their synthesis, the biological role of eicosanoids, drugs that block their synthesis, the consequences of their use for medicinal purposes.
Eicosanoids include oxidized derivatives of eicosanoic acids: eicosotrienoic (C20:3), arachidonic (C20:4), thynodonic (C20:5) fatty acids. The activity of eicosanoids differs significantly from the number of double bonds in the molecule, which depends on the structure of the original fatty acid.
Prostaglandins (Pg) - are synthesized in almost all cells, except for erythrocytes and lymphocytes. There are types of prostaglandins A, B, C, D, E, F. The functions of prostaglandins are reduced to a change in the tone of the smooth muscles of the bronchi, the genitourinary and vascular systems, the gastrointestinal tract, while the direction of the changes is different depending on the type of prostaglandins, cell type and conditions . They also affect body temperature. Prostacyclins are a subspecies of prostaglandins (Pg I), cause dilation of small vessels, but still have a special function - they inhibit platelet aggregation. Their activity increases with an increase in the number of double bonds. Synthesized in the endothelium of the vessels of the myocardium, uterus, gastric mucosa. Thromboxanes (Tx) are formed in platelets, stimulate their aggregation and cause vasoconstriction. Their activity decreases with an increase in the number of double bonds. Leukotrienes (Lt) are synthesized in leukocytes, in the cells of the lungs, spleen, brain, and heart. There are 6 types of leukotrienes A, B, C, D, E, F. In leukocytes, they stimulate mobility, chemotaxis and cell migration to the focus of inflammation; in general, they activate inflammation reactions, preventing its chronicity. They also cause contraction of the muscles of the bronchi (in doses 100-1000 times less than histamine).
Eicosanoids cannot be deposited, they are destroyed within a few seconds, and therefore the cell must constantly synthesize them from incoming ω6- and ω3-series fatty acids.
Glucocorticoids inhibit the synthesis of all types of eicosanoids, as they inhibit phospholipase A2, and thus reduce the amount of substrate for their synthesis. Aspirin and other non-steroidal anti-inflammatory drugs inhibit only the cyclooxygenase pathway.
Although the action of all types of eicosanoids is not fully understood, there are examples of the successful use of drugs - analogues of eicosanoids for the treatment of various diseases. For example, PG E1 and PG E2 analogs inhibit gastric acid secretion by blocking type II histamine receptors in gastric mucosal cells. These drugs, known as H2 blockers, speed up the healing of stomach and duodenal ulcers. The ability of PG E2 and PG F2α to stimulate uterine muscle contraction is used to induce labor.
3. . We are talking about Lesch-Nyhan syndrome. This disease is associated with a defect in hypoxanthine: - guanine - phosphoribosyltransferase, catalyzing the conversion of hypoxanthine and guanine into IMP and GMP, respectively (reutilization pathway); the activity of this enzyme in patients is thousands of times lower than normal or not active at all. As a result, hypoxanthine and guanine are not reused for nucleotide synthesis, but are completely converted into uric acid, which leads to hyperuricemia. What causes neurological symptoms is still unknown.
Ticket 14
1. Mineral elements. Classification. The biological role of macro-, micro- and ultramicroelements.
Features of iron metabolism in the body Under the mineral substances in the diet, they mean the chemical elements necessary in small quantities that enter the body with food in the form of mineral salts. They have no energy value, but perform many important functions.
regulation of metabolism - they are involved in the synthesis of many enzymes, hormones and vitamins, and are also part of some of them. This allows them to regulate most of the body's biochemical reactions. For example, digestive enzymes such as pepsin and trypsin are only active when combined with zinc.
maintenance of acid-base balance in the blood and cells of the body. This is ensured by a constant ratio of alkaline (sodium, potassium and calcium) and acidic (phosphorus, chlorine and sulfur) elements.
regulation of water-salt metabolism - maintain a constant osmotic pressure inside and between cells.
plastic - necessary for the construction and regeneration of tissues, especially bones (calcium, phosphorus) and teeth (fluorine).
are part of complex organic compounds, such as proteins, including hemoglobin (iron compound with protein) and metalloproteins (metal compounds with proteins).
generation (potassium, sodium) and transmission (calcium) of nerve impulses - this ensures a timely response to all internal and external stimuli.
participation in the work of muscles - their contraction (calcium) and relaxation (magnesium, sodium, potassium).
MacroelementsMacroelements include oxygen (65-75%), carbon (15-18%), hydrogen (8-10%), nitrogen (2.0-3.0%), potassium (0.15-0.4%) , sulfur (0.15-0.2%), phosphorus (0.2-1.0%), chlorine (0.05-0.1%), magnesium (0.02-0.03%), sodium (0.02-0.03%), calcium (0.04-2.00%), iron (0.01-0.015%). Elements such as C, O, H, N, S, P are part of organic compounds.
Carbon - is a part of all organic substances; a skeleton of carbon atoms forms their basis. In addition, it is fixed in the form of CO2 during photosynthesis and released during respiration;
Oxygen - is a part of almost all organic substances of the cell. Formed during photosynthesis during the photolysis of water. For aerobic organisms, it serves as an oxidizing agent during cellular respiration, providing cells with energy. In the largest quantities in living cells is contained in the composition of water.
Hydrogen - is a part of all organic substances of the cell. It is found in the highest concentrations in water. Some bacteria oxidize molecular hydrogen for energy.
Nitrogen - is a part of proteins, nucleic acids and their monomers - amino acids and nucleotides. It is excreted from the body of animals in the composition of ammonia, urea, guanine or uric acid as the end product of nitrogen metabolism. In the form of nitric oxide, NO (in low concentrations) is involved in the regulation of blood pressure.
Sulfur - is part of the sulfur-containing amino acids, therefore it is found in most proteins. It is present in small amounts as a sulfate ion in the cytoplasm of cells and intercellular fluids.
Phosphorus - is part of ATP, other nucleotides and nucleic acids (in the form of phosphoric acid residues), in bone tissue and tooth enamel (in the form of mineral salts), and is also present in the cytoplasm and intercellular fluids (in the form of phosphate ions).
Magnesium is a cofactor for many enzymes involved in energy metabolism and DNA synthesis; maintains the integrity of ribosomes and mitochondria, is part of chlorophyll. In animal cells, it is necessary for the functioning of muscle and bone systems.
Calcium - is involved in blood coagulation, and also serves as one of the universal second messengers, regulating the most important intracellular processes (including participating in the maintenance of membrane potential, necessary for muscle contraction and exocytosis). Insoluble calcium salts are involved in the formation of bones and teeth of vertebrates and the mineral skeletons of invertebrates.
Sodium - is involved in maintaining the membrane potential, generating a nerve impulse, osmoregulation processes (including the work of the kidneys in humans) and creating a blood buffer system.
Potassium - is involved in maintaining the membrane potential, generating a nerve impulse, regulating the contraction of the heart muscle. It is contained in intercellular substances.
Chlorine - maintains the electrical neutrality of the cell.
MicroelementsMicroelements, which make up from 0.001% to 0.000001% of the body weight of living beings, include vanadium, germanium, iodine (part of thyroxine, thyroid hormone), cobalt (vitamin B12), manganese, nickel, ruthenium, selenium, fluorine ( tooth enamel), copper, chromium, zinc
Zinc - is part of the enzymes involved in alcoholic fermentation, in the composition of insulin
Copper - is part of the oxidative enzymes involved in the synthesis of cytochromes.
Selenium - is involved in the regulatory processes of the body.
Ultramicroelements make up less than 0.0000001% in the organisms of living beings, they include gold, silver have a bactericidal effect, mercury inhibits the reabsorption of water in the renal tubules, affecting enzymes. Platinum and cesium are also referred to ultramicroelements. Some also include selenium in this group; with its deficiency, cancer develops. The functions of ultramicroelements are still little understood.
2. Phosphatides-glycerides, structure, biological role Glycerophospholipids. The structural basis of glycerophospholipids is glycerol. Glycerophospholipids (formerly known as phosphoglycerides or phosphoacylglycerols) are molecules in which two fatty acids are ester-linked to glycerol at the first and second positions; in the third position there is a phosphoric acid residue, to which, in turn, various substituents can be attached, most often amino alcohols.
Representatives of phosphoglycerides: phosphatidic acids, ethanolamine phosphatides, choline phosphatides, serine phosphatides, inosid phosphatides, cardiolipin and acetal phosphatides. Biological role: they are part of cell membranes, forming their lipid base. They are yavl. emulsifiers for acylglycerides in the intestine. They stabilize the solubility of cholesterol in the blood.
3. Agents that cause DNA damage are diverse: external exposures
(ultraviolet, infrared, radioactive, etc.), spontaneous local
temperature changes, free radicals, chemical mutagens, etc. Damage
DNA is divided into: 1) base damage and 2) chain damage.
Base damage:
1) Hydrolytic cleavage of bases occurs spontaneously or under the influence of the above factors. The pentose phosphate backbone of the chain is preserved.
2) Hydrolytic deamination of bases: cytosine is converted to uracil; 5-methylcytosine - to thymine; adenine to hypoxanthine.
3) Formation of thymine dimers (initiated by ultraviolet irradiation)
Damage to DNA chains:
1) Single strand breaks
2) Crosslinks
An example of thymine dimer repair.
carried out by DNA polymerase-p, the last internucleotide bond is formed by DNA ligase.
Ticket 15
1. The concept of biogeochemical provinces. Regional pathologies associated with a lack of individual trace elements (iodine, selenium, etc.)
Biogeochemical provinces are regions of the biosphere within which, due to the lack or excess of a certain chemical element, natural geochemical anomalies are distinguished. In the Chel region, diseases associated with a deficiency of I (endemic goiter) are common. Lack of iodine leads to Graves' disease, depresses the activity of the central nervous system, and reduces emotional tone. Symptoms of iodine deficiency in the body are poor health, decreased performance. In children with a lack of iodine, there is a lag in growth, deviations in mental development. The daily intake of iodine is 0.1-0.2 milligrams.
Selenium is an essential micronutrient whose importance is associated with its key role in the antioxidant systems of cells. The level of selenium in the blood is maintained within the range of 1.9-3.17 µM/L. Selenium is a powerful antioxidant, a component of glutathione peroxidase, phospholipid-glutathione peroxidase, other oxidoreductases and some transferases. Gensu Province in China is an endemic region of selenium deficiency, known for the existence of local Qisheng disease - a special form of multifocal necrotizing myocardial dystrophy.. The lowest in the world the geochemical content of selenium (and the lowest life expectancy in Europe for forty-year-old men) are noted in Finnish Karelia. Sweden, Denmark and New Zealand, characterized by geochemical selenium deficiency, are also among the leaders in the incidence of atherosclerosis and some neoplasms. A relationship has been found between selenium deficiency in pregnant women and the development of cystic fibrosis in the fetus. Selenium deficiency causes arrhythmias, myopathies, azoospermia, liver necrosis, acne, and in severe cases, dilated cardiomegaly and congestive heart failure.
2. Digestion of simple and complex lipids, the role of emulsification, enzymes, the role of bile in lipid digestion, hepato-enteric circulation of bile acids. Transport of lipid digestion products into the blood. Impaired lipid digestion The digestion of lipids is complicated by the fact that their molecules are completely or partially hydrophobic. To overcome this interference, the emulsification process is used, when hydrophobic molecules (TAG, CS esters) or hydrophobic parts of molecules (PL, CS) are immersed inside the micelles, while hydrophilic ones remain on the surface facing the aqueous phase.
Digestion in the mouth. although prolonged chewing of food contributes to the partial emulsification of fats. Digestion in the stomach. The stomach's own lipase does not play a significant role in lipid digestion. However, in adults, the warm environment and gastric peristalsis cause some emulsification of fats. At the same time, even a low-active lipase breaks down insignificant amounts of fat. Digestion in the intestines Hydrolysis of cholesterol esters is carried out by cholesterol esterase of pancreatic juice. Digestion of TAG in the intestine is carried out under the influence of pancreatic lipase with an optimum pH of 8.0-9.0. It enters the intestine in the form of prolipase, activated with the participation of colipase. Colipase, in turn, is activated by trypsin and then forms a complex with lipase in a 1:1 ratio. Pancreatic lipase cleaves off fatty acids associated with the C1 and C3 carbon atoms of glycerol. As a result of her work, 2-monoacylglycerol (2-MAG) remains. 2-MAGs are absorbed or converted by monoglycerol isomerase into 1-MAGs. The latter is hydrolyzed to glycerol and fatty acids. Approximately 3/4 of TAG after hydrolysis remains in the form of 2-MAG, and only 1/4 of the TAG is completely hydrolyzed. Pancreatic juice also contains trypsin-activated phospholipase A2, which cleaves fatty acid from C2. The activity of phospholipase C and lysophospholipase was found. In the intestinal juice there is the activity of phospholipase A2 and C. There is also evidence of the presence of phospholipases A1 and D in other cells of the body.
Bile is a complex liquid with an alkaline reaction. It produces a dry residue - about 3% and water - 97%. Two groups of substances are found in the dry residue: sodium, potassium, bicarbonate ions, creatinine, cholesterol (CS), phosphatidylcholine (PC), which are actively secreted by hepatocytes and bile acids. Bile acids: PC: CS equal to 65:12:5.
The role of bile
Along with pancreatic juice, neutralization of acidic chyme coming from the stomach. In this case, carbonates interact with HCl, carbon dioxide is released and the chyme is loosened, which facilitates digestion.
Enhances intestinal peristalsis.
Provides fat digestion:
emulsification for subsequent lipase action, a combination [bile acids + fatty acids + monoacylglycerols] is needed,
reduces surface tension, which prevents fat droplets from draining,
the formation of micelles that can be absorbed.
Thanks to items 1 and 2, it ensures the absorption of fat-soluble vitamins (vitamin A, vitamin D, vitamin K, vitamin E).
Excretion of excess cholesterol, bile pigments, creatinine, metals Zn, Cu, Hg, drugs. For cholesterol, bile is the only route of excretion; 1-2 g / day can be excreted with it.
The main types of bile acids found in the human body are the so-called primary bile acids (primarily secreted by the liver): cholic acid and chenodeoxycholic acid, as well as secondary (formed from primary bile acids in the colon under the action of intestinal microflora): deoxycholic acid, lithocholic , allocholic and ursodeoxycholic acids
Lipid absorption. After the breakdown of polymeric lipid molecules, the resulting monomers are absorbed in the upper small intestine in the initial 100 cm. Normally, 98% of dietary lipids are absorbed.
1. Short fatty acids (no more than 10 carbon atoms) are absorbed and pass into the blood without any special mechanisms. Glycerol is also directly absorbed.2. Other digestion products (fatty acids, cholesterol, monoacylglycerols) form micelles with a hydrophilic surface and a hydrophobic core with bile acids. Their size is 100 times smaller than the smallest emulsified fat droplets. Through the aqueous phase, the micelles migrate to the brush border of the mucosa. Here, micelles disintegrate and lipid components penetrate into the cell, after which they are transported to the endoplasmic reticulum. Bile acids can also partially enter the cells and then into the blood of the portal vein, but most of them remain in the chyme and reach the ileum, where they are absorbed by active transport .
Disorders of digestion and absorption of fats. Steatorrhea One of the causes is a violation of the secretion of bile from the gallbladder with a mechanical obstruction of the outflow of bile. This condition may be the result of narrowing of the bile duct by stones that form in the gallbladder, or compression of the bile duct by a tumor that develops in surrounding tissues. A decrease in bile secretion leads to a violation of the emulsification of dietary fats and, consequently, to a decrease in the ability of pancreatic lipase to hydrolyze fats.
Violation of the secretion of pancreatic juice and, consequently, insufficient secretion of pancreatic lipase also leads to a decrease in the rate of hydrolysis of fats. In both cases, a violation of the digestion and absorption of fats leads to an increase in the amount of fat in the feces - steatorrhea (fatty stools) occurs. Normally, the fat content in feces is no more than 5%. With steatorrhea, the absorption of fat-soluble vitamins (A, D, E, K) and essential fatty acids is impaired, therefore, with long-term steatorrhea, a deficiency of these essential nutritional factors develops with corresponding clinical symptoms. In case of violation of the digestion of fats, substances of a non-lipid nature are also poorly digested, since fat envelops food particles and prevents the action of enzymes on them.
3. The child has hereditary fructose intolerance, which occurs with a genetically determined defect in fructose-1-phosphate aldolase. It does not appear while the baby is breastfeeding. Symptoms occur when fruits, juices, sucrose are added to the diet.
The defect in fructose-1-phosphate aldolase is accompanied by the accumulation of fructose-1-phosphate, which inhibits the activity of phosphoglucomutase, which converts glucose-1-phosphate to glucose-6-phosphate and ensures the inclusion of the product of the glycogen phosphorylase reaction into metabolism. Therefore, there is an inhibition of the breakdown of glycogen at the stage of formation of glucose-1-phosphate, resulting in the development of hypoglycemia. As a result, lipid mobilization and fatty acid oxidation are accelerated. Metabolic acidosis may be a consequence of the acceleration of fatty acid oxidation and the synthesis of ketone bodies, which replace the energy function of glucose. ketone bodies are acids and at high concentrations lower blood pH. The result of inhibition of glycogenolysis and glycolysis is a decrease in ATP synthesis. In addition, the accumulation of phosphorylated glucose leads to impaired metabolism of inorganic phosphate and hypophosphatemia. To replenish intracellular phosphate, the breakdown of adenine nucleotides is accelerated. Their breakdown products are hypoxanthine, xanthine and uric acid. An increase in the amount of uric acid and a decrease in the excretion of urates in conditions of metabolic acidosis are manifested in the form of hyperuricemia. Gout can be a consequence of hyperuricemia even at a young age. The prognosis for such children, if they continue to take foods containing fructose, is unfavorable. They develop chronic liver and kidney dysfunction.