Isoenzymes, or isoenzymes- This multiple forms of enzyme, catalyzing the same reaction, but differing from each other in physical and chemical properties, in particular by affinity for the substrate, the maximum rate of the catalyzed reaction (activity), electrophoretic mobility or regulatory properties.

In living nature there are enzymes whose molecules consist of two or more subunits with the same or different primary, secondary or tertiary structure. Subunits are often called protomers, and the combined oligomeric molecule is called multimer(Fig. 14.8 a-d).

It is believed that the process of oligomerization gives protein subunits increased stability and resistance to the action of denaturing agents, including heat, the influence of proteinases, etc. However, at the current stage of knowledge, it is impossible to unambiguously answer the question of the importance of the quaternary structure for the catalytic activity of enzymes, since there are no methods yet , allowing under “mild” conditions to destroy only the quaternary structure. Typically used harsh processing methods (extreme pH values, high concentrations of guanidine chloride or urea) lead to the destruction of not only the quaternary, but also the secondary and tertiary structures of the stable oligomeric enzyme, the protomers of which are denatured and, as a result, devoid of biological activity.

Rice. 14.8. Models of the structure of some oligomeric enzymes: a – glutamate dehydrogenase molecule, consisting of 6 protomers (336 kDa); b – RNA polymerase molecule; c – half a catalase molecule; d – molecular complex of pyruvate dehydrogenase

It should be noted that there are no covalent, principally valent bonds between the subunits. The bonds are mostly non-covalent, so such enzymes dissociate quite easily into protomers. A surprising feature of such enzymes is the dependence of the activity of the entire complex on the method of packaging of individual subunits. If genetically distinct subunits can exist in more than one form, then, accordingly, an enzyme formed from two or more types of subunits, combined in different quantitative proportions, can exist in several similar, but not identical forms. Such types of enzyme are called isoenzymes (isoenzymes or, less commonly, isozymes).

One of the most studied enzymes, the multiplicity of forms of which has been studied in detail by gel electrophoresis, is lactate dehydrogenase (LDH), which catalyzes the reversible conversion of pyruvic acid into lactic acid. It can consist of four subunits of two different H- and M-types (cardiac and muscle). The active enzyme is one of the following combinations: HHHH, HHHM, HHMM, HMMM, MMMM or H4, H3M, H2M2, HM3, M4. They correspond to the isoenzymes LDH 1, LDH 2, LDH 3, LDH 4, and LDH 5. At the same time, the synthesis of H- and M-types is carried out by different genes and is expressed differently in different organs.

Since H-protomers at pH 7.0-9.0 carry a more pronounced negative charge than M-protomers, the H 4 isoenzyme will migrate with highest speed in an electric field to the positive electrode (anode). The M4 isoenzyme will move towards the anode at the lowest speed, while the remaining isoenzymes will occupy intermediate positions (Fig. 14.9).

Rice. 14.9. Distribution and relative amounts of LDH isoenzymes in various organs

Each tissue normally has its own ratio of forms (isoenzyme spectrum) of LDH. For example, in the cardiac muscle the H4 type predominates, i.e. LDH 1, and in the skeletal muscles and liver the M4 type predominates, i.e. LDH 5.

These circumstances are widely used in clinical practice, since studying the appearance of LDH isoenzymes (and a number of other enzymes) in blood serum may be of interest for the differential diagnosis of organic and functional lesions of organs and tissues. By changes in the content of isoenzymes in the blood serum, one can judge both the topography of the pathological process and the degree of damage to an organ or tissue.

In some cases, the subunits have an almost identical structure and each contains a catalytically active site (for example, β-galactosidase, consisting of four subunits). In other cases, the subunits are not identical. An example of the latter is tryptophan synthase, which consists of two subunits, each of which is endowed with its own (but not the main) enzymatic activity; however, only when combined into a macromolecular structure do both subunits exhibit tryptophan synthase activity.

The term " multiple forms of enzyme" applies to proteins that catalyze the same reaction and occur naturally in organisms of the same species. The term " isoenzyme» applies only to those multiple forms of enzymes that appear as a result of genetically determined differences in the primary structure of the protein (but not to forms resulting from modification of one primary sequence).

Maximum catalyzed rate (), electrophoretic mobility or regulatory properties.

Rice. 4.5. Models of the structure of some oligomers.

It should be noted that there are no covalent, principally valent bonds between the subunits. The bonds are mostly non-covalent, so they dissociate quite easily into protomers. Amazing feature Such is the dependence of the entire complex on the method of packaging the individual subunits among themselves. If genetically distinguishable subunits can exist in more than one form, then, accordingly, and, formed from two or more types of subunits, combined in different quantitative proportions, can exist in several similar, but not identical forms. Such varieties are called (isoenzymes or, less commonly, isozymes). In particular, if it consists of 4 subunits of two different types - H and M (cardiac and muscle), then the active one can be one of the following combinations: HNNNN, HHNM, HHMM, HMMMM, MMMM, or H4, H3M, N 2 M 2, NM 3, M 4, corresponding to LDH 1, LDH 2, LDH 3, LDH 4 and LDH 5. At the same time, the synthesis of H- and M-types is carried out differently and is expressed differently in different organs.

In some cases, the subunits have an almost identical structure and each contains a catalytically active site (for example, β-galactosidase, consisting of 4 subunits). In other cases, the subunits are not identical. An example of the latter is tryptophan synthase, consisting of 2 subunits, each of which is endowed with its own (but not the main) enzymatic one, however, only when combined into a macromolecular structure do both subunits exhibit tryptophan synthase activity.

The term "multiple forms" applies to those that catalyze the same and occur naturally in the same species. The term "" applies only to those multiple forms that appear due to genetically determined differences in (and not to forms resulting from modification of one primary sequence).

One of the most studied 4, the multiplicity of forms of which has been studied in detail by gel electrophoresis, is LDH, which catalyzes the reversible transformation into milk. Five LDHs are formed from 4 subunits of approximately the same size, but two different types. Since H-protomers carry a more pronounced negative charge at pH 7.0–9.0 than M-protomers, consisting of 4 H-type subunits (H 4), will migrate at the highest speed in an electric field to a positive one ( ). It will move towards M4 at the lowest speed, while the remaining isoenzymes will occupy intermediate positions. It should be emphasized that

Warburg found that yeast aldolases from various animal tissues differ in a number of properties. Pepsin, trypsin, and chymotrypsin also differed in solubility, pH, and temperature optimum.

At the end of the fifties, biochemists Wieland and Pfleiderer, as well as other researchers, isolated pure crystalline preparations of the enzyme from animal tissues lactate dehydrogenase and subjected them to electrophoresis. As a result of electrophoresis, the enzyme was divided, as a rule, into 5 factions, having different electrophoretic mobility. All these fractions had lactate dehydrogenase activity. Thus, it was established that the enzyme lactate dehydrogenase is present in tissues in several forms. These forms, in accordance with their electrophoretic mobility, were designated LDH1, LDH2, LDH3. LDH4, LDH5. (LDH is an abbreviation for lactate dehydrogenase), and number 1 denotes the component with the highest electrophoretic mobility.

Studies of lactate dehydrogenase enzymes isolated from different organs of animals have shown that they differ both in electrophoretic and chromatographic properties, as well as in chemical composition, thermal stability, sensitivity to the action of inhibitors, K m and other properties. When analyzing lactate dehydrogenase of different animal species, very large interspecies differences were revealed, however, within a given species, the distribution of isoenzymes is characterized by great constancy.

Lactate dehydrogenase was the first enzyme whose individual components were studied in detail. Somewhat later, data were obtained on the multiple forms and molecular heterogeneity of a number of other fermeates, and in 1959 it was proposed to call such forms isoenzymes or isoenzymes. The Enzyme Commission of the International Biochemical Union has officially recommended this term to designate multiple forms of enzymes of the same biological species.

So, isoenzymes - this is a group of enzymes from the same source, possessing the same type of substrate specificity, catalyzing the same chemical reaction, but differing in a number of physicochemical properties.

The presence of multiple forms of enzymes, or isoenzymes, has been established by more than For100 enzymes, extracted from various types animals, plants and microorganisms. Isoenzymes do not always consist of two or more subunits. For a number of enzymes, individual isofermsates are different in chemical structure proteins that have the same catalytic activity but consist of only one subunit.

The main criterion for the nomenclature of isoenzymes is currently their electrophoretic mobility. This is explained by the fact that, compared with other methods of characterizing enzymes, electrophoresis provides the highest resolution.

To date, as a result of the study of plant isoenzymes, it has been established that many enzymes are present in plants in the form of multiple forms. Let's take a look at some of these enzymes.

Malate dehydrogenase (1.1.1.37) has a rather complex isoenzyme composition. In cotton seeds and spinach leaves, 4 malate dehydrogenase isoenzymes were found, differing in electrophoretic mobility, and the molecular weight of each of the four spinach isoenzymes was approximately 60 thousand. Different plants contain an unequal number of malate dehydrogenase isoenzymes. For example, 7-10 isoenzymes were found in the seeds of various varieties of wheat, 4-5 in the roots of corn, and 9-12 isoenzymes of malate dehydrogenase were found in various organs (root, cotyledon, subcotyledon and epicotyledon), and the number of isoenzymes varied depending on from the phase of plant development.

It was noted that the molecular weights of the malate dehydrogenase isoenzyme sometimes varied significantly. For example, cotton leaves contain 7 isoenzymes of malate dehydrogenase, of which 4 isoenzymes are isoforms that have different electrical charges, but the same molecular weight, equal to approximately 60 thousand. The fifth isoenzyme had a molecular weight of about 500 thousand and was an oligomer in at least one of the isoforms of malate dehydrogenase with a molecular weight of 60 thousand. Since in these studies the molecular weights were determined approximately, it can be assumed that this isoenzyme consists of 8 subunits of the isoenzyme with a molecular weight of 60 thousand.

Plant resistance and susceptibility to diseases is often associated with the regulation of isoenzyme synthesis. As a response to the introduction of infection in plants, the intensity of metabolism of chemicals, primarily redox ones, is increased. Therefore, the activity of OM enzymes and the number of their isoenzymes increase when plants are damaged.

Increased activity and an increase in the number of peroxidase and o-diphenoloxidase isoenzymes are observed in various diseases of corn, beans, tobacco, clover, flax potatoes, oats and other plants. Figure 22 schematically shows the change in the number of peroxidase isoenzymes and their activity when tomatoes are affected by late blight. If the leaves of healthy plants contained four peroxidase isoenzymes, then in the affected leaves their number increased to nine, and the activity of all isoenzymes increased significantly.

When studying changes in the isoenzyme composition of mitochondrial peroxidase and polyphenoloxidase during the viral pathogenesis of tobacco mosaic virus-resistant and non-resistant tobacco species, it was found that viral infection causes qualitatively different changes in the isoenzyme composition of tobacco types of different resistance. In a resistant species, the activity of a number of isoenzymes increases to a greater extent than in a susceptible species. Thus, depending on the plant’s potential ability to biosynthesize enzymes, the plant’s susceptibility to infectious diseases changes.

Glutamate dehydrogenase

Esterases

Saharaza

Biological role of isoenzymes in plants.

IF indicates the great lability of the enzymatic apparatus of plants, making it possible to carry out the necessary metabolic processes. in a cell when environmental conditions change, ensures the specificity of the exchange of chemicals. for a given plant organ or tissue. Promotes plant adaptability to changing indoor conditions. environment.

The simultaneous presence in cells of multiple forms of the same enzyme, along with other regulatory mechanisms, contributes to the consistency of metabolic processes. in the cell and rapid adaptation of plants to changing environmental conditions.

In fact, we noted that individual isozerments differ in temperature optima, pH optima, relation to inhibitors, and other properties. It follows that if, for example, temperature conditions change sharply and become unfavorable for the manifestation of the catalytic activity of some isoenzymes, then their activity is suppressed. However, this fermeatative process in plants does not stop completely, since other isoenzymes of the same enzyme, for which this temperature is favorable, begin to exhibit catalytic activity. If, for some reason, the pH of the reaction medium changes, then the activity of some isoenzymes is also weakened, but isoenzymes that have a different pH optimum begin to exhibit catalytic activity instead. High concentrations of salts inhibit the activity of many enzymes, which is one of the reasons for the deterioration of plant growth on saline soils. However, even at high concentrations of salts in cells, enzymatic processes do not stop completely, since individual isoenzymes respond differently to increased salt concentrations: the activity of some isoenzymes decreases, while others increase.

Resistance and susceptibility to diseases is often based on the regulation of IF synthesis.

The biosynthesis of isoenzymes is determined by genetic factors and each plant species is characterized by a set of isoenzymes specific to this species, i.e. species specificity in isoenzyme composition is manifested.

Different organs of the same plant differ in IF. The study of the properties of lactate dehydrogenase isoenzymes isolated from various animal tissues showed that all isoenzymes have approximately the same molecular weight (about 140 thousand) under conditions, for example, under the influence of treatment with 42 M urea, each of the isoenzymes dissociates into 4 subunits with molecular weight of about 35 thousand. Thus, each of the five isoenzymes of lactate dehydrogenase is a tetramer. It has been established that all lactate dehydrogenase isoenzymes are possible combinations of only two types of subunits, conventionally designated by the letters A and B. Different combinations of these types of subunits form all five lactate dehydrogenase isoenzymes (Fig. 18). This shows that the isoenzymes of lactate dehydrogenase have a strictly ordered structure, and the individual subunits in the molecule of this enzyme protein are connected by hydrogen bonds, which can be broken under the influence of a concentrated solution of urea.

The question arises: how do the individual subunits of lactate dehydrogenase differ from each other and what is associated with the different electrophoretic mobility of individual isoenzymes? Quite definite answers have now been received to this question. It turned out that subunits A and B are t-c amino acids. Subunit B contains a larger number of acidic small amino acids compared to subunit A. In this regard, all lactate dehydrogenase isoenzymes (LDH1 - LDH2) differ in the amount of these amino acids, their molecules have different electrical charge values ​​and different electrophoretic mobility. Lactate dehydrogenase isoenzymes also differ in a number of other properties, in particular Michaelis constants Km, relation to a number of inhibitors, and thermostability.

Enzymes that catalyze the same chemical reaction, but differ in the primary structure of the protein, are called isoenzymes, or isoenzymes. They catalyze the same type of reaction with a fundamentally identical mechanism, but differ from each other in kinetic parameters, activation conditions, and features of the connection between the apoenzyme and the coenzyme.

The nature of the appearance of isoenzymes is varied, but most often due to differences in the structure of the genes encoding these isoenzymes. Consequently, isoenzymes differ in the primary structure of the protein molecule and, accordingly, in physical and chemical properties. Methods for determining isoenzymes are based on differences in physicochemical properties.

In their structure, isoenzymes are mainly oligomeric proteins. Moreover, one or another tissue preferentially synthesizes certain types of protomers. As a result of a certain combination of these protomers, enzymes with different structures are formed - isomeric forms. The detection of certain isoenzyme forms of enzymes allows their use for diagnosing diseases.

Isoforms of lactate dehydrogenase. The enzyme lactate dehydrogenase (LDH) catalyzes the reversible oxidation of lactate (lactic acid) to pyruvate (pyruvic acid) (see section 7).

Lactate dehydrogenase- oligomeric protein with a molecular weight of 134,000 D, consisting of 4 subunits of 2 types: M (from English, muscle - muscle) and H (from English, heart - heart). The combination of these subunits underlies the formation of 5 isoforms of lactate dehydrogenase (Fig. 2-35, A). LDH 1 and LDH 2 are most active in the heart muscle and kidneys, LDH4 and LDH5 - in skeletal muscles and liver. Other tissues contain various forms of this enzyme.

LDH isoforms differ in electrophoretic mobility, which makes it possible to determine the tissue identity of LDH isoforms (Fig. 2-35, B).

Creatine kinase isoforms. Creatine kinase (CK) catalyzes the formation of creatine phosphate:

The KK molecule is a dimer consisting of two types of subunits: M (from English, muscle) and B (from English, brain). From these subunits, 3 isoenzymes are formed - BB, MB, MM. The BB isoenzyme is found primarily in the brain, MM in skeletal muscles, and MB in cardiac muscle. KK isoforms have different electrophoretic mobilities (Fig. 2-36).

CK activity should normally not exceed 90 IU/l. Determination of CK activity in blood plasma has diagnostic value in case of myocardial infarction (there is an increase in the level of the MB isoform). The amount of the MM isoform may increase during trauma and damage to skeletal muscles. The BB isoform cannot penetrate the blood-brain barrier, therefore it is practically undetectable in the blood even during strokes and has no diagnostic value.

Isoenzymes- these are enzymes, the synthesis of which is encoded by different genes, they have different primary structures and different properties, but they catalyze the same reaction. Types of isoenzymes:

Organ - glycolysis enzymes in the liver and muscles.

Cellular - cytoplasmic and mitochondrial malate dehydrogenase (the enzymes are different, but they catalyze the same reaction).

Hybrid - enzymes with a quaternary structure, formed as a result of non-covalent binding of individual subunits (lactate dehydrogenase - 4 subunits of 2 types).

Mutant - formed as a result of a single gene mutation.

Alloenzymes are encoded by different alleles of the same gene.

10. I. Use of enzymes for medicinal purposes in turn, is divided into two types: 1) application for replacement therapy and 2) in order to influence the enzyme on the site of the disease.

For the purpose of replacement therapy, they are most widely used digestive enzymes, when the patient is found to be deficient. Examples include gastric juice preparations or pure pepsin or acidin-pepsin, which is indispensable for gastritis with secretory insufficiency and dyspepsia in children. Pancreatin - the drug, which is a mixture of pancreatic enzymes, is used for pancreatitis, mainly of a chronic nature. Well-known drugs have the same meaning Cholenzym, panzinorm, etc.

Another area of ​​application of replacement therapy is the treatment of diseases associated with the so-called enzymopathies. These are congenital or hereditary diseases in which the synthesis of any enzymes is impaired. These diseases are usually extremely severe; children with a hereditary lack of any enzyme do not live long, suffer from severe mental and mental disorders, physical and mental retardation. mental development. Replacement therapy can sometimes help overcome these disorders.

A number of enzyme preparations are used in surgical practice for cleaning the wound surface from pus, microbes, excess granulation tissue; in the clinic of internal medicine they are used: to liquefy viscous secretions, exudates, blood clots, for example, in severe inflammatory diseases of the lungs and bronchi. These are mainly enzymes - hydrolases, capable of breaking down natural biopolymers - proteins, NA, polysaccharides. Due to their anti-inflammatory effect, they are also used for thrombophlebitis, inflammatory-dystrophic forms steam O dontosis, osteomyelitis, sinusitis, otitis and other inflammatory diseases.

Among them are enzymes such as trypsin, chymotrypsin, RNA-ase, DNA-ase, fibrinolysin. Fibirinolysin also used to remove intravascular thrombi. RNase and DNase are successfully used to treat some viral infections, for example to destroy herpes virus.

Enzymes such as hyaluronidase, collagenase, lidase, are used to combat excess scar formations.

Asparaginase- an enzyme produced by some strains of Escherichia coli. It has a therapeutic effect on some forms of tumors. The therapeutic effect is associated with the ability of the enzyme to disrupt the metabolism of the amino acid asparagine, which is necessary for tumor cells to grow.

The use of enzyme preparations for medicinal purposes is still a very young area of ​​medical science. The limitation here is the complexity of the technology and the high cost of obtaining pure enzyme preparations in crystalline form, suitable for storage and use in humans. In addition, when using enzyme preparations, other circumstances must also be taken into account:

1) Enzymes are proteins, and therefore in some cases can cause an unwanted allergic reaction.

2) Rapid decomposition of the introduced enzymes (the protein drug is therefore immediately captured by “scavenger” cells - macrophages, fibroblasts, etc. Hence, large concentrations of drugs are required to achieve the desired effect.

3) However, with increasing concentrations, enzyme preparations may turn out to be toxic.

And yet, in cases where these obstacles can be overcome, enzyme preparations have an excellent therapeutic effect.

For example, these disadvantages are partially eliminated by converting enzymes into the so-called “immobilized” form.

You will read more about methods of enzyme immobilization and methods of their use in your teaching aids.

Isoenzymes are isofunctional proteins. They catalyze the same reaction, but differ in some functional properties due to differences in:

Amino acid composition;

Electrophoretic mobility;

Molecular weight;

Kinetics of enzymatic reactions;

Method of regulation;

Stability, etc.

Isoenzymes are molecular forms of an enzyme; differences in amino acid composition are caused by genetic factors.

Examples of isoenzymes: glucokinase and hexokinase.

Hexokinase can phosphorylate any six-membered cycle, hexokinase can only convert glucose. After eating a meal rich in glucose, glucokinase begins to work. Hexokinase is a stationary enzyme. It catalyzes the breakdown of glucose at low concentrations entering the body. They differ in localization (glucokinase - in the liver, hexokinase - in muscles and liver), physiological significance, Michaels constant.

If the enzyme is an oligomeric protein, then isoforms can result from different combinations of protomers. For example, lactate dehydrogenase consists of 4 subunits. H – cardiac type subunits, M – muscle type. There may be 5 combinations of these subunits, and, therefore, 5 isoenzymes: NNMM (LDH 1 - in the heart muscle), NNMM (LDH 2), NNMM (LDH 3), NMMM (LDH 4), MMMM (LDH 5 - in the liver and muscles). [rice. these 4 letters are in circles.

It is necessary to distinguish isoenzymes from multiple forms of enzymes. Multiple Forms of Enzymes are enzymes that are modified after their synthesis, for example phosphorylase A and B.

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Most of the hemechromagenic pigments in the human body are formed during the breakdown of heme. The main source of heme is hemoglobin. In red blood cells, the hemoglobin content is 80%, the lifespan

Pathology of pigment metabolism
As a rule, it is associated with a violation of the processes of heme catabolism and is expressed by hyperbilirubinemia and manifests itself in jaundice of the skin and visible mucous membranes. Accumulating in the central nervous system, bilirubin causes

Types of changes in the biochemical composition of blood
I. Absolute and relative. Absolute ones are caused by a violation of the synthesis, decay, and elimination of a particular compound. Relative due to changes in volume c

Protein composition of blood
Functions of blood proteins: 1. maintain oncotic pressure (mainly due to albumin); 2. determine the viscosity of blood plasma (mainly due to albumin);

Total protein
Normally, total blood protein is 65-85 g/l. Total protein is the sum of all proteins in the blood. Hypoproteinemia – decrease in albumin. Reasons:

Globulins are normal 20-30 g/l
I. α1-globulins α-antitrypsin – inhibits trypsin, pepsin, elastase, and some other blood proteases. Performs as an anti-inflammatory

Residual nitrogen
Residual nitrogen is the sum of the nitrogen of all non-protein nitrogen-containing substances in the blood. Normal is 14-28 mmol/l. 1. Metabolites: 1.1. amino acids (25%); 1.2. creat

Carbohydrate metabolism
Glucose in capillary blood on an empty stomach is 3.3-5.5 mmol/l. 1. Hyperglycemia (increased glucose): 1.1. pancreatic hyperglycemia – in the absence of insulin

Lipid metabolism
Cholesterol is normal 3-5.2 mmol/l. In plasma it is found in LDL, VLDL (atherogenic fractions) and HDL (antiatherogenic fraction). Probability of developing atherosclerosis

Mineral metabolism
Sodium is the major extracellular ion. Na+ levels in the blood are influenced by mineralocorticoids (aldosterone retains sodium in the kidneys). Sodium levels increase due to heme

Blood plasma enzymes
They are classified: 1. Functioning enzymes (plasma enzymes themselves). For example, renin (increases blood pressure through angiotensin II), cholinesterase (breaks down acetylcholine). Their activity is higher in

Physical properties of urine of a healthy person, their changes in pathology
I. The normal amount of urine is 1.2-1.5 liters. Polyuria is an increase in the amount of urine due to: 1) increased filtration (under the influence of adrenaline, phi increases

Indicators of the chemical composition of urine
Total nitrogen is the total nitrogen of all nitrogen-containing substances in the urine. Normal is 10-16 g/day. In case of pathologies, total nitrogen can: ü increase – hyperazoturia

Features of metabolism in nervous tissue
Energy exchange. In brain tissue, cellular respiration is increased (aerobic processes predominate). The brain consumes more oxygen than constantly working ser

Chemical transmission of nervous excitation
The transfer of excitation from one cell to another occurs with the help of neurotransmitters: - neuropeptides; - AK; - acetylcholine; - biogenic amines (adrenaline,