What is creatine phosphate? Energy processes in muscle for maximum growth. Chronic heart failure

Among the high-energy phosphorylated compounds, there is one that plays a special role in the energy of excitable tissues, such as muscle and nervous tissue. This compound, creatine phosphate, or phosphocreatine (Figure 14-13), serves as a reservoir of high-energy phosphate groups. The hydrolysis of creatine phosphate is slightly higher than the hydrolysis of ATP.

Creatine phosphate can transfer its phosphate group to ADP in a reaction catalyzed by creatine kinase:

Thanks to creatine phosphate, the concentration of ATP in muscle cells is maintained at a constant and quite high level. This is especially important for skeletal muscles, working intermittently, but sometimes very intensely at high speed. Whenever a portion of a muscle cell's ATP is used for contraction, ADP is formed as a result of ATP hydrolysis. Creatine phosphate, with the participation of creatine kinase, quickly transfers its phosphate group to ADP molecules, and normal ATP levels are restored. The content of creatine phosphate in muscles is 3-4 times higher than the content of ATP (Table 14-4); therefore, a sufficient amount of phosphate groups can be stored in the form of creatine phosphate, completely ensuring the maintenance of a constant ATP level during short periods of increased muscle activity.

Rice. 14-12. In the cilia and flagella of eukaryotic cells, mechanical force is developed through the use of ATP. A. Transverse section of the cilium. These structures consist of nine pairs of microtubules forming an outer ring and two single central microtubules (9 + 2 arrangement; Section 2.16). Cilia are surrounded by a membrane, which is an outgrowth of the cell membrane. The energy for the characteristic movements of the cilia (wavy, sliding or rotational) is supplied by the hydrolysis of ATP. These movements are carried out by cilia due to the sliding or twisting of paired microtubules, which is very reminiscent of the ATP-dependent sliding of thick and thin filaments relative to each other observed in skeletal muscles. From the outer (paired) microtubules extend equally spaced processes or protrusions resembling myosin heads in thick muscle filaments. These protrusions consist of dynein molecules, a fairly large protein with ATPase activity. Dynein-catalyzed ATP gylrolysis supplies energy for mechanical movement—sliding or twisting of microtubules. It has been proposed that central microtubules regulate the speed of cilia. B. Individual phases of cilium beating in the gills of a sea worm, whose cilia are about 30 µm long. These characteristic movements informs cilia of ATP-dependent sliding of tubular filaments relative to each other.

Rice. 14-13. Creatine phosphate in muscles plays the role of a reserve donor of high-energy phosphate groups. It acts as a kind of buffer, ensuring a constant ATP concentration.

Due to the reversibility of the creatine kinase reaction, accumulated creatine during the recovery period is again phosphorylated by ATP to creatine phosphate. Since there is no other metabolic pathway for the formation and breakdown of creatine phosphate, this compound is well suited to perform its function as a reservoir of phosphate groups.

In the muscles of many invertebrates, the role of the carrier of the reserve form of energy is not creatine phosphate, but arginine phosphate. Compounds that, like creatine phosphate and arginine phosphate, serve as reserve sources of energy are called phosphagens.

14.16. ATP also supplies energy for active transport across membranes

The chemical energy of ATP is also used to perform osmotic work, i.e. the work required to transfer any ions or molecules across the membrane from one compartment to another, in which their concentration is higher. We can calculate the amount of free energy required to transport 1 mole of unionized solute across a membrane, for example from the environment into a cell, if we know the concentrations of the solute in unbound form in the environment and in the cell (Figure 14-14). For this calculation we use the general equation

where is the molar concentration of a given solute in the environment, is its molar concentration in the cell, R is the gas constant and T is the absolute temperature. Using this equation, we can determine the amount of free energy required to move 1 mole of glucose against a hundredfold concentration gradient, for example, from a medium with an initial glucose concentration to a compartment where its final concentration will be . Substituting the corresponding values ​​into the equation, we get

Rice. 14-14. Active transport of a solute against a concentration gradient. Starting from the moment of equilibrium, i.e. from that moment. When the concentrations of a given solute are the same in both compartments, active transport of the solute from one compartment to the other ensures its movement against the concentration gradient. To create and maintain a concentration gradient of any solute between compartments located on both sides of the membrane, free energy is required. If for some reason the energy stops flowing, then the substance from the compartment with a higher concentration begins to diffuse back, and diffusion continues until then. until equilibrium is established again, that is, until the concentrations of the substance on both sides of the membrane are equal.

The change in free energy is expressed in this case as a positive value, and this means that 2.72 kcal of free energy, which are required to transfer 1 mole of glucose (or any neutral substance) against a hundredfold concentration gradient, must be transferred to the system due to some conjugate reactions that can serve as a source of energy.

Concentration gradients between the two sides of cell membranes (transmembrane gradients) vary greatly. Perhaps the maximum concentration gradient in the body is maintained by the plasma membrane of the parietal cells of the gastric mucosa, which secrete hydrochloric acid into the gastric juice. The concentration in gastric juice can reach while the concentration of ions in cells is approximately . This means that parietal cells have the ability to secrete hydrogen ions even against an order gradient. Apparently, these cells have some kind of very active membrane “pumps” for the secretion of hydrogen ions, since a significant amount of energy is required to maintain such a high concentration gradient. The transfer of substances across membranes against a concentration gradient is called active transport. The formation of the stomach is stimulated by a special membrane-bound enzyme - the so-called transporting ATPase. During the formation of gastric juice, for each molecule of cytosolic ATP hydrolyzed to ADP and phosphate, two ions are released from the cytosol through the plasma membrane.

Another important example of active transport is the transport of ions across the plasma membrane in all animal cells. This process is best studied in erythrocytes. It has been established that the concentration in the cytosol of erythrocytes reaches approximately whereas in the blood plasma it is only . At the same time, the concentration in blood plasma reaches and in erythrocytes it is approximately equal. To maintain such high transmembrane gradients, ATP energy is required. The erythrocyte membrane contains a specialized enzyme called β-transporting ATPase, which functions both as an enzyme and as a molecular pump. This ATPase catalyzes the hydrolytic cleavage of ATP to ADP and phosphate, and uses the free energy released to pump ions from the environment into the cell, and ions from the cell into the environment (Fig. 14-15). The stage at which energy transfer occurs in this process is the transfer of the terminal phosphate group of ATP to the -ATPase molecule.

Rice. 14-15. Scheme explaining the action of -ATPase. Transport into the cell (where its concentration is higher than in the environment) and transport from the cell to the environment (where the concentration of these ions is higher than in the cell) requires free energy. Its source is the hydrolysis of ATP. For every ATP molecule hydrolyzed to ADP, three ions leave the cell and two ions enter it from the environment. This ion transport involves two steps. At the first stage, the ATPase molecule is phosphorylated by ATP. and this allows it to attach an ion. At the second stage, an ion attaches, resulting in the transfer of K through the membrane with the elimination of free phosphate entering the cytosol. ATP and its hydrolysis products (ADP and) remain in the cell.

Lyophilisate for the preparation of solution for infusion in the form of a white or almost white powder, with possible aggregation of particles.

Glass facons (1) - cardboard boxes.

The description of the drug is based on the officially approved instructions for use of the drug and was made in 2019. Update date: 05/23/2019

pharmachologic effect

Creatine phosphate (phosphocreatine) plays a key role in providing energy to the muscle contraction mechanism. In the myocardium and skeletal muscles, creatine phosphate is a reserve form of biochemical energy that is used for ATP resynthesis, due to hydrolysis, provides energy for the process of muscle contraction. For ischemia muscle tissue the content of creatine phosphate in myocytes rapidly decreases, which is one of the leading causes of impaired contractility. Creatine phosphate improves the metabolism of the myocardium and muscle tissue, slows down the decrease in contractility of the heart muscle during ischemia, and has a cardioprotective effect on ischemic myocardium.

Experimental cardiopharmacological studies have confirmed the metabolic role of creatine phosphate and its protective properties towards the myocardium:

a) intramuscular administration of creatine phosphate has a dose-dependent protective effect in various cardiomyopathies induced by isoprenaline in rats and pigeons, thyroxine in rats, emetine in guinea pigs, p-nitrophenol in rats;

b) creatine phosphate has a positive inotropic effect on the isolated heart of a frog, guinea pig, rat, as well as under conditions of glucose deficiency, calcium or potassium overdose;

c) creatine phosphate counteracts the negative inotropic effect induced by anoxia in isolated guinea pig atrium;

d) the addition of creatine phosphate to cardioplegic solutions enhances myocardial protection in various experimental models, both in an isolated organ and in vivo:

• on the rat heart during cardiopulmonary bypass and ischemic cardiac arrest, perfusion with cardioplegic solutions with the addition of creatine phosphate in both normal and hypothermia states protects the heart from ischemic damage; this protective effect with the addition of potassium, magnesium and procaine is optimal at a creatine phosphate concentration of 10 mmol/l;
• on a working isolated rat heart, under conditions of regional ischemia (ligation of the left anterior descending coronary artery for 15 minutes), pre-ischemic infusion of creatine phosphate (10 mmol/l) has a protective effect against the development of reperfusion arrhythmia;
• on an isolated dog heart and in vivo (on a normal and hypertrophic heart) after cardiac arrest using hyperpotassium solutions, perfusion of cardioplegic solutions with creatine phosphate plays a protective role; at the same time, a decrease in the degradation of ATP and creatine phosphate, preservation of the structure of mitochondria and sarcolemma, and improvement of functional recovery after reperfusion arrhythmia are recorded;
• on the pig heart in vivo under conditions of circulatory bypass, the addition of creatine phosphate to cardioplegic solutions provides the best protection myocardium;

e) creatine phosphate plays a protective role in experimental myocardial infarction and coronary occlusion:

• in dogs during an experimental myocardial infarction obtained by ligation of the circumflex artery, the administration of creatine phosphate (200 mg/kg bolus followed by an infusion of 5 mg/kg/min) stabilizes hemodynamic parameters, has antiarrhythmic and antifibrillatory effects, prevents a decrease in the contractile function of the heart during ischemia, thereby limiting the expansion of the infarction zone;
• in rats under conditions of coronary ligation, creatine phosphate reduces the frequency and duration of ventricular fibrillation;
• IV infusion of creatine phosphate reduces the infarct area in rabbits and cats after coronary artery ligation;

f) the cardioprotective effect of creatine phosphate is associated with stabilization of the sarcolemma, preservation of the cellular pool of adenine nucleotides to inhibit enzymes of nucleotide catabolism, preventing the degradation of phospholipids in the ischemic myocardium, can improve microcirculation in ischemic areas and inhibit ADP-induced platelet aggregation.

Pharmacokinetics

In rabbits, after a single intramuscular injection of creatine phosphate, Cmax of creatine phosphate in the bloodstream, amounting to 25-28% of the administered dose, is observed 20-40 minutes after administration. The concentration of creatine phosphate decreases slowly and 250 minutes after administration, the bloodstream contains 9% of exogenous creatine phosphate. After a single intramuscular injection of creatine phosphate, an increase in ATP levels is also observed. The effect is detected 40 minutes after administration and lasts up to 250 minutes. In this case, the maximum increase in ATP concentration by 25% occurs 100 minutes after the administration of creatine phosphate. After intravenous administration in rabbits, creatine phosphate remains in the bloodstream with a gradual decrease in content over 30 minutes. In this case, there is also an increase in the ATP concentration in the blood by 24% with a return to normal levels after 300 minutes.

In humans, under conditions of a single intravenous administration, T1/2 of creatine phosphate begins from 0.09 to 0.2 hours. After administration of creatine phosphate in a dose of 5 g by slow infusion, the content of creatine phosphate in the blood is about 5 nmol/ml after 40 minutes, and 40 minutes after administration of creatine phosphate in a dose of 10 g, the content of creatine phosphate in the blood is about 10 nmol/ml. After intramuscular administration, creatine phosphate appears in the bloodstream within 5 minutes, reaching Cmax after 30 minutes - about 10 nmol/ml for a dose of 500 mg and about 11-12 nmol/ml for a dose of 750 mg. 60 minutes after administration, the concentration of creatine phosphate in the blood decreases to 4-5 nmol/ml. 120 minutes after administration, the residual content of exogenous creatine phosphate is 1-2 nmol/ml.

Indications for use

As part of combination therapy for the following diseases:

• acute myocardial infarction;
• chronic heart failure;
• intraoperative myocardial ischemia;
• intraoperative ischemia of the lower extremities;
• metabolic disorders of the myocardium under conditions of hypoxia;
• in sports medicine to prevent the development of acute and chronic physical overstrain syndrome and improve the adaptation of athletes to extreme physical activity.

Dosage regimen

The drug is administered only intravenously (iv, stream or drip) in accordance with the doctor's prescription for 30-45 minutes, 1 g 1-2 times a day.

Creatine phosphate is administered to the maximum short time from the moment signs of ischemia appear, which improves the prognosis of the disease.

The contents of the bottle are dissolved in 10 ml of water for injection, 10 ml of 0.9% sodium chloride solution for infusion or 5% glucose solution for infusion. Shake the bottle vigorously until completely dissolved. As a rule, complete dissolution of the drug takes at least 3 minutes.

Creatine phosphate is used in cardioplegic solutions at a concentration of 10 mmol/l (~2.1 g/l) to protect the myocardium during cardiac surgery. Add to the solution immediately before administration.

Acute myocardial infarction

• 2-4 g of the drug, diluted in 50 ml of water for injection, as a rapid intravenous infusion, followed by an intravenous infusion of 8-16 g in 200 ml of a 5% dextrose (glucose) solution over 2 hours.

• 2-4 g in 50 ml of water for injection intravenously (infusion duration is at least 30 minutes) 2 times a day.

• 2 g in 50 ml of water for injection intravenously (infusion duration is at least 30 minutes) 2 times a day. If necessary, a course of infusions of 2 g of the drug 2 times a day can be carried out for 6 days. Best results treatments were recorded in patients who received the first dose of the drug no later than 6–8 hours from the onset of clinical manifestations of the disease.

Chronic heart failure

Depending on the patient’s condition, you can begin treatment with “shock” doses of 5-10 g of the drug in 200 ml of a 5% dextrose (glucose) solution intravenously at a rate of 4-5 g/hour for 3-5 days, and then continue for intravenous drip administration (infusion duration of at least 30 minutes) 1-2 g of the drug diluted in 50 ml of water for injection, 2 times a day for
2-6 weeks or immediately begin intravenous drip administration of maintenance doses of Creatine Phosphate (1-2 g in 50 ml of water for injection 2 times a day for 2-6 weeks).

Intraoperative myocardial ischemia

A course of intravenous drip infusions lasting at least 30 minutes of 2 g of the drug in 50 ml of water for injection 2 times a day is recommended for 3-5 days before surgery and for 1-2 days after it. During surgical intervention Creatine phosphate is added to the regular cardioplegic solution at a concentration of 10 mmol/l or 2.5 g/l immediately before administration.

Intraoperative ischemia of the lower extremities

2-4 g of the drug Creatine phosphate in 50 ml of water for injection as a rapid intravenous infusion before surgery, followed by an intravenous drip of 8-10 g of the drug in 200 ml of a 5% dextrose (glucose) solution at a rate of 4-5 g /h during surgery and during reperfusion.

Metabolic disorders of the myocardium under conditions of hypoxia

History of Creatine

Creatine was discovered in 1832 by the French scientist Chevreul, who discovered a previously unknown component of skeletal muscle, which he later named creatine, from the Greek kreas, which means “meat.”

After Chevreul's discovery of creatine in 1835, another scientist, Lieberg, confirmed that creatine is a common component of mammalian muscle. Around the same time, researchers Heinz and Pettenkofer discovered a substance in urine called “creatinine.” They suggested that creatinine is formed from creatine accumulated in muscles. Already at the beginning of the 20th century, scientists conducted a number of studies of creatine as a dietary supplement. It has been found that not all creatine taken orally is excreted in the urine. This indicated that some of the creatine remained in the body.

Explorers Folin and Denis in 1912 and 1914 Accordingly, they determined that dietary creatine supplementation increased creatine content in muscle cells. In 1923, Hahn and Meyer calculated the total creatine content in the body of a man weighing 70 kg, which turned out to be approximately 140 grams. Already in 1926, it was experimentally proven that the introduction of creatine into the body stimulates the growth of muscle mass, causing nitrogen retention in the body. In 1927, researchers Fiske and Sabbarow discovered “phosphocreatine,” which is a chemically bonded molecule of creatine and phosphate that accumulates in muscle tissue. Free forms of creatine and phosphorylated phosphocreatine are recognized as key metabolic intermediates in skeletal muscle.

The first study to clearly show the effects of creatine in humans was conducted in the late 1980s in the laboratory of Dr. Eric Haltman in Sweden. The study found that consuming 20 grams of creatine monohydrate daily for 4-5 days increased muscle creatine content by approximately 20%. The results of this work, however, were published only in 1992 in the journal Clinical Science, since then the history of taking creatine in bodybuilding begins.

The idea of ​​"loading" and subsequent maintenance dosing was developed by Dr Greenhoff at the University of Nottingham in 1993-1994, the results of which were published jointly with Dr Hultman. Dr. Greenhoff and his colleagues conducted studies in muscle tissue to study the effects of creatine loading.

In 1993, the Scandinavian Journal of Medicine, Science and Sports published an article showing that creatine supplementation could cause significant increases in body weight and muscle strength (even after just one week of use) and that it was the basis for improved training performance. high intensity.

In 1994, Anthony Almada and his colleagues conducted research at Texas Woman's University. The main purpose of the research was to demonstrate that the increase in body weight with creatine use occurs due to an increase in “lean” muscle mass (without the participation of fat) and that taking creatine leads to an increase strength indicators(results were checked in the bench press). The research results were published in the journal Acta Physiologica Scandinavica.

Since 1993-1995 among the new products sports nutrition there is no more popular one in bodybuilding food additives than creatine. In fact, from that time on, the victorious march of creatine began across countries and continents in the most various types sports

In the early 90s of the last century, low-level creatine supplements were already available in Britain, and only after 1993 a high-quality creatinine supplement was developed to increase strength, available to the mass consumer. It was released by the company Experimental and Applied Sciences (EAS) introducing creatine under the trade name Phosphagen.

In 1998, MuscleTech Research and Development launched Cell-Tech, the first supplement to combine creatine, carbohydrates and alpha lipoic acid. Alpha lipoic acid further increased muscle phosphocreatine levels and total creatine concentrations. Research in 2003 confirmed the effectiveness of this combination, but it must be admitted that the level of effectiveness is quite low.

But Sci Fit scientists went further and developed in 2001 the new kind creatine processing – Kre-Alkalyn, “hacking the code of creatine”, as they wrote about this development in scientific journals in the world of sports and bodybuilding, and patenting this invention, receiving patent No. 6,399,611. Three years later, this news was replaced by a new one, since the disastrous inferiority of this approach was proven.

Another important event occurred in 2004, when the world first heard about Creatine ethyl ester (CEE), which instantly grew in popularity. Currently, CEE is widely used and produced by many companies along with creatine monohydrate. But its effectiveness compared to creatine monohydrate has not been proven.

In addition, in the last decade, tri-creatine malate (Tri-Creatine Malate), dicreatine malate, creatine malate ethyl ester, creatine alpha-ketoglutarate and some other forms of creatine have been synthesized, but they have not gained much popularity due to their low efficiency.

Biological role of creatine

Creatine is a natural substance found in human and animal muscles and is required for energy metabolism and movement. The human body contains about 100-140 g of this substance, which acts as a source of energy for muscles. Daily consumption Creatine under normal conditions is approximately 2 g. Creatine is as important for life as protein, carbohydrates, fats, vitamins and minerals. Creatine can be synthesized by the body independently from 3 amino acids: glycine, arginine and methionine. These amino acids are components of protein.

In humans, the enzymes involved in creatine synthesis are localized in the liver, pancreas and kidneys. Creatine can be produced in any of these organs, and then transported by the blood to the muscles. Approximately 95% of the total creatine pool is stored in skeletal muscle tissue.

When increasing physical activity Creatine consumption also increases, and its supply must be replenished through diet or through the body's own natural production.

Decisive factor for achieving high results in sports is the body's ability to release large amounts of energy in a short period of time. In principle, our body constantly receives energy by breaking down carbohydrates and fat.

The immediate source of energy for skeletal muscle contraction is a molecule called ATP (adenosine triphosphate). The amount of ATP immediately available is limited and is decisive for athletic activity.

All fuel sources - carbohydrates, fats and protein - are first converted through various chemical reactions into ATP, which then becomes available as the only molecule the body uses for energy. When ATP releases energy to provide energy muscle contractions, the phosphate group is broken off and a new molecule called ADP (adenosine diphosphate) is formed. This reaction is reversed by creatine phosphate, an energy-rich substance.

Creatine combines with phosphate in the body to form phosphocreatine, which is a determinant of energy production in muscle tissue.

Effects of Creatine

Increased strength

In bodybuilding, during high-intensity exercise, the need for ATP in working muscles increases significantly - hundreds of times higher than at rest. Depleted stores of ATP and phosphocreatine must be constantly replenished in order for muscle contractions to continue at peak levels of frequency and intensity. By increasing phosphocreatine by taking creatine monohydrate, you can increase the amount of ATP and thus increase muscle strength.

Creatine phosphoric acid (creatine phosphate, phosphocreatine) - 2-[methyl-(N"-phosphonocarboimidoyl)amino]acetic acid. Colorless crystals, soluble in water, easily hydrolyzed with cleavage of phosphamide N-P connections in acidic environment, stable in alkaline environment.

The acid was discovered by Philip and Grace Eggleton of the University of Cambridge and independently by Cyrus Fiske and Yellapragada Subbarao of Harvard Medical School in 1927.

Laboratory synthesis - phosphorylation of creatine POCl 3 in an alkaline environment.

Creatine phosphate is a product of reversible metabolic N-phosphorylation of creatine, which, like ATP, is a high-energy compound. However, unlike ATP, which is hydrolyzed at the pyrophosphate O-P connections, creatine phosphate is hydrolyzed at the N-P phosphamide bond, which causes a significantly greater energy effect of the reaction. Thus, during hydrolysis, the change in free energy for creatine is G 0 ~ −43 kJ/mol, while during hydrolysis of ATP to ADP G 0 ~ −30.5 kJ/mol.

Creatine phosphate is found mainly in excitable tissues (muscle and nervous tissue) and its biological function is to maintain a constant ATP concentration due to the reversible rephosphorylation reaction:

This reaction is catalyzed by cytoplasmic and mitochondrial creatine kinase enzymes; when ATP is consumed (and, accordingly, the concentration drops), for example, when muscle cells contract, the reaction equilibrium shifts to the right, which leads to the restoration of the normal ATP concentration.

The concentration of creatine phosphate in resting muscle tissue is 3-8 times higher than the concentration of ATP, which makes it possible to compensate for the consumption of ATP during short periods of muscle activity; during the rest period, in the absence of muscle activity, glycolysis and oxidative phosphorylation of ADP into ATP occurs in the tissue, resulting in the equilibrium of the reaction shifts to the left and the concentration of creatine phosphate is restored.

In tissues, creatine phosphate undergoes spontaneous non-enzymatic hydrolysis with cyclization into creatinine, excreted in the urine; the level of creatinine excretion depends on the state of the body, changing under pathological conditions, and is a diagnostic sign.

Creatine phosphate is one of the phosphagens - N-phosphorylated guanidine derivatives, which are an energy depot that ensures rapid ATP synthesis. Thus, in many invertebrates (for example, insects), the role of phosphagen is played by arginine phosphoric acid, and in some annelids - N-phospholombricin.

Topic: “PECULIARITIES OF THE METABOLISM OF GLYCINE, SERINE, SULFUR-CONTAINING AND AROMATIC AMINO ACIDS”

1. Paths of formation and use of glycine and serine in the body. The role of tetrahydrofolic acid in the formation and transfer of one-carbon groups.
2. Ways of formation and use of cysteine ​​in the body. S-Adenosylmethionine, its participation in methyl group transfer reactions. The role of methylcobalamin and methyl-THFA in the regeneration of methionine in the body. Methyl conjugation.
3. Biosynthesis of creatine and creatine phosphate, biological role. Formation and release of creatinine. Clinical and diagnostic value of determining the content of creatine and creatinine in blood and urine.
4. Metabolism of phenylalanine and tyrosine, features of their catabolism, participation in the synthesis of hormones, neurotransmitters and pigments. Features of the catabolism of phenylalanine and tyrosine.
5. Congenital disorders of phenylalanine and tyrosine metabolism (phenylketonuria, alkaptonuria, albinism): main symptoms, biochemical diagnosis, dietary features.

Exchange of serine and glycine. Formation and transfer of one-carbon groups.

The main role in the exchange reactions of serine and glycine is played by enzymes that contain tetrahydrofolic acid (THFA) as a coenzyme. THFA is formed in the body as a result of the reduction of folic acid (vitamin Bc).

folic acid

TGFC

25.1.2. The reactive centers in the THFA molecule are nitrogen atoms in positions 5 and 10. Hydrogen atoms at N5 and N10 can be replaced by various one-carbon groups: methyl (-CH3), methylene (-CH2-), methylene (=CH-), formyl (- CH=O) and some others. The main sources of one-carbon groups in the cell are serine and glycine.

5,10-Methylene-THFA is used as a methyl group donor in biosynthesis reactions thymidyl nucleotide.

The oxidation of 5,10-methylene-THFA produces 5,10-methenyl-THFA and 10-formyl-THFA. These THPA derivatives serve as sources of carbon atoms in the process biosynthesis of purine nucleotides (adenyl and guanyl).

When 5,10-methylene-THFA is reduced, 5-methyl-THFA is formed. This compound is interesting because it can supply a methyl group for methionine regeneration from homocysteine ​​(see below).

25.1.3. Amino acid glycine, in addition to participating in protein synthesis and the formation of various one-carbon groups, is a precursor to a number of specialized biomolecules:

• both carbon atoms and the glycine nitrogen atom can be included in the structure of the purine core (atoms C4, C5 and N7);
• glycine is the main precursor of porphyrins (prosthetic group of hemoglobin, myoglobin, cytochromes);
• glycine is involved in the synthesis of creatine, a precursor of creatine phosphate, which is involved in the bioenergetics of muscle and nervous tissue;
• glycine is part of the peptide coenzyme glutathione;
• participates in the formation of conjugates (glycocholic acid, hippuric acid).

Metabolism of methionine and cysteine. Transmethylation reactions

The methyl group of methionine bonded to the sulfur atom is also a mobile one-carbon group capable of participating in transmethylation reactions (methyl group transfer). The active form of methionine, directly involved in these transformations, is S-adenosylmethionine, which is formed by the interaction of methionine with ATP.

Examples of transmethylation reactions involving S-adenosylmethionine are given in Table 25.1.

Table 25.1

Use of the methyl group of S-adenosylmethionine in transmethylation reactions

Here are some examples of these reactions.

1) Formation of phosphatidylcholine from phosphatidylethanolamine- key reaction of phospholipid synthesis:

Phosphatidylcholine is the main phospholipid component of biological membranes; it is part of lipoproteins, takes part in the transport of cholesterol and triacylglycerols; disruption of phosphatidylcholine synthesis in the liver leads to fatty infiltration.

2) Formation of adrenaline from norepinephrine- final reaction of adrenal medulla hormone synthesis:

Adrenaline is released into the blood during emotional stress and is involved in the regulation of carbohydrate and lipid metabolism in the body.

3) Methyl conjugation reactions- one of the stages of neutralization of foreign compounds and endogenous biologically active substances:

As a result of methylation, the reactive SH and NH groups of substrates are blocked. The reaction products are inactive and are excreted from the body in the urine.

25.2.3. After donating the methyl group, S-adenosylmethionine is converted to S-adenosylhomocysteine. The latter is broken down into adenosine and homocysteine. Homocysteine ​​can be converted back into methionine due to the methyl group of 5-methyl-THFA (see previous paragraph):

Methylcobalamin, a derivative of vitamin B12, participates in this reaction as a coenzyme. With a lack of vitamin B12, the synthesis of methionine from homocysteine ​​is disrupted and 5-methyl-THFA accumulates. Since the reaction to form 5-methyl-THFA from 5,10-methylene-THFA is irreversible, folic acid deficiency occurs at the same time.

25.2.4. Another way to use homocysteine, as already mentioned, is to participate in cysteine ​​synthesis. Biological role of cysteine:

• is part of the protein, where it can form disulfide bonds that stabilize the spatial structure of the macromolecule;
• participates in the synthesis of glutathione, and the cysteine ​​SH group determines the reactivity of this coenzyme;
• is a precursor of thioethanolamine in the HS-CoA molecule;
• serves as a precursor for taurine in conjugated bile acids;
• is the source of the sulfur atom in organic sulfates (chondroitin sulfate, heparin, FAPS).

Biosynthesis of creatine and its subsequent transformations.

The synthesis of creatine in human tissues occurs in two stages. At the first stage, guanidine acetate is formed in the kidneys:

At the second stage, a transmethylation reaction occurs in the liver:

25.3.2. Creatine synthesized in the liver enters the blood and is delivered to the muscles. There it interacts with ATP, resulting in the formation of the high-energy compound creatine phosphate. This reaction is easily reversible.

At rest, muscles accumulate creatine phosphate (its content in non-working muscle is 3-8 times higher than the ATP content). When switching to muscle work, the direction of the reaction changes and ATP is formed, which is necessary for muscle contraction.

The formation of ATP with the participation of creatine phosphate is the fastest way to generate ATP. The supply of creatine phosphate ensures intense muscle work for 2 - 5 seconds. During this time, a person manages to run 15 - 50 meters. Meanwhile, other mechanisms of ATP formation are activated: mobilization of muscle glycogen, oxidation of substrates coming from the liver and adipose tissue.

The concentration of creatine in the blood of healthy adults is approximately 50 µmol/L; it is practically absent in urine. The appearance of creatine in the urine is not always a symptom of the disease. Thus, in young children and adolescents, the urine always contains creatine (physiological creatinuria). In case of muscle diseases, when the formation of creatine phosphate is disrupted, the content of creatine in the blood increases and its excretion in the urine increases.

25.3.3. As a result of non-enzymatic dephosphorylation of creatine phosphate, creatinine is formed - creatine anhydride.

Creatinine is one of the end products of nitrogen metabolism in the body; it is excreted in the urine. The daily excretion of creatinine in a healthy person is proportional to its muscle mass. Creatinine is not reabsorbed in the renal tubules, so its daily excretion is an indicator of the filtration function of the kidneys. The content of creatinine in the blood decreases with muscle diseases and increases with impaired renal function. Urinary creatinine excretion decreases in both cases.

Metabolism of phenylalanine and tyrosine.

The exchange of phenylalanine and tyrosine in human tissues can be represented as follows (see Figure 25.1).

Figure 25.1. Pathways for the exchange of phenylalanine and tyrosine in tissues (the numbers indicate the most common enzyme defects; the following is a description of these disorders).

25.4.2. There are a number of known congenital disorders of phenylalanine and tyrosine metabolism.

Phenylketonuria- a congenital disorder of the process of hydroxylation of phenylalanine to tyrosine. The disease is most often caused by the absence or deficiency of the enzyme phenylalanine hydroxylase (indicated by number 1 in Figure 25.1), less often by a violation of the formation of tetrahydrobiopterin.

Early symptoms of phenylketonuria are increased excitability and motor activity, vomiting and feeding difficulties; from the 3rd to the 5th month, intellectual development is impaired, and the reaction to the environment disappears. Over time, children develop seizures. Hair and eyes are usually less pigmented than other family members. In the absence of treatment, the life expectancy of patients is 20 - 30 years.

The biochemical basis of phenylketonuria is accumulation phenylalanine in organism. A high concentration of amino acid stimulates the production of an enzyme that converts phenylalanine into phenylpyruvate(normally this enzyme is inactive). By reduction, phenylpyruvate passes into phenyllactate, and by decarboxylation - into phenylacetate. These products, along with phenylalanine, are found in significant quantities in the urine of patients.

There is now good evidence that high concentrations of phenylalanine are primarily responsible for toxic brain damage. An increased content of phenylalanine inhibits the transport of tyrosine and other amino acids through biological membranes. This leads to a limitation of protein synthesis in brain cells and disruption of the synthesis of neurotransmitters.

Early diagnosis of the disease cannot be made based only on clinical symptoms. Diagnosis is made biochemically by screening all newborns. Treatment of patients with phenylketonuria is based on limiting the intake of phenylalanine in the body and reducing the concentration of this amino acid in the plasma. For this purpose, artificial nutritional mixtures are used that do not contain phenylalanine (for example, berlofen).

Alkaptonuria- a congenital disorder of phenylalanine metabolism caused by the absence of the enzyme homogentisic acid oxidase (number 2 in Figure 25.1). This leads to disruption of the formation of maleylacetoacetate, which is further broken down to fumarate and acetoacetate. In the early childhood the only manifestation of enzyme deficiency is a change in urine color. Homogentisic acid is secreted into the lumen of the tubules and is excreted in significant quantities in the urine. In air it oxidizes and then polymerizes into a colored compound, which turns the diapers black. The excretion of homogentisic acid depends on the content of phenylalanine and tyrosine in food.

The consequence of the accumulation of homogentisic acid in the body is ochronosis- a slate-blue tint of the ear and nasal cartilage caused by the accumulation of pigment in them. The development of ochronosis can be prevented if early age limit the intake of phenylalanine and tyrosine from food.

Albinism develops in the absence of the enzyme tyrosinase in pigment cells (indicated by number 3 in Figure 25.1), which is involved in the formation of melanin. As a result, the patient's hair, skin and eyes are deprived of this pigment. With albinism, there is increased sensitivity to sunlight and some visual impairment.