Metabolism. Basic processes of cellular metabolism

Principles of regulation of metabolic pathways

All chemical reactions in the cell proceed with the participation of enzymes. Therefore, in order to influence the rate of the metabolic pathway, it is sufficient to regulate the amount or activity of enzymes. There are usually key enzymes in metabolic pathways that regulate the rate of the entire pathway. These enzymes (one or more in the metabolic pathway) are called regulatory enzymes; they catalyze, as a rule, the initial reactions of the metabolic pathway, irreversible reactions, rate-limiting reactions (the slowest ones), or reactions at the point of switching of the metabolic pathway (branch points).

Regulation of the rate of enzymatic reactions is carried out at 3 independent levels:

• change in the number of enzyme molecules;
• availability of substrate and coenzyme molecules;
• a change in the catalytic activity of the enzyme molecule.

Regulation of the catalytic activity of enzymes

The regulation of the catalytic activity of one or several key enzymes of a given metabolic pathway plays a crucial role in changing the rate of metabolic pathways. This is a highly effective and fast way to regulate metabolism.

The main ways to regulate the activity of enzymes:

• allosteric regulation;
• regulation by protein-protein interactions;
• regulation by phosphorylation/dephosphorylation of the enzyme molecule;
• regulation by partial (limited) proteolysis.

Allosteric regulation

Allosteric enzymes are enzymes whose activity is regulated not only by the number of substrate molecules, but also by other substances called effectors. The effectors involved in allosteric regulation are often cellular metabolites of the very pathway they regulate.

Allosteric enzymes play an important role in metabolism, as they react extremely quickly to the slightest changes in the internal state of the cell. Allosteric regulation is of great importance in the following situations:

• during anabolic processes. Inhibition by the end product of the metabolic pathway and activation by the initial metabolites allow regulation of the synthesis of these compounds;
• during catabolic processes. In the case of ATP accumulation in the cell, the metabolic pathways that provide energy synthesis are inhibited. In this case, the substrates are spent on the reactions of storage of reserve nutrients;
• to coordinate anabolic and catabolic pathways. ATP and ADP are allosteric effectors that act as antagonists;
• To coordinate parallel flowing and interconnected metabolic pathways (for example, the synthesis of purine and pyrimidine nucleotides used for the synthesis of nucleic acids). Thus, the end products of one metabolic pathway may be allosteric effectors of another metabolic pathway.

allosteric effectors. An effector that causes a decrease (inhibition) of enzyme activity is called a negative effector or inhibitor. An effector that causes an increase (activation) of enzyme activity is called a positive effector or activator.

Various metabolites often serve as allosteric effectors. The end products of the metabolic pathway are often inhibitors of allosteric enzymes, and the starting materials are activators. This is the so-called heterotropic regulation. This type of allosteric regulation is very common in biological systems.

A rarer case of allosteric regulation is when the substrate itself can act as a positive effector. Such regulation is called homotropic (effector and substrate are the same substance). These enzymes have multiple substrate binding sites that can serve a dual function: catalytic and regulatory. Allosteric enzymes of this type are used in a situation where the substrate accumulates in excess and must be quickly converted into a product.

Enzymes with allosteric regulation can be identified by studying the kinetics of these enzymes.

Features of the structure and functioning of allosteric enzymes:

usually these are oligomeric proteins consisting of several protomers or having a domain structure;

they have an allosteric center spatially distant from the catalytic active center;

effectors attach to the enzyme non-covalently in allosteric (regulatory) centers;

allosteric centers, as well as catalytic ones, can exhibit different specificity with respect to ligands: it can be absolute and group specific. Some enzymes have several allosteric centers, some of which are specific to activators, others to inhibitors.

the protomer on which the allosteric center is located is a regulatory protomer, in contrast to the catalytic protomer containing the active center in which the chemical reaction takes place;

allosteric enzymes have the property of cooperativity: the interaction of the allosteric effector with the allosteric center causes a consistent cooperative change in the conformation of all subunits, leading to a change in the conformation of the active center and a change in the affinity of the enzyme to the substrate, which reduces or increases the catalytic activity of the enzyme;

the regulation of allosteric enzymes is reversible: detachment of the effector from the regulatory subunit restores the initial catalytic activity of the enzyme;

allosteric enzymes catalyze the key reactions of this metabolic pathway.

Figure 3. Scheme explaining the work of an allosteric enzyme. A - the action of a negative effector (inhibitor); B - the action of a positive effector (activator).

Localization of allosteric enzymes in the metabolic pathway.

The rate of metabolic processes depends on the concentration of substances used and formed in a given chain of reactions. Such regulation seems logical, since with the accumulation of the end product, it (the end product) can act as an allosteric inhibitor of the enzyme that most often catalyzes the initial stage of this metabolic pathway:

The enzyme that catalyzes the conversion of substrate A to product B has an allosteric center for a negative effector, which is the end product of the metabolic pathway F. If the concentration of F increases (i.e. substance F is synthesized faster than it is consumed), the activity of one of the initial enzymes is inhibited. This regulation is called negative feedback or retroinhibition. Negative feedback is a common mechanism for the regulation of cell metabolism.

In the central metabolic pathways, the parent substances can be activators of key enzymes of the metabolic pathway. As a rule, enzymes that catalyze the key reactions of the final stages of the metabolic pathway undergo allosteric activation:

As an example, we can consider the principles of regulation of glycolysis, a specific (initial) pathway for the breakdown of glucose (Fig. 4). One of the end products of the breakdown of glucose is the ATP molecule. With an excess of ATP in the cell, retroinhibition of the allosteric enzymes phosphofructokinase and pyruvate kinase occurs. With the formation of a large amount of fructose-1,6-bisphosphate, allosteric activation of the pyruvate kinase enzyme is observed.

Figure 4. Schematic of the positive and negative regulation of glucose catabolism.

The ATP molecule is involved in the retro-inhibition of the allosteric enzymes phosphofructokinase and pyruvate kinase. Fructose-1,6-bisphosphate is an activator of the metabolic pathway of glucose breakdown. Pluses marked activation, minuses - inhibition of enzymes.

Thanks to this regulation, the coherence of the flow of the metabolic pathway of glucose breakdown is carried out.

Three types of mechanisms are involved in the regulation of metabolic pathways. The first of them, which reacts most quickly to any change in the situation, is associated with the action of allosteric enzymes (Fig. 13-15), the catalytic activity of which can change under the influence of special substances that have a stimulating or inhibitory effect (they are called effectors or modulators; section 9.18 ).

As a rule, allosteric enzymes occupy a place at the beginning or near the beginning of a given multienzymatic sequence and catalyze that stage of it, which limits the rate of the entire process; Usually, the role of such a stage is played by an almost irreversible reaction.

Rice. 13-15. Regulation of the catabolic pathway by the type of feedback, i.e. due to the inhibition of the allosteric enzyme by the end product of this process. The letters J, K, L, etc. denote the intermediate products of this metabolic pathway, and the letters E1, E2, E3, etc., the enzymes that catalyze the individual steps. The first step is catalyzed by an allosteric enzyme (ED) which is inhibited by the end product of this reaction sequence. Allosteric inhibition is indicated by a dashed red arrow that connects the inhibitory metabolite to the reaction catalyzed by the allosteric enzyme.

In catabolic processes accompanied by the synthesis of ATP from ADP, this end product, ATP, often acts as an allosteric inhibitor of one of the early stages of catabolism. An allosteric inhibitor of one of the early stages of anabolism is often the end product of biosynthesis, for example, some amino acid (Sec. 9.18). The activity of some allosteric enzymes is stimulated by specific positive modulators. An allosteric enzyme regulating one of the catabolic reaction sequences may, for example, be subject to the stimulatory effect of positive modulators-ADP or AMP and the inhibitory effect of a negative modulator-ATP. Cases are also known when an allosteric enzyme of one metabolic pathway reacts in a specific way to intermediate or end products of other metabolic pathways. This makes it possible to coordinate the rate of action of various enzyme systems.

The second type of mechanisms that regulate metabolism in higher organisms is hormonal regulation (Fig. 13-16). Hormones are called special chemicals (chemical "intermediaries") produced by various endocrine glands and released directly into the blood; they are carried by the blood to other tissues or organs and here stimulate or inhibit certain types of metabolic activity. The hormone adrenaline, for example, is secreted by the adrenal medulla and carried by the blood to the liver, where it stimulates the breakdown of glycogen into glucose, which causes blood sugar levels to rise. In addition, adrenaline stimulates the breakdown of glycogen in skeletal muscles; this process leads to the formation of lactate and to the storage of energy in the form of ATP. Adrenaline causes these effects by attaching to specific receptor sites on the surface of muscle or liver cells.

The binding of adrenaline serves as a signal; this signal is transmitted to the internal parts of the cell and causes a covalent modification here, under the influence of which glycogen phosphorylase (the first enzyme in the system catalyzing the conversion of glycogen into glucose and other products; Section 9.22) passes from a less active form to a more active one (Fig. 13-16 ).

The third type of mechanisms that regulate metabolism is associated with a change in the concentration of this enzyme in the cell. The concentration of any enzyme at any given moment is determined by the ratio of the rates of its synthesis and decay. The rate of synthesis of some enzymes under certain conditions increases dramatically; the concentration of this enzyme in the cell also increases accordingly. If, for example, an animal receives a diet rich in carbohydrates but poor in protein, then in the liver it has an extremely low content of enzymes that under normal conditions catalyze the breakdown of amino acids to acetyl-CoA. Since these enzymes are practically not needed with such a diet, they are not produced in large quantities. It is worth, however, to transfer the animal to a diet rich in protein, and within a day in its liver the content of enzymes will noticeably increase, which will now be required for the breakdown of digestible amino acids.

Rice. 13-16. Hormonal regulation of the enzymatic reaction. As a result of the attachment of the hormone adrenaline to specific receptors located on the surface of liver cells, cyclic adenylate is formed with the participation of an enzyme associated with the membrane (adenylate cyclase). The latter functions as an allosteric activator, or intracellular mediator, under the action of which glycogen phosphorylase changes from an inactive form to an active one, which leads to an acceleration in the conversion of liver glycogen into blood glucose. This metabolic pathway is described in detail in Chap. 25.

Rice. 13-17. enzyme induction. A high intracellular concentration of substrate A can stimulate the biosynthesis of the enzymes E1, E2 and E3. The content of these enzymes in the cell increases, and thus it is possible to accelerate those reactions, as a result of which the excess of substrate A is removed. An excess of substrate A, therefore, serves as a signal for the cell nucleus, forcing it to “turn on” the genes that control the formation of the enzymes El, E2 and E3. The inclusion of genes means the synthesis of the corresponding messenger RNA; it enters the ribosomes, and as a result, the synthesis of enzymes E1, E2 and E3 is carried out in them.

Liver cells, therefore, have the ability to turn on or off the biosynthesis of specific enzymes, depending on the nature of the nutrients entering them. This phenomenon is called enzyme induction (Fig. 13-17).

In living organisms that are in constant contact and exchange with the environment, there are continuous chemical changes that make up their metabolism (many enzymatic reactions). The scale and direction of metabolic processes are very diverse. Examples:

a) The number of E. coli cells in a bacterial culture can double by 2/3 in 20 minutes in a simple medium with glucose and inorganic salts. These components are absorbed, but only a few are released into the environment by a growing bacterial cell, and it consists of approximately 2.5 thousand proteins, 1 thousand organic compounds, various nucleic acids in the amount of 10-3 * 10 molecules. Obviously, these cells are participating in a grandiose biological spectacle, in which a huge amount of biomolecules necessary for cell growth is planned to be supplied. No less impressive is the metabolism of an adult, who maintains the same weight and body composition for about 40 years, although during this time he consumes about 6 tons of solid food and 37,850 liters of water. All substances in the body are converted (complex to simple and vice versa) 2/3 series of consecutive compounds, each of which is called a metabolite. Each transformation is a stage of metabolism.

The set of such successive stages catalyzed by individual enzymes is called the metabolic pathway. From the totality of figurative metabolic pathways, their joint functioning, metabolism is formed. This is carried out sequentially and not randomly (synthesis of amino acids, breakdown of glucose, fatty acids, synthesis of purine bases). We know very little, hence the mechanism of action of medicinal substances is very transparent!!!

The entire metabolic pathway is usually controlled by the first - second stage of metabolism (limiting factor, enzymes with an allosteric center - regulatory).

Such stages are called key, and metabolites at these stages are called key metabolites.

Metabolites that are on cross metabolic pathways are called nodal metabolites.

There are cyclic ways of exchange a) another substance is usually involved and disappears b) the cell manages with a small amount of metabolites - savings. Control pathways for the conversion of essential nutrients

Albinism endemic goiter

homogenous pigment. to-that Thyroxine

melanin

Alcapturia

carbon dioxide and water

Metabolic regulation

Each reaction proceeds at a rate commensurate with the needs of the cell ("smart" cells!). These specific ones determine the regulation of metabolism.

I. Regulation of the rate of entry of metabolites into the cell (transfer is affected by water molecules and the concentration gradient).

a) simple diffusion (for example, water)

b) passive transport (no energy consumption, such as pentoses)

c) active transport (carrier system, ATP)

II. Control of the amount of certain enzymes Suppression of the synthesis of enzymes by the end product of metabolism. This phenomenon is a rough control of metabolism, for example, the synthesis of enzymes that synthesize GIS is suppressed in the presence of GIS in a medium, a bacterial culture. Rough control - since it is implemented for a long time until the finished enzyme molecules are destroyed. Induction of one or more enzymes by substrates (increase in the concentration of a specific enzyme). In mammals, a similar phenomenon is observed several hours or days later in response to an inductor.

III. Control of catalytic activity a) covalent (chemical) modification b) allosteric modification (+/-) of the bond how it instantly acts in response to a change in the intracellular environment. These regulatory mechanisms are effective at the cellular and subcellular levels, at the intercellular and organ levels of regulation, which is carried out by hormones, neurotransmitters, intracellular mediators, and prostaglandins.

Metabolic pathways:

1) catabolic

2) anabolic

3) ampholytic (bind the first two)

catabolism- a sequence of enzymatic reactions, as a result of which destruction occurs mainly due to the oxidation reactions of large molecules (carbohydrates, proteins, lipids, nucleic acids) with the formation of lungs (lactic and acetic acids, carbon dioxide and water) and the release of energy contained in covalent bonds of various compounds, part of the energy is stored in the form of macroergic bonds, which are then used for mechanical work, the transport of substances, and the biosynthesis of large molecules.

There are three stages of catabolism:

Stage I - Digestion. Large food molecules are broken down into building blocks under the influence of digestive enzymes in the gastrointestinal tract, with the release of 0.5-1% of the energy contained in the bonds.

Stage II - Unification. A large number of products formed in stage 1 gives in stage 2 simpler products, the number of which is small, while about 30% of the energy is released. This stage is also valuable because the release of energy at this stage gives rise to the synthesis of ATP in anoxic (anaerobic) conditions, which is important for the body in hypoxic conditions.

III stage - Krebs cycle. (tricarboxylic acids / citric acid). In essence, this is the process of converting a two-carbon compound (acetic acid) into 2 mol of carbon dioxide, but this path is very complex, cyclic, multi-enzymatic, the main supplier of electrons to the respiratory chain, and, accordingly, ATP molecules in the process of oxidative phosphorylation. Almost all enzymes of the cycle are located inside the mitochondria; therefore, the electron donors of the TCA freely donate electrons directly to the respiratory chain of the mitochondrial membrane system.

Scheme of the tricarboxylic acid cycle.

Succinyl CoA - contains a macroergic thioether bond capable of transforming into a macroergic bond of GTP (substrate phosphorylation).

FAD - passes electrons to the CoQ of the respiratory chain: electron

alphaketoglutarate water isocitrate

alphaketoglutarate succinyl CoA CO2

In addition to all TTK is the 1st stage of anabolism at the same time.

1) various enzyme systems.

2) the localization of processes is different (for example, fatty acid oxidation occurs in mitochondria, and synthesis occurs in the cytoplasm).

3) various mechanisms of allosteric and genetic regulation.

4) different qualitative composition of the end products of anabolism.

5) energy expenditure during anabolism and release during katab

There are also amphibolic pathways in the body (at the same time there is a process of decay and a process of synthesis). The largest:

a) glycolysis of phosphotriose acetyl CoA

b) CTK acetyl CoA CO2 + H2O

The decay has been dismantled, but various compounds can be formed from many TCA products:

A) oxaloacetic acid asp, asn, glu

B) alphaketoglutarate glu, hln, glu

C) citric acid into the cytoplasm acetyl CoA

fatty acid,

steroids

D) succinyl CoA heme

DYNAMIC BIOCHEMISTRY

ChapterIV.8.

Metabolism and energy

Metabolism or metabolism - a set of chemical reactions in the body that provide it with the substances and energy necessary for life. In the metabolism, two main stages can be distinguished: preparatory - when the substance received by the alimentary route undergoes chemical transformations, as a result of which it can enter the bloodstream and then penetrate into the cells, and the actual metabolism, i.e. chemical transformations of compounds that have penetrated into cells.

metabolic pathway - this is the nature and sequence of chemical transformations of a particular substance in the body. The intermediate products formed during metabolism are called metabolites, and the last compound of the metabolic pathway is the final product.

The process of breaking down complex substances into simpler ones is called catabolism. So, proteins, fats, carbohydrates that enter the food, under the action of digestive tract enzymes, break down into simpler components (amino acids, fatty acids and monosaccharides). This releases energy. The reverse process, i.e., the synthesis of complex compounds from simpler ones is called anabolism . It comes with energy. From the amino acids, fatty acids and monosaccharides formed as a result of digestion, new cellular proteins, membrane phospholipids and polysaccharides are synthesized in cells.

There is a concept amphibolism when one compound is destroyed, but another is synthesized.

metabolic cycle is a metabolic pathway, one of the end products of which is identical to one of the compounds involved in this process.

A private metabolic pathway is a set of transformations of one specific compound (carbohydrates or proteins). The common metabolic pathway is when two or more types of compounds are involved (carbohydrates, lipids and partly proteins are involved in energy metabolism).

Substrates of metabolism - compounds coming from food. Among them are the main nutrients (proteins, carbohydrates, lipids) and minor, which come in small quantities (vitamins, minerals).

The intensity of metabolism is determined by the need of the cell for certain substances or energy, regulation is carried out in four ways:

1) The total rate of reactions of a certain metabolic pathway is determined by the concentration of each of the enzymes of this pathway, the pH value of the medium, the intracellular concentration of each of the intermediate products, the concentration of cofactors and coenzymes.

2) The activity of regulatory (allosteric) enzymes, which usually catalyze the initial stages of metabolic pathways. Most of them are inhibited by the end product of this pathway and this type of inhibition is called "feedback".

3) Genetic control that determines the rate of synthesis of a particular enzyme. A vivid example is the appearance of inducible enzymes in the cell in response to the intake of the corresponding substrate.

4) Hormonal regulation. A number of hormones are capable of activating or inhibiting many enzymes of the metabolic pathways.

Living organisms are thermodynamically unstable systems. For their formation and functioning, a continuous supply of energy in a form suitable for multifaceted use is necessary. To obtain energy, almost all living creatures on the planet have adapted to hydrolyze one of the pyrophosphate bonds of ATP. In this regard, one of the main tasks of the bioenergetics of living organisms is the replenishment of used ATP from ADP and AMP.

The main source of energy in the cell is the oxidation of substrates with atmospheric oxygen. This process is carried out in three ways: the addition of oxygen to a carbon atom, the elimination of hydrogen, or the loss of an electron. In cells, oxidation proceeds in the form of a sequential transfer of hydrogen and electrons from the substrate to oxygen. In this case, oxygen plays the role of a reducing compound (oxidizing agent). Oxidative reactions proceed with the release of energy. Relatively small changes in energy are characteristic of biological reactions. This is achieved by splitting the oxidation process into a number of intermediate stages, which makes it possible to store it in small portions in the form of macroergic compounds (ATP). The reduction of an oxygen atom upon interaction with a pair of protons and electrons leads to the formation of a water molecule.

tissue respiration

This is the process of consumption of oxygen by the cells of the tissues of the body, which is involved in biological oxidation. This type of oxidation is called aerobic oxidation . If the final acceptor in the hydrogen transfer chain is not oxygen, but other substances (for example, pyruvic acid), then this type of oxidation is called anaerobic.

That. biological oxidation is the dehydrogenation of a substrate with the help of intermediate hydrogen carriers and its final acceptor.

respiratory chain (enzymes of tissue respiration) are carriers of protons and electrons from the oxidized substrate to oxygen. An oxidizing agent is a compound capable of accepting electrons. This ability is quantified redox potential in relation to the standard hydrogen electrode, the pH of which is equal to 7.0. The lower the potential of the compound, the stronger its reducing properties and vice versa.

That. any compound can only donate electrons to a compound with a higher redox potential. In the respiratory chain, each subsequent link has a higher potential than the previous one.

The respiratory chain is made up of:

1. NAD - dependent dehydrogenase;

2. FAD-dependent dehydrogenase;

3. Ubiquinone (Ko Q);

4. Cytochromes b , c , a + a 3 .

NAD-dependent dehydrogenases . Contains as a coenzyme ABOVE and NADP. The pyridine ring of nicotinamide is capable of attaching electrons and hydrogen protons.

FAD and FMN-dependent dehydrogenases contain as a coenzyme phosphoric ester of vitamin B 2 ( FAD).

Ubiquinone (Co Q ) takes hydrogen from flavoproteins and turns into hydroquinone.

Cytochromes - chromoprotein proteins capable of attaching electrons due to the presence of iron porphyrins as prosthetic groups in their composition. They accept an electron from a slightly stronger reducing agent and donate it to a stronger oxidizing agent. The iron atom is bonded to the nitrogen atom of the imidazole ring of the histidine amino acid on one side of the plane of the porphyrin ring, and on the other side to the sulfur atom of methionine. Therefore, the potential ability of the iron atom in cytochromes to bind oxygen is suppressed.

AT cytochrome c the porphyrin plane is covalently linked to the protein through two cysteine ​​residues, and in cytochromesb and , it is not covalently bound with protein.

AT cytochrome a+a 3 (cytochrome oxidase) instead of protoporphyrin contains porphyrin A, which differs in a number of structural features. The fifth coordination position of iron is occupied by an amino group belonging to an amino sugar residue that is part of the protein itself.

In contrast to the heme of hemolgobin, the iron atom in cytochromes can reversibly change from two to a trivalent state; this ensures the transport of electrons (See Appendix 1 "Atomic and electronic structure of hemoproteins" for more details).

The mechanism of operation of the electron transport chain

The outer membrane of the mitochondria (Fig. 4.8.1) is permeable to most small molecules and ions, while the inner membrane is permeable to almost all ions (except H protons) and to most uncharged molecules.

All of the above components of the respiratory chain are built into the inner membrane. The transport of protons and electrons along the respiratory chain is provided by the potential difference between its components. Moreover, each increase in potential by 0.16 V releases energy sufficient for the synthesis of one ATP molecule from ADP and H 3 RO 4. When one molecule of O 2 is consumed, 3 ATP.

The processes of oxidation and formation of ATP from ADP and phosphoric acid i.e. phosphorylation takes place in mitochondria. The inner membrane forms many folds - cristae. The space is limited by the inner membrane - the matrix. The space between the inner and outer membranes is called intermembrane.

Such a molecule contains three macroergic bonds. Macroergic or rich in energy is a chemical bond, upon breaking of which more than 4 kcal / mol is released. During the hydrolytic breakdown of ATP to ADP and phosphoric acid, 7.3 kcal / mol is released. Exactly the same amount is spent for the formation of ATP from ADP and the rest of phosphoric acid, and this is one of the main ways of storing energy in the body.

In the process of electron transport along the respiratory chain, energy is released, which is spent on the addition of a phosphoric acid residue to ADP to form one ATP molecule and one water molecule. In the process of transferring one pair of electrons along the respiratory chain, 21.3 kcal / mol is released and stored in the form of three ATP molecules. This is about 40% of the energy released during electronic transport.

This way of storing energy in a cell is called oxidative phosphorylation or coupled phosphorylation.

The molecular mechanisms of this process are most fully explained by Mitchell's chemo-osmotic theory, put forward in 1961.

Mechanism of oxidative phosphorylation (fig.4.8.2.):

1) NAD-dependent dehydrogenase is located on the matrix surface of the inner membrane of mitochondria and donates a pair of hydrogen electrons to FMN-dependent dehydrogenase. In this case, a pair of protons also passes from the matrix to FMN, and as a result, FMN H2 is formed. At this time, a pair of protons belonging to NAD is pushed into the intermembrane space.

2) FAD-dependent dehydrogenase donates a pair of electrons to Co Q and pushes a couple of protons into the intermembrane space. Having received electrons Q accepts a couple of protons from the matrix and turns into Co Q H 2 .

3) Co Q H 2 pushes a pair of protons into the intermembrane space, and a pair of electrons is transferred to cytochromes and then to oxygen to form a water molecule.

As a result, when a pair of electrons is transferred along the chain from the matrix to the intermembrane space, 6 protons (3 pairs) are pumped, which leads to the creation of a potential difference and a pH difference between the surfaces of the inner membrane.

4) The potential difference and the pH difference ensure the movement of protons through the proton channel back to the matrix.

5) This reverse movement of protons leads to the activation of ATP synthase and the synthesis of ATP from ADP and phosphoric acid. With the transfer of one pair of electrons (i.e. three pairs of protons), 3 ATP molecules are synthesized (Fig. 4.7.3.).

Uncoupling of the processes of respiration and oxidative phosphorylation occurs when protons begin to penetrate the inner membrane of the mitochondria. In this case, the pH gradient levels off and the driving force of phosphorylation disappears. Chemical substances - uncouplers are called protonophores, they are able to carry protons through the membrane. These include 2,4-dinitrophenol, thyroid hormones, etc. (Fig. 4.8.3.).

The resulting ATP is transferred from the matrix to the cytoplasm by translocase enzymes, while one ADP molecule and one phosphoric acid molecule are transferred to the matrix in the opposite direction. It is clear that a violation of the transport of ADP and phosphate inhibits the synthesis of ATP.

The rate of oxidative phosphorylation depends primarily on the content of ATP, the faster it is consumed, the more ADP accumulates, the greater the need for energy and, therefore, the more active the process of oxidative phosphorylation. Regulation of the rate of oxidative phosphorylation by ADP concentration in the cell is called respiratory control.

LITERATURE TO THE CHAPTER IV.8.

1. Byshevsky A. Sh., Tersenov O. A. Biochemistry for a doctor // Ekaterinburg: Ural worker, 1994, 384 p.;

2. Knorre D. G., Myzina S. D. Biological chemistry. - M .: Higher. school 1998, 479 pp.;

3. Lehninger A. Biochemistry. Molecular bases of the structure and functions of the cell // M.: Mir, 1974, 956 p.;

4. Pustovalova L.M. Workshop on biochemistry // Rostov-on-Don: Phoenix, 1999, 540 p.;

5. Stepanov V. M. Molecular biology. Structure and functions of proteins // M.: Vysshaya shkola, 1996, 335 p.;

Moscow Medical Academy named after I.M. Sechenov

Department of General Chemistry

Abstract work №1

1st year students of group 9

Faculty of VSO correspondence department

Romashkova Ekaterina Dmitrievna

Moscow 2010

Mechanisms of regulation of metabolic processes

The activity of all metabolic pathways is constantly regulated, which ensures that the synthesis and degradation of metabolites correspond to the physiological needs of the body. This section discusses the mechanisms of such regulation. In more detail, the issues of regulation of cellular metabolism are presented on. The flow of metabolites in metabolism is determined primarily by the activity enzymes.To influence one or another pathway, it is sufficient to regulate the activity of the enzyme catalyzing the slowest step. These enzymes are called key enzymes are found in most metabolic pathways. The activity of a key enzyme is regulated at three independent levels,

transcription control. Control of enzyme biosynthesis(1) carried out at the genetic level. First of all, we are talking about the synthesis of the corresponding mRNA (mRNA), as well as transcriptions the gene encoding the enzyme, i.e. about transcription regulation.Participated in this process regulatory proteins(RP) (transcription factors), the action of which is directed directly to DNA. In addition, there are special regulatory regions in the genes - promoters- and binding sites of regulatory proteins (regulatory elements). The effectiveness of these proteins is influenced by metabolites or hormones. If this mechanism enhances the synthesis of the enzyme, they speak of induction, if it reduces or suppresses - oh repression. The processes of induction and repression are carried out only in a certain period of time.

Interconversion. Significantly faster than transcriptional control is the interconversion of key enzymes (2). In this case, the enzyme is present in the cell in an inactive form. With a metabolic need for a signal from the outside and through the mediation of a second messenger activating enzyme(E 1) converts the key enzyme into a catalytically active form. If the need for this metabolic pathway disappears, inactivating enzyme(E 2) turns the key enzyme back into an inactive form. The process of interconversion in most cases consists in ATP-dependent phosphorylation enzymatic proteins protein kinase and, accordingly, dephosphorylation phosphatase.In most cases, the phosphorylated form of the enzyme is more active, but there are also opposite cases.

modulation by ligands. An important parameter that controls the flow of the metabolic pathway is the need for the first reagent (here it is metabolite A). The availability of the metabolite A increases with an increase in the activity of the metabolic pathway (3) in which A is formed, and decreases with an increase in the activity of other pathways (4) in which A is consumed. The availability of A may be limited due to its transport to other parts of the cell.

Often the limiting factor is also coenzyme availability(5). If the coenzyme is regenerated via a second independent pathway, this pathway may limit the rate of the main reaction. Thus, for example, glycolysis and the citrate cycle are regulated by NAD + availability. Since NAD + is regenerated in the respiratory chain, the latter regulates glucose and fatty acid catabolism. Finally, the activity of a key enzyme can be regulated ligand(substrate, reaction end product, coenzyme, other effector) as allosteric effector by binding it not in the active site itself, but in another place of the enzyme, and as a result, a change in enzymatic activity. Inhibition of a key enzyme is often caused by the end products of the reaction of the corresponding metabolic chain (inhibition by type of feedback) or a metabolite involved in another pathway. The first reactant of the reaction chain can also stimulate the activation of the enzyme.

Hormonal regulation of metabolism

Enzyme-catalyzed activation and, accordingly, inactivation of key enzymes of intermediate metabolism are called interconversions. Such processes are under various control, including hormonal. This section discusses the processes of interconversions that regulate the metabolism of glycogen in the liver.

A. Hormonal regulation of glycogen breakdown

Glycogen serves as a reserve of carbohydrates in the body, from which glucose phosphate is quickly created in the liver and muscles by splitting. glycogen phosphorylase(pictured below left). Both enzymes act on the surface of insoluble glycogen particles, where, depending on the state of metabolism, they can be in an active or inactive form. When fasting or in stressful situations (wrestling, running), the body's need for glucose increases. In such cases, hormones are released adrenalin and glucagon. They activate the breakdown and inhibit the synthesis of glycogen. Adrenaline acts in the muscles and liver, while glucagon only works in the liver.

Both hormones bind to receptors on the plasma membrane (1) and activated through G-proteins adenylate cyclase(2), which catalyzes the synthesis of 3",5"-cyclo-AMP (cAMP) from ATP (ATP). The mirror opposite is the effect on this “ secondary messenger » phosphodiesterase cAMP (3), hydrolyzing cAMP to AMP (AMP). In the liver, diesterase is induced by insulin, which therefore does not interfere with the action of the other two hormones (not shown). cAMP binds and thereby activates protein kinase A(4), which acts in two directions: on the one hand, with the help of phosphorylation with the participation of ATP as a coenzyme, it translates into an inactive D-form glycogen synthase and consequently stops the synthesis of glycogen (5); on the other hand, it activates - also by phosphorylation - another protein kinase, phosphorylase kinase(eight). Active phosphorylase kinase phosphorylates inactive b-form glycogen phosphorylase, turning it into an active a-form (7). This leads to the release of glucose-1-phosphate from glycogen (8), which, after conversion to glucose-6-phosphate with the participation of phosphoglucomutase, is included in glycolysis (9). In addition, free glucose is formed in the liver, which enters the blood (10).

As cAMP levels decrease, they become activated phosphoprotein phosphatase(11), which dephosphorylate various phosphoproteins of the described cascade and thereby stop the breakdown of glycogen and initiate its synthesis. These processes take place within a few seconds, so that glycogen metabolism quickly adapts to the changed conditions.

B. Interconversion of glycogen phosphorylase

Structural changes that accompany the interconversions of glycogen phosphorylase were established by X-ray diffraction analysis. The enzyme is dimer with second order symmetry. Each subunit has an active site, which is located inside the protein and in the b-form is poorly accessible to the substrate. Interchange starts with phosphorylation of a serine residue(Ser-14) near the N-terminus of each of the subunits. Arginine residues of neighboring subunits bind to phosphate groups. Binding initiates conformational rearrangements that significantly increase the enzyme's affinity for the allosteric AMP activator. The action of AMP and the effect of conformational changes on the active sites lead to the emergence of a more active α-form. After the removal of phosphate residues, the enzyme spontaneously assumes the original b-conformation.

Hormonal regulation of fatty acid metabolism

metabolism enzyme hormonal regulation

adrenaline and glucagon activate intracellular lipase. The action of these hormones is mediated by the adenylate cyclase cascade of reactions, starting with the activation of adenylate cyclase and ending with the phosphorylation of lipase, which then becomes active and cleaves ester bonds in TAG. Glycerol as a plasma-soluble substance is transported to the liver, where it is used in gluconeogenesis reactions. Fatty acid are transported by the blood in the form of complexes with serum albumin to various organs and tissues, where they are included in the oxidation process.

Hormonal regulation The metabolism of proteins provides a dynamic balance of their synthesis and decay.

· Protein Anabolism controlled by adenohypophysis hormones ( growth hormone), pancreas ( insulin), male gonads ( androgen). Strengthening the anabolic phase of protein metabolism with an excess of these hormones is expressed in increased growth and weight gain. Lack of anabolic hormones causes growth retardation in children.

· Protein catabolism regulated by thyroid hormones thyroxine and triiodothyronone), cortical ( glucocorticoids) and cerebral ( adrenalin) substances of the adrenal glands. An excess of these hormones enhances the breakdown of proteins in tissues, which is accompanied by depletion and a negative nitrogen balance. Lack of hormones, for example, the thyroid gland is accompanied by obesity.