All living organisms with a cellular structure can be characterized as open systems. In the process of their life, they must constantly exchange energy and matter with the environment. Energy is needed by living cells for the biosynthesis of complex organic substances, performing various types of movement, reproduction, osmoregulation, excretion of metabolic products, etc.
There is an assumption that in the process of evolution, the first organisms to appear on our planet were those that used ready-made organic substances accumulated in the World Ocean through abiogenic synthesis as energy sources. Such organisms are called heterotrophic
. At that time, the Earth's atmosphere contained virtually no oxygen,
therefore, these organisms could obtain energy from organic substances using various redox reactions and store it in the form of ATP and NADH. These reactions took place under anaerobic (i.e., oxygen-free) conditions. To build their inherent organic substances, they also used ready-made organic substances as building blocks. Therefore, they should be called more strictly chemoorganotrophs
- organisms that use ready-made organic substances as a source of carbon and electrons (reduction equivalents) and obtain energy (ATP) in redox reactions. Later, organisms appeared that began to use sunlight as an energy source for the synthesis of ATP ( photoorganotrophs
), and then carbon dioxide as a source of carbon ( photolithotrophs
) - photosynthetic bacteria, plants (lower and higher). Such organisms are often called photosynthetics
, and photolithotrophs are called autotrophs
, emphasizing that they are capable of synthesizing organic substances from inorganic substances (carbon dioxide). A separate group of autotrophic organisms consists of chemosynthetics
(chemolithotrophs
) - organisms that use energy obtained from the oxidation of inorganic substances to produce ATP and reducing equivalents.
The accumulation of organic matter in nature as a result of the activity of autotrophs stimulated the further flourishing of its consumers - heterotrophs. Molecular oxygen, which is a powerful oxidizing agent, began to appear in the atmosphere. Oxygen was formed during photosynthesis as a by-product. Thanks to the presence of oxygen, it became possible to more efficiently and fully use the energy stored in organic substances. Thus arose aerobic organisms capable of completely oxidizing complex organic substances to water and carbon dioxide with the help of oxygen. However, up to the present day there have been preserved mixotrophic organisms that combine the properties of autotrophs, i.e. having the ability to photosynthesize, and heterotrophs that feed on ready-made organic substances. These include, for example, Chlamydomonas or Euglena green.
So, to obtain energy, living organisms (both heterotrophs and autotrophs - for example, green plants in the dark or their non-photosynthetic cells) decompose and oxidize organic compounds. The set of biochemical reactions of the decomposition of complex substances into simpler ones, which are accompanied by the release and storage of energy in the form of ATP (a universal energy-rich compound), is called energy metabolism(catabolism, or dissimilation).
Along with energy metabolism reactions, processes constantly occur in cells in which complex organic substances inherent to a given organism, low molecular weight (amino acids, sugars, vitamins, organic acids, nucleotides, lipids) and biopolymers (proteins, polysaccharides, nucleic acids) are synthesized. All these substances are necessary for the cell to build various cellular structures and perform various functions. To synthesize these substances, cells use carbon dioxide, which is obtained from the external environment (autotrophs), or more complex organic compounds (heterotrophs), as well as energy and reducing equivalents accumulated in the process of energy metabolism. The set of biosynthetic processes occurring in living organisms with the expenditure of energy (and often reducing equivalents) is called plastic exchange(anabolism or assimilation).
Energy and plastic metabolism occurring in cells are closely interrelated processes. They happen simultaneously and constantly. Thus, many intermediate products that are formed during energy metabolism reactions are used in biosynthesis reactions as starting compounds. And the energy stored in the form of macroergic bonds of ATP during dissimilation is constantly used in synthesis processes. Therefore, plastic and energy exchange cannot be considered in isolation from each other: these are two sides of the same process - metabolism (metabolism ), constantly occurring in all living systems and constituting the biochemical basis of life.
Questions.
Features of enzymatic catalysis. Regulation of enzyme activity. Application of enzymes and their modulators in medicine.
1. Enzymes. Nomenclature. Classification of enzymes.
2. Levels of enzyme organization.
3. The mechanism of action of enzymes. The concept of the active center of an enzyme, stages of enzymatic catalysis.
4. Kinetics of enzymatic reactions. Dependence of the enzymatic reaction on various factors. The Michaelis-Menten equation, the role of Km and Vmax in the characterization of enzymes.
5. Enzyme inhibitors. Types of inhibition. Graphical representation of the dependence of the rate of an enzymatic reaction on the presence of various types of inhibitors.
6. Mechanisms for regulating enzyme activity. Examples.
7. Allosteric enzymes. Regulation of their activity. Examples.
8. Enzymodynamics. Enzyme therapy. Examples.
Introduction to metabolism. Biological oxidation.
1. The most important signs of living matter. Features of living organisms as open thermodynamic systems.
2. The concept of the processes of catabolism and anabolism. Functions of cellular metabolism. Basic principles of metabolic organization: stages, convergence, unification. Stages of generation according to Krebs.
3. Scheme of catabolism of basic nutrients. The concept of general and specific pathways of catabolism.
4. Concept of biological oxidation. Conjugation of exergonic and endergonic processes in the body (using the example of glucose phosphorylation).
5. Ways to utilize oxygen. Characteristics of high-energy substrates, the ATP-ADP cycle, the use of ATP as a universal source of energy.
6. Substrate phosphorylation: essence, biological significance of the process, examples.
7. Oxidative phosphorylation: essence, biological significance of the process.
8. Electron transport chain (ETC), coupling of respiration and ATP synthesis in mitochondria, oxidative phosphorylation coefficient. Inhibitors and uncouplers of CPE.
9. Oxidative decarboxylation of pyruvic acid: scheme, enzymes, connection with ATP synthesis. The structure of the pyruvate dehydrogenase complex: enzymes, coenzymes, regulation of the process.
10. Regulation and anabolic function of the TCA cycle.
Carbohydrate metabolism.
1. Food hydrocarbons. Scheme of hydrocarbon digestion in the gastrointestinal tract. Causes of milk intolerance.
2. Glycogen synthesis in the liver and skeletal muscles. Regulation of these processes.
3. Glycogen breakdown in the liver and skeletal muscles. Regulation of these processes.
4. Glycolysis: general characteristics, stages, process reactions, regulated enzymes, energy effect. The fate of glycolysis products under aerobic conditions: process diagram, connection with ATP synthesis.
5. Anaerobic breakdown of glucose (anaerobic glycolysis). Fate of glycolysis products under anaerobic conditions. Biological significance of anaerobic breakdown of glucose.
6. Biosynthesis of glucose (gluconeogenesis). Substrates, energy costs, regulated enzymes. Cori cycle.
7. Pentose phosphate pathway (PPP) of glucose oxidation. Biological significance.
Exchange of amino acids, proteins, nucleotides.
1. Nutritional value of various proteins. Nitrogen balance. Clinical manifestation of lack of protein in food.
2. Digestion of proteins in the gastrointestinal tract. Biological significance of digestion. Process diagram. Characteristics of digestive enzymes.
3. The formation of hydrochloric acid and its role in the digestion of proteins. Regulation of hydrochloric acid secretion. Diagnostic value of gastric juice analysis. Pathological changes in acidity and pathological components of gastric juice.
4. Transamination of amino acids, biological significance, substrates, enzymes, the role of vitamins in this process.
5. Oxidative deamination (direct, indirect) of amino acids. Scheme of the process, stages, enzymes, biological significance of the process.
7. Mechanisms of ammonia toxicity, symptoms of ammonia poisoning. Pathways of ammonia formation in the body.
8. Ways to neutralize ammonia. Mechanisms of ammonia transport in the body: glutamine and glucose-alanine cycles.
9. Urea synthesis: reaction scheme, summary equation. Relationship with TsTK. Clinical significance of determining the concentration of urea in the blood and urine, the reasons for the increase and decrease in the concentration of urea.
10. Synthesis of creatine, creatine phosphate, creatinine. The functions of these compounds in the body.
11. Catabolism of purine nucleotides. The level of uric acid in blood serum is normal and the reasons for its increase. Gout.
12. Methionine metabolism and its role in metabolism.
1.5. Lumen of lipids and lipoproteins.
1. Scheme of digestion of food lipids in the gastrointestinal tract: stages, substrates, enzymes, the role of hydrolysis products, the role of bile acids. Steatorrhea.
2. Stages of fatty acid catabolism: enzyme reactions. Energy effect of complete oxidation of C16.0. Regulation of the β-oxidation process of IVFA.
3. Stages of fatty acid biosynthesis: reactions, enzymes. Regulation of the biosynthesis process of IVFA.
4. Mobilization of TAG in adipose tissue. Regulation of the process and fate of lipolysis products.
5. Scheme for the synthesis of glycerol phospholipids. An idea of the role of lecithin in the functioning of lung surfactant.
6. TAG biosynthesis: sequence of reactions, substrates, enzymes. Features of synthesis in the liver, adipose tissue, enterocytes. Process regulation.
7. Structure and functions of cholesterol in the human body. Foundation, ways of using cholesterol in the body and removing it. Metabolic and hormonal regulation of biosynthesis.
8. Functions of bile acids and their regulation. Enterohepatic circulation of bile acids, biological significance.
9. Biological significance and structures of ketone bodies. Synthesis of ketone bodies in the liver, regulation of the process. Understanding ketonemia, ketonuria and ketoacidosis.
10. Classification of drugs. Structure and composition of plasma lipoprotein particles. Apoproteins and their functions. Enzymes involved in drug metabolism. Catalyzed reactions and their role in drug metabolism.
11. Chylomicrons (CM): functions, formation and metabolism.
12. LDL and VLDL: formation, functions and metabolism.
13. HDL: formation, functions and metabolism.
14. Chemical modification of lipids and proteins of LDL and LDL receptors. Molecular mechanisms of atherosclerosis development. Atherogenic coefficient.
Related information.
Q=∆H + W
where: Q – heat energy
ΔН – enthalpy
W – work
Thus, cells, receiving energy from the external environment in the form of light quanta (photosynthesis) or chemical energy of organic and inorganic substances, and storing it in compounds with high energy potential (ATP), convert it into electrical or chemical energy contained in a molecule. ATP is the main carrier of chemical energy in all living organisms. ATP can transfer its energy to other biomolecules, losing its terminal phosphate group, turning into ADP, that is, performing the work of contractile, motor apparatus for transporting substances across the membrane. Useless thermal work is released into the environment - the entropy of the environment (∆S) increases.
Second law of thermodynamics
The system strives for its disorder. This is documented by the increase in entropy ΔS and is expressed by the equation:
ΔH = ΔG + TΔS
where: ΔH – thermal energy,
ΔG – Gibbs free energy,
T – absolute temperature.
The entropy value is constant and has a positive minimum value. This occurs due to the fact that the increase in the level of entropy in the system during the degradation of nutrients is compensated by the removal of final products from the system and the intensification of biosynthetic processes, and this value is reduced to the required stationary parameters.
If metabolism stops, the Gibbs energy of the system decreases, entropy increases (that is, the quality of energy decreases), and enthalpy, which characterizes the measure of the thermal content of the system, decreases. It always strives for a minimum and when it is reached, the body dies. Therefore, the task of an organism or biosystem is a high level of enthalpy and free energy. The system tends to maintain the entropy value at a lower stationary level.
It is known that the higher the hardness of a substance, the lower its entropy. So the entropy of diamond (0.57 e.u.) is half the entropy of graphite (1.7 e.u.). Carbides, borides and other very hard substances are characterized by low entropy. The entropy of an amorphous body is slightly greater than the entropy of a crystalline body. An increase in the degree of dispersion of the system also leads to a slight increase in its entropy.
Entropy increases as the molecule of a substance becomes more complex; so for gases N 2 O, N 2 O 3, N 2 O 5 the entropy is 52.6, respectively; 73.4 and 85.0 e.u. The entropy of branched hydrocarbons is less than the entropy of unbranched hydrocarbons. The entropy of a cycloalkane is less than the entropy of its corresponding alkene.
Let us consider in more detail the factors necessary to maintain a steady state. In order for metabolism to take place, that is,
substrate S → X ↔ Y → P(end products of degradation)
implementation V 1, V 2, V 3 – const.
metabolism
the substrate concentration (S) must ensure saturation of the enzyme catalyzing this transformation. This reaction must be unidirectional, creating a net flow towards substrate degradation. Such reactions control the operation of the system and are its limiting links - they are kinetically irreversible. An example of such a reaction in the body is the glucokinase reaction, which leads to the formation of gl-6-phosphate from glucose in the presence of ATP and Mg 2+. This is the limiting link in glycolysis, which determines the speed of the process as a whole.
Conditions for maintaining a stationary flow.
1. The final stages of metabolism must be kinetically irreversible (CO 2 H 2 O);
2. Since the final products are excreted from the body, the entropy in the biosystem is maintained almost constant;
3. A constant flow of nutrients and energy is only one of the conditions for maintaining a steady state;
4. The presence of a structural organization that allows the absorption and use of nutrients and energy.
Introduction to metabolism. Principles of metabolic organization.
Metabolism– can be defined as the totality of all bioorganic reactions catalyzed by enzymes.
Intermediate exchange begins from the moment nutrients enter the blood and until the end products of metabolism are removed and provide the body with the substances and energy necessary for its life.
Metabolism is a highly integrated and focused process. Integration is possible due to the existence of the relationship between the metabolism of carbohydrates, proteins and fats, etc. The relationship is ensured by a common energy supply, common intermediate metabolites, at the level of which there is an intersection of specific metabolic processes (gl-6-ph, PVK, acetyl-CoA), general metabolic processes (TCA cycle, oxidative phosphorylation). Integration is also possible due to the relationship between tissues and organs. Integrating systems include the nervous system (the center for processing information and making decisions when conditions change); endocrine system (production of hormones that transmit information into the cell); vascular system (serves for the transport of not only nutrients, but also hormones).
The sequence of metabolism in the body allows us to distinguish 4 stages of metabolism, that is, metabolism is characterized by dynamism and stages.
Stage 1– at this stage, the supply of nutrients to the internal tissues of the body is prepared during the process of digestion in the gastrointestinal tract. There are:
a) distant digestion - for example, the breakdown of proteins under the action of pepsin in the stomach cavity or trypsin in the intestinal lumen.
b) parietal or membrane - for example, the action of peptidases fixed on the surface of cells of the intestinal mucosa;
c) intracellular - for example, in lysosomes, digestion under the action of proteolytic enzymes.
In addition to the enzymes of the macroorganism, enzymes of the intestinal microflora also participate in digestion.
Stage 2– resorption – processes of absorption of nutrients through the intestinal mucosa.
Stage 3– interstitial metabolism – enzymatic processes of synthesis and breakdown, regulated by the neurohumoral pathway.
Stage 4– excretion – excretion of metabolic products.
The concept of the processes of catabolism and anabolism.
The set of chemical transformations of substances that occur in the body, starting from the moment they enter the blood and until the end products of metabolism are released from the body, is called intermediate metabolism(intermediate exchange). Intermediate metabolism can be divided into two processes - catabolism (dissimilation) and anabolism (assimilation).
Catabolism called the enzymatic breakdown of relatively large organic molecules, usually in higher organisms, by the oxidative route. Catabolism is accompanied by the release of energy contained in the complex structures of organic molecules and its storage in the form of the energy of phosphate bonds of ATP (exergonic process, with the release of Gibbs energy and storage in the form of ATP).
Anabolism is the enzymatic synthesis of large molecular cellular components, such as polysaccharides, nucleic acids, proteins, lipids, which are characterized by significant Gibbs energy and low entropy, as well as the synthesis of some biosynthetic precursors of simpler compounds, with stronger bonds (low Gibbs energy values and high values entropy - CO 2, NH 3, urea, creatinine).
Anabolic processes occur in cells simultaneously and are inextricably linked with each other. Essentially, they should be considered not as two separate processes, but as two sides of a common process - metabolism, in which the transformation of substances is closely intertwined with the transformation of energy.
Catabolism.
The breakdown of basic nutrients in the cell is a series of sequential enzymatic reactions that make up the 3 main stages of catabolism (Hans Krebs) - dissimilation.
Stage 1– large organic molecules break down into their constituent specific structural blocks. Thus, polysaccharides are broken down into hexoses or pentoses, proteins into amino acids, nucleic acids into nucleotides and nucleosides, lipids into fatty acids, glycerides and other substances.
The amount of energy released at this stage is small - less than 1%.
Stage 2– even simpler molecules are formed, and the number of their types is significantly reduced. It is important to emphasize that here products are formed that are common to the metabolism of different substances - these are, as it were, nodes connecting different metabolic pathways. These include: pyruvate – formed during the breakdown of carbohydrates, lipids, amino acids; acetyl-CoA - combines the catabolism of fatty acids, carbohydrates, amino acids.
Products obtained at the 2nd stage of catabolism enter 3rd stage, which is known as the Krebs cycle - the tricarboxylic acid cycle (TCA), in which terminal oxidation processes occur. During this stage, all products are oxidized to CO 2 and H 2 O. Almost all the energy is released in the 2nd and 3rd stages of catabolism.
All of the above stages of catabolism or dissimilation, which are known as the “Krebs scheme,” most accurately reflect the most important principles of metabolism: convergence and unification. Convergence– the combination of various metabolic processes characteristic of individual types of substances into single ones common to all types. Next stage - unification– a gradual decrease in the number of participants in metabolic processes and the use of universal metabolic products in metabolic reactions.
At the first stage, the principle of unification is clearly visible: instead of many complex molecules of very different origins, fairly simple compounds are formed in the amount of 2-3 dozen. These reactions occur in the gastrointestinal tract and are not accompanied by the release of large amounts of energy. It is usually dissipated as heat and is not used for other purposes. The significance of the first stage chemical reactions is to prepare the nutrients for the actual release of energy.
At the second stage, the principle of convergence is clearly visible: the merging of various metabolic pathways into a single channel - that is, into the 3rd stage.
At the 2nd stage, about 30% of the energy contained in nutrients is released. The remaining 60-70% of the energy is released in the tricarboxylic acid cycle and the associated terminal oxidation process. In the terminal oxidation system or respiratory chain, which is based on oxidative phosphorylation, unification reaches its peak. Dehydrogenases that catalyze the oxidation of organic substances in the TCA cycle transfer only hydrogen to the respiratory chain, which undergoes identical transformations during oxidative phosphorylation.
Anabolism.
Anabolism also goes through three stages. The starting substances are those that undergo transformations at the 3rd stage of catabolism. Thus, stage 3 of catabolism is the initial stage of anabolism. The reactions of this stage have a dual function - amphibolic. For example, protein synthesis from amino acids.
Stage 2 – formation of amino acids from keto acids in transamination reactions.
Stage 3 – combining amino acids into polypeptide chains.
Also, as a result of sequential reactions, the synthesis of nucleic acids, lipids, and polysaccharides occurs.
In the 60-70s of the 20th century, it became clear that anabolism is not a simple reversal of catabolic reactions. This is due to the chemical characteristics of chemical reactions. A number of catabolic reactions are practically irreversible. Their flow in the opposite direction is prevented by insurmountable energy barriers. In the course of evolution, bypass reactions were developed that involved the expenditure of energy from high-energy compounds. The catabolic and anabolic pathways differ, as a rule, in their localization in the cell - structural regulation.
For example: the oxidation of fatty acids occurs in mitochondria, while the synthesis of fatty acids is catalyzed by a set of enzymes localized in the cytosol.
It is due to different localization that catabolic and anabolic processes in the cell can occur simultaneously.
Principles of Metabolic Integration
Thus, the metabolic pathways are diverse, but in this diversity lies unity, which is a specific feature of metabolism.
This unity lies in the fact that from bacteria to the highly organized tissue of a higher organism, the biochemical reactions are identical. Another manifestation of unity is the cyclical nature of the most important metabolic processes. For example, tricarboxylic acid cycle, urea cycle, pentose cycle. Apparently, cyclic reactions selected during evolution turned out to be optimal for ensuring physiological functions.
When analyzing the organization of metabolic processes in the body, the question naturally arises: how is the maintenance of processes achieved in accordance with the needs of the body at different periods of its life? Those. How is “homeostasis” maintained (a concept that was first formulated by Cannon in 1929) in the context of constantly changing life situations, i.e. - when the internal and external environment changes. It was already mentioned above that the regulation of metabolism ultimately comes down to changing the activity of enzymes. At the same time, we can talk about a hierarchy of metabolic regulation.
Chapter 5.
Elements of chemical thermodynamics
1. Organization of chemical reactions. Energy cycles
2. Fundamentals of thermodynamics
3. Laws of thermodynamics
4. Introduction to metabolism. Principles of organization of metabolism. Concept of the process of catabolism and anabolism.
5. Hierarchy of metabolic regulation
6. Energy metabolism. What is bioenergy?
7. Proton potential.
8. Structural features of ATP. The role of macroergs in metabolism.
9. An idea of biological oxidation, its role and types, enzymes and coenzymes of this process. ATP synthesis reactions. Oxidation of energy substrates. Carriers of electrons and protons. Generation of proton potential. Oxidative phosphorylation coefficient. Mechanisms of its regulation.
10. Ways to utilize oxygen.
11. ATP synthesis.
12. Common metabolic pathways. The tricarboxylic acid cycle is its amphibolic essence. Energy metabolism. Proton potential.
Biologically important high-energy compounds. Concept of biological oxidation. The role of biological oxidation.
13. Oxidation-reduction reactions. Pathways for oxygen utilization: oxidase and oxygenase.
14. ATP synthesis. ATP synthesis by substrate and oxidative phosphorylation.
Generation of proton potential. ATP synthesis due to proton potential.
15. Situational tasks, theoretical tasks and laboratory practical work on the topic “Biochemical thermodynamics”.
16. Energy metabolism and the general path of catabolism.
Biochemical thermodynamics– a branch of biochemistry that deals with the study of energy transformations accompanying biochemical reactions. Its fundamental principles help explain why some reactions occur and others do not. Non-biological systems can perform work using thermal energy, while biological systems operate in an isothermal mode and use chemical energy to carry out life processes.
The vital activity of an organism is determined by the peculiarities of the organization of biological structures, metabolism and energy, the transfer of genetic information and regulatory mechanisms.
Damage to any of these links leads to the development of a pathological process and disease. Knowledge of the molecular mechanisms of life and their disorders is the basis for the search and clinical use of drugs of various biological natures.
Organization of chemical reactions.
Chains of chemical reactions form metabolic pathways or cycles, each of which performs a specific function. It is customary to distinguish between central and special metabolic pathways. Central cycles are common to the breakdown and synthesis of basic macromolecules. They are very similar in any representatives of the living world. Special cycles are characteristic of the synthesis and decomposition of individual monomers, macromolecules, cofactors, etc.
Energy cycles.
Due to the variety of forms of nutrition and energy consumption, living organisms in nature are closely related to each other. The relationship in nutrition and the use of energy sources can be represented in the form of unique energy cycles of living nature.
The main components of this cycle:
The sun is a source of extraterrestrial energy,
Autotrophs that capture solar energy and synthesize carbohydrates and other organic substances from CO 2
Heterotrophs - animal organisms that consume organic matter and oxygen produced by plants
Phototrophs are plants that produce oxygen through photosynthesis.
Energy losses associated with the life activity of all organisms on Earth are compensated by the energy of the Sun. It should be emphasized that animal and human cells use highly reduced substances (carbohydrates, lipids, proteins) as energy material, i.e. containing hydrogen. Hydrogen is an energetically valuable substance. Its energy is converted into the energy of chemical bonds of ATP.
Metabolism of substances and energy is the basis of the life of organisms and is one of the most important specific characteristics of living matter, distinguishing living from non-living. The most complex regulation of metabolism at different levels is ensured by the work of many enzyme systems; this is the self-regulation of chemical transformations.
Enzymes are highly specialized proteins that are synthesized in the cell from simple building blocks - amino acids. Metabolism is carried out with the participation of several hundred different types of enzymes. Enzyme-catalyzed reactions provide 100% yield without the formation of by-products. Each enzyme accelerates only a certain chain of reactions of a given compound, without affecting other reactions with its (compound) participation. Therefore, many reactions can take place in a cell without the danger of contaminating the cell with by-products. Hundreds of reactions in cells with the participation of enzymes are organized in the form of sequential reactions - stationary flow.
During chemical transformations, a restructuring of the electronic shells of interacting atoms, molecules and ions occurs and a redistribution of chemical bond forces occurs, which leads to the release of energy (if the result of the interaction is the strengthening of bonds between atoms, ions and molecules), or to absorption (if these bonds become weaker ). Therefore, all chemical reactions are characterized not only by profound qualitative changes and strictly defined stoichiometric ratios between the amounts of the initial substances and the substances formed as a result of the reaction, but also by well-defined energy effects.
Laws of thermodynamics
First law of thermodynamics.
The concept of the processes of catabolism and anabolism.
The set of chemical transformations of substances that occur in the body, starting from the moment they enter the blood and until the end products of metabolism are released from the body, is called intermediate metabolism(intermediate exchange). Intermediate metabolism can be divided into two processes - catabolism (dissimilation) and anabolism (assimilation).
Catabolism called the enzymatic breakdown of relatively large organic molecules, usually in higher organisms, by the oxidative route. Catabolism is accompanied by the release of energy contained in the complex structures of organic molecules and its storage in the form of the energy of phosphate bonds of ATP (exergonic process, with the release of Gibbs energy and storage in the form of ATP).
Anabolism is the enzymatic synthesis of large molecular cellular components, such as polysaccharides, nucleic acids, proteins, lipids, which are characterized by significant Gibbs energy and low entropy, as well as the synthesis of some biosynthetic precursors of simpler compounds, with stronger bonds (low Gibbs energy values and high values entropy - CO 2, NH 3, urea, creatinine).
Anabolic processes occur in cells simultaneously and are inextricably linked with each other. Essentially, they should be considered not as two separate processes, but as two sides of a common process - metabolism, in which the transformation of substances is closely intertwined with the transformation of energy.
Catabolism.
The breakdown of basic nutrients in the cell is a series of sequential enzymatic reactions that make up the 3 main stages of catabolism (Hans Krebs) - dissimilation.
Stage 1– large organic molecules break down into their constituent specific structural blocks. Thus, polysaccharides are broken down into hexoses or pentoses, proteins into amino acids, nucleic acids into nucleotides and nucleosides, lipids into fatty acids, glycerides and other substances.
The amount of energy released at this stage is small - less than 1%.
Stage 2– even simpler molecules are formed, and the number of their types is significantly reduced. It is important to emphasize that here products are formed that are common to the metabolism of different substances - these are, as it were, nodes connecting different metabolic pathways. These include: pyruvate – formed during the breakdown of carbohydrates, lipids, amino acids; acetyl-CoA - combines the catabolism of fatty acids, carbohydrates, amino acids.
Products obtained at the 2nd stage of catabolism enter 3rd stage, which is known as the Krebs cycle - the tricarboxylic acid cycle (TCA), in which terminal oxidation processes occur. During this stage, all products are oxidized to CO 2 and H 2 O. Almost all the energy is released in the 2nd and 3rd stages of catabolism.
All of the above stages of catabolism or dissimilation, which are known as the “Krebs scheme,” most accurately reflect the most important principles of metabolism: convergence and unification. Convergence– the combination of various metabolic processes characteristic of individual types of substances into single ones common to all types. Next stage - unification– a gradual decrease in the number of participants in metabolic processes and the use of universal metabolic products in metabolic reactions.
At the first stage, the principle of unification is clearly visible: instead of many complex molecules of very different origins, fairly simple compounds are formed in the amount of 2-3 dozen. These reactions occur in the gastrointestinal tract and are not accompanied by the release of large amounts of energy. It is usually dissipated as heat and is not used for other purposes. The significance of the first stage chemical reactions is to prepare the nutrients for the actual release of energy.
At the second stage, the principle of convergence is clearly visible: the merging of various metabolic pathways into a single channel - that is, into the 3rd stage.
At the 2nd stage, about 30% of the energy contained in nutrients is released. The remaining 60-70% of the energy is released in the tricarboxylic acid cycle and the associated terminal oxidation process. In the terminal oxidation system or respiratory chain, which is based on oxidative phosphorylation, unification reaches its peak. Dehydrogenases that catalyze the oxidation of organic substances in the TCA cycle transfer only hydrogen to the respiratory chain, which undergoes identical transformations during oxidative phosphorylation.
Anabolism.
Anabolism also goes through three stages. The starting substances are those that undergo transformations at the 3rd stage of catabolism. Thus, stage 3 of catabolism is the initial stage of anabolism. The reactions of this stage have a dual function - amphibolic. For example, protein synthesis from amino acids.
Stage 2 – formation of amino acids from keto acids in transamination reactions.
Stage 3 – combining amino acids into polypeptide chains.
Also, as a result of sequential reactions, the synthesis of nucleic acids, lipids, and polysaccharides occurs.
In the 60-70s of the 20th century, it became clear that anabolism is not a simple reversal of catabolic reactions. This is due to the chemical characteristics of chemical reactions. A number of catabolic reactions are practically irreversible. Their flow in the opposite direction is prevented by insurmountable energy barriers. In the course of evolution, bypass reactions were developed that involved the expenditure of energy from high-energy compounds. The catabolic and anabolic pathways differ, as a rule, in their localization in the cell - structural regulation.
For example: the oxidation of fatty acids occurs in mitochondria, while the synthesis of fatty acids is catalyzed by a set of enzymes localized in the cytosol.
It is due to different localization that catabolic and anabolic processes in the cell can occur simultaneously.
Principles of Metabolic Integration
Thus, the metabolic pathways are diverse, but in this diversity lies unity, which is a specific feature of metabolism.
This unity lies in the fact that from bacteria to the highly organized tissue of a higher organism, the biochemical reactions are identical. Another manifestation of unity is the cyclical nature of the most important metabolic processes. For example, tricarboxylic acid cycle, urea cycle, pentose cycle. Apparently, cyclic reactions selected during evolution turned out to be optimal for ensuring physiological functions.
When analyzing the organization of metabolic processes in the body, the question naturally arises: how is the maintenance of processes achieved in accordance with the needs of the body at different periods of its life? Those. How is “homeostasis” maintained (a concept that was first formulated by Cannon in 1929) in the context of constantly changing life situations, i.e. - when the internal and external environment changes. It was already mentioned above that the regulation of metabolism ultimately comes down to changing the activity of enzymes. At the same time, we can talk about a hierarchy of metabolic regulation.
Energy metabolism
Bioenergy – is a science that studies the energy supply of living beings, in other words, the transformation of the energy of external resources into biologically useful work. The first stage of energy conversion is the energization of the membrane - this is the generation transmembrane difference in the electrochemical potential of hydrogen ions or proton potential (ΔμH +) and transmembrane difference in the electrochemical potential of sodium or sodium potential (ΔμNa +).
Chapter 6.
Concept of biological oxidation
Biological oxidation is the totality of all redox reactions occurring in living organisms.
Ways to utilize oxygen
Oxygen is a strong oxidizing agent. The redox potential of the oxygen/water pair is +0.82 V. Oxygen has a high affinity for electrons. There are two ways to utilize oxygen in the body: oxidase and oxygenase.
Oxidation
Oxidase pathway Oxygenase pathway
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complete incomplete
Oxidation oxidation
final product monooxy-dioxy-peroxide
Genase genase oxidation
H 2 O H 2 O 2 way way
R-OH HO-R-OH R-O-O-H
Oxidase pathway
The oxidase pathway for oxygen utilization is based on the dehydrogenation reaction, which results in the elimination of 2 hydrogen atoms (2H↔2H + +2ē) from the oxidized substrate with their subsequent transfer to oxygen.
Two pairs of electrons are required to completely reduce oxygen to water.
(4ē). At the same time, 2 ē are added to ½ O 2.
2ē ½O 2 + 2ē OH -
RH 2 + ½O 2 R + H 2 O OH - + 2H + -- 2 H 2 O
Incomplete reduction of oxygen to hydrogen peroxide requires one pair of electrons (2 ē). One electron is added at a time.
O 2 + ē O 2 - superoxide anion radical
O 2 + H + HO 2 peroxide radical
HO 2 + ē HO 2 - peroxide ion
HO - 2 + H + H 2 O 2 hydrogen peroxide
Oxygenase pathway
The oxygenase pathway for oxygen utilization is based on the direct inclusion of oxygen into the oxidized substrate, with the formation of compounds with one or more hydroxyl groups or organic compounds with a peroxide group.
Monooxygenases– enzymatic systems that catalyze the inclusion of only one oxygen atom into the modified substrate, and the second oxygen atom is reduced to water in the presence of NADPH+H + as a source of hydrogen.
RH 2 + O 2 + NADPH + H + → R-OH + NADP + + H 2 O
Dioxygenases– enzymatic systems that catalyze the inclusion of two oxygen atoms into the substrate.
RH 2 + 2O 2 + NADPH + H + HO-R-OH + NADP +
Common metabolic pathways.
Acetyl-CoA is a central metabolite for the conversion of glucose, fatty acids and some amino acids.
OH OH
TPP – hydroxyethyl
At the second stage, the acyl residue is accepted by coenzyme A (KoA-SH) and acetyl-CoA is formed. Translocation of the acyl residue is catalyzed by the second enzyme of the complex - dihydrolipoyltransacetylase . The carrier of the acyl residue is the prosthetic group of the enzyme - lipoic acid
(vitamin-like compound), which can be in two forms: oxidized and reduced.
(Restored form)
At the third stage, oxidation of the reduced form of lipoic acid occurs. The acceptor of two hydrogen atoms is the coenzyme NAD +. The oxidation reaction is catalyzed by a third enzyme - dihydrolipoyl dehydrogenase, the prosthetic group of which is FAD.
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NADH + H + supplies the respiratory chain with 2H + and 2ē and ensures the synthesis of 3 moles of ATP.
Regulation of the pyruvate dehydrogenase complex (PDH)
The formation of acetyl-CoA from pyruvate is an irreversible reaction, since ΔG = - 33.5 kJ/mol. The activity of the pyruvate dehydrogenase complex is regulated in various ways: allosteric regulation and through reversible phosphorylation (covalent modification). [ATP] / [ADP] and [NAD + ] / [NADH] are the most important signals reflecting the energy needs of the cell. PDH is active in its dephosphorylated form. PDH protein kinase converts the enzyme into an inactive phosphorylated form, and phosphatase maintains PDH in an active dephosphorylated state. When the cell is saturated with ATP (the molar ratio [ATP]/[ADP] increases), protein kinase is activated, which inhibits PDH.
ATP is the removed product of the oxidative decarboxylation reaction of PVK. In addition to ATP, reaction products activate protein kinase: acetyl-CoA and NADH. When excess energy is produced, the regulatory system blocks the formation of Acetyl-CoA and, as a result, reduces the rate of the TCA cycle and ATP synthesis.
Fig.6-1. Regulation of protein kinase pyruvate decarboxylase activity by
Tricarboxylic acid cycle
This cycle is also called the Krebs cycle, in honor of Hans Krebs (Nobel Prize winner 1953), who determined the sequence of these reactions. The tricarboxylic acid cycle (TCA) - on the one hand, is the final stage of the catabolism of proteins, carbohydrates and lipids, which is accompanied by the generation of reduced coenzymes - universal energy substrates - FADH 2, NADPH + H +. The reduced coenzymes are further used by the mitochondrial electron transport chain to generate ATP from ADP and PhN. On the other hand, intermediate products of the TCA cycle are substrates for the biosynthesis of endogenous protein substances, carbohydrate and lipid compounds, and other compounds.
Catabolic function of the TCA cycle.
The TCA cycle is a sequence of 8 reactions, as a result of which acetyl-CoA (active acetic acid) is oxidized to two molecules of CO 2 i.e. to the final product of metabolism.
Acetyl-CoA is a two-carbon acyl group characterized by a very strong C-C bond. Direct cleavage of the C-C bond in acetyl-CoA is a difficult chemical task. In nature, there is a very common solution to such problems - this is a cyclic transformation. The TCA cycle begins with the condensation reaction of acetyl-CoA with oxaloacetate (OAA) to form citrate (citric acid) and ends with the formation of OAA during the oxidation of malate, i.e. the cycle closes. All TCA cycle enzymes are localized in the mitochondrial matrix and are soluble proteins. An exception is succinate dehydrogenase, which is localized on the surface of the inner mitochondrial membrane.
Condensation reaction.
Acetyl-CoA + OAA + H 2 O → citrate + KoA-SH
The reaction is catalyzed by a regulated enzyme - citrate synthase. This is an irreversible energy-dependent reaction, since ΔG = - 32.2 kJ/mol. The source of energy in this reaction is the energy of breaking the thioester bond in the acetyl-CoA molecule.
Citrate is a tricarboxylic hydroxy acid. The hydroxyl group is located at the tertiary C atom. By analogy with tertiary alcohols, citrate does not oxidize.
Isomerization reaction.
As a result of this reaction, the hydroxo group moves from the 3rd to the 2nd position of the citrate carbon chain and the formation of an isomer of citric acid - isocitrate. Aconitase, an enzyme with absolute stereospecificity, catalyzes the sequential elimination of H2O and then its addition to another position.
Citrate → aconitate → isocitrate
Isocitrate is an isomer of citric acid, in which the OH group is located at the secondary carbon atom. By analogy with secondary alcohols, isocitrate can undergo oxidation to form a keto acid.
Oxidation reaction.
Succinate fumarate
FAD FADN 2
The reaction is catalyzed by FAD-dependent succinate dehydrogenase. The enzyme has absolute stereospecificity. The reaction product is fumarate (trans isomer). Reduced coenzyme FADH 2 supplies the respiratory chain with 2H + and 2ē for ATP generation
Hydration reaction
Fumarate +H 2 O → malate
The addition of water to fumarate is catalyzed by fumarase (the traditional name for the enzyme). The reaction product is hydroxy acid - malate (malic acid).
Oxidation reaction.
Malate OAA
NAD + NADH + H +
The reaction is catalyzed by NAD + - dependent malate dehydrogenase.
OAA is included in the condensation reaction with a new acetyl-CoA molecule, i.e. The central heating system closes. The reduced coenzyme NADH+H + supplies the respiratory chain with 2H + and 2ē and is involved in the process of oxidative phosphorylation.
Stoichiometry of TTC.
CH 3 -CO-S-KoA + 2H 2 O + ZNAD + + FAD + GDP + H 3 PO 4 → 2CO 2 + 3NADH + ZN + + FADH 2 , +GTP + KoA-SH, ΔG=-40.0 kJ/mol
Thus, as a result of one revolution of the cycle, KoA-SH is cleaved from acetyl-CoA, and the acetyl residue is cleaved to 2 molecules of CO 2. This metabolic process is accompanied by:
The formation of 4 reduced coenzymes: 3 molecules of NADH +H + and 1 molecule of FADH 2;
GTP + ADP→GDP +ATP
Energy effect of TCA.
Due to oxidative phosphorylation:
3NADH + H + → (6H + and 6ē) CPE → 3 x TATP = 9 ATP
FADN 2 → 2Н + and 2ē → CPE → 2ATP.
Due to substrate phosphorylation - 1 ATP
Total: during the oxidation of 1 molecule of Acetyl-CoA, provided that oxidation reactions are coupled with oxidative phosphorylation, 12 ATP molecules are generated.
Anabolic function of the TCA cycle.
CTK serves as a source of intermediates (intermediate metabolites), which are substrates for many biosynthetic reactions.
1. Succinyl-CoA is a substrate for the biosynthesis of porphyrins . The introduction of an iron cation into the porphyrin leads to the formation of the heme-prosthetic group of hemoproteins (hemoglobin, myoglobin, catalase, cytochromes, etc.).
2. Citrate can, with the help of carrier proteins, be transported from the mitochondrial matrix to the cytoplasm, where, under the action of the enzyme citrate lyase be cleaved to form cytosolic acetyl-CoA - a substrate for the synthesis of cholesterol, IVH.
Citrate + ATP + CoA → OAA + Acetyl-CoA + ADP + H 3 PO 4.
Z. OAA- using the malate-aspartate shuttle mechanism, it is transported from the mitochondrial matrix to the cytoplasm, where it is converted into aspartate in the transamination reaction. , in turn, can be transformed into other amino acids and participate in protein biosynthesis. Aspartate is also used in the synthesis of nitrogenous bases and, thus, is involved in the synthesis of nucleotides and nucleic acids. OAA (oxal acetate) in the cytoplasm can undergo decarboxylation under the action of phosphoenolpyruvate carboxykinase in the presence of GTP to form PEP, an intermediate metabolite involved in glucose synthesis (gluconeogenesis).
4. α-Ketoglutarate enters the cytoplasm, where it is converted into glutamine, proline, histidine, arginine, which are further included in the synthesis of proteins and other biologically important compounds. Thus, the TCA cycle is an amphibolic cycle.
Proton potential.
The transmembrane difference in the electrochemical potential of the hydrogen ion, ΔμH + or proton potential, occupies a central position in the system of energy transformation processes occurring in the inner membrane of mitochondria. Due to the energy of external resources, protons are transported through the biological membrane against the forces of the electric field in the direction of greater concentration, resulting in the generation of an electrochemical potential difference. ΔμH + consists of 2 components: electrical in the form of a transmembrane gradient of electrical potentials (Δφ) and chemical, in the form of transmembrane hydrogen ion concentration (ΔрН). ΔμН + =Δφ +ΔрН Potential energy accumulated in the form of Δφ and ΔрН can be utilized in a useful way, in particular, in the synthesis of ATP.
The role of ATP in metabolism
In biological systems, ATP is constantly produced and constantly consumed. ATP turnover is very high. For example, a person at rest uses about 40 kg of ATP per day. Energy-consuming processes can be carried out under the condition of constant regeneration of ATP from ADP. Thus, the ATP-ADP cycle is the main mechanism of energy exchange in biological systems.
ATP synthesis
The ATP synthesis reaction is the phosphorylation reaction of ADP by inorganic phosphate (Figure 6-1).
ADP + H 3 PO 4 → ATP + H 2 O .
This is an endergonic reaction, which occurs only when free energy is supplied from the outside, since ΔG = + 30.5 kJ/mol
(+ 7.3 kcal/mol). Consequently, ATP synthesis can occur only under the condition of energetic coupling with exergonic reactions. Depending on the source of free energy, there are two ways of ATP synthesis: substrate phosphorylation and oxidative phosphorylation.
COUN COUN
ΔG= - 61.9 kJ/mol (- 14.8 kcal/mol).
By directly transferring the energy-rich phosphoric acid residue from these high-energy compounds to ADP, ATP is synthesized.
ΣPEP +ADP→PVK +ATP
High-energy compounds also include compounds with thioether bonds. For example, succinyl~S-KoA. When the thioether bond is broken, energy is released, which is used for the synthesis of GTP (GDP + H 3 PO 4 → GTP + H 2 O). Succinyl~S-KoA + GDP +H 3 PO 4 → Succinate + GTP + HS~CoA, ΔG=-35.5 kJ/mol.
Types of vectors
FMN + 2H + + 2ē ↔ FMNN 2
Iron-sulfur centers
These are protein non-heme iron-containing electron carriers. There are several types of iron-sulfur centers: Fe-S, Fe 2 -S 2, Fe 4 -S 4. Iron atoms of complexes can donate and accept electrons, alternately turning into ferro-(Fe 2+) - and ferri-(Fe 3+) - condition. All iron-sulfur centers donate electrons to ubiquinone.
Fe 3+ -S + 2ē ↔ Fe 2+ -S
Ubiquinone, coenzyme-Q(KoQ) is the only non-protein electron carrier.
CoQ (quinone) CoQ (semiquinone) CoQH 2 (hydroquinone)
Upon reduction, ubiquinone acquires not only electrons, but also protons. Upon one-electron reduction, it turns into semiquinone, an organic free radical. E o =+0.01
Cytochromes– protein electron carriers containing heme iron as a prosthetic group. The functioning of cytochromes is based on a change in the oxidation state of the iron atom Fe 3+ +ē ↔ Fe 2+. Various cytochromes are designated by letter indices: b, c 1, c, a, a 3. Cytochromes differ in the structure of the protein part and heme side chains, and therefore they have different values of redox potentials (oxidation-reduction potentials). Cytochrome “b” E o= +0.08, “c i” E o = +0.22, “c” E o = +0.25,« aa z» E o = +0.29. Distinctive feature cytochrome With is that it is loosely bound to the outer surface of the inner mitochondrial membrane and easily leaves it.
All these electron carriers can be grouped into four enzymatic complexes, structured in the inner membrane of mitochondria, representing an enzymatic ensemble called “respiratory enzymes”, “cytochrome system”, “CPE” (electron transport chain).
Complex I – NADH dehydrogenase (NADH-CoQ reductase). Prosthetic groups - FMN, FeS. Electron acceptor – KoQ.
Complex III – CoQH 2 dehydrogenase (KoQH 2-cyt.c-reductase). Prosthetic groups: FeS, cytochromes b 1, b 2, c 1. Electron acceptor – cytochrome - p.
Complex IV – cytochrome oxidase. Prosthetic groups: cytochromes aa3, Cu 2+. Electron acceptor– oxygen.
Complex II – succinate dehydrogenase (Succinate-CoQ reductase). Prosthetic groups FAD, FeS. Electron acceptor – KoQ.
Electrons are transported between complexes using mobile carriers - ubiquinone And cytochrome-c.
Redox carriers in the CPE are arranged in order of increasing standard oxidative potentials, which ensures the spontaneous transport of two electrons along the respiratory chain from NADH + H + to oxygen, the final electron acceptor. The transfer of two electrons along the CPE is useful work and is accompanied by a step-by-step release of Gibbs free energy (ΔG), which is further used in the synthesis of ATP. The step-by-step release of energy leads to the fact that the electrons that reduce oxygen are at a lower energy level compared to electrons found in reduced NADH +H + at the beginning of the chain.
H. Generation of proton potential ΔμН +
How is the transport of electrons along the respiratory chain coupled with the transformation of released electrical energy into the energy of chemical bonds of ATP? This question was answered in 1961 by the English scientist Peter Mitchell. His concept was that the driving force for ATP synthesis is electrochemical potential, proton potential – ΔμH + . ΔμH + . = Δ pH+ Δ φ
pH is the proton gradient, Δφ is the electrical potential difference. In 1978
P. Mitchell was awarded the Nobel Prize and the chemiosmotic theory became generally accepted.
According to P. Mitchell's theory, the energy released gradually during the transport of electrons along the respiratory chain is used to pump protons from the mitochondrial matrix into the intermembrane space. Transport of 2H+ from the mitochondrial matrix to the intermembrane space creates a proton concentration gradient - ΔрН and leads to the appearance of a negative charge on the membrane surface from the matrix and a positive charge from the intermembrane space, which creates an electrical potential difference - Δφ. The source of protons in the mitochondrial matrix is NADH + H +, FADH 2, water. The ability to generate proton potential is provided by:
1) the impermeability of the inner mitochondrial membrane to ions in general and, especially, to protons.
2) separate transport of protons and electrons along the respiratory chain. This is ensured by the presence of 2 types of carriers: only for electrons and for electrons and protons at the same time.
4. ATP synthesis due to proton potential
Vitamin C (ascorbic acid). Structure, daily requirement, food sources, vitamin deficiency. Participation in redox processes, steroidogenesis and collagen formation. Hydroxylation reactions of proline and lysine.
Ascorbic acid is a lactone of an acid similar in structure to glucose. It exists in two forms: reduced (AA) and oxidized (dehydroascorbic acid, DAC).
Both of these forms of ascorbic acid quickly and reversibly transform into each other and, as coenzymes, participate in redox reactions. Ascorbic acid can be oxidized by atmospheric oxygen, peroxide and other oxidizing agents. DAK is easily reduced by cysteine, glutathione, and hydrogen sulfide. In a slightly alkaline environment, the lactone ring is destroyed and biological activity is lost. When food is cooked in the presence of oxidizing agents, some of the vitamin C is destroyed.
Sources vitamin C - fresh fruits, vegetables, herbs, rose hips, sea buckthorn, black currants, lemons, oranges, apples.
Daily requirement human vitamin C is 50-75 mg.
Biological functions. The main property of ascorbic acid is its ability to easily oxidize and reduce. Together with DAA, it forms a redox couple in cells with a redox potential of +0.139 V. Thanks to this ability, ascorbic acid is involved in many hydroxylation reactions: Pro and Lys residues in the synthesis of collagen (the main protein of connective tissue), in the hydroxylation of dopamine, in the synthesis of steroids hormones in the adrenal cortex
In the intestine, ascorbic acid reduces Fe 3+ to Fe 2+, promoting its absorption, accelerates the release of iron from ferritin, and promotes the conversion of folate into coenzyme forms. Ascorbic acid is classified as a natural antioxidant (see section 8). The famous American scientist L. Pauling, a two-time Nobel Prize laureate, attached great importance to this role of vitamin C. He recommended using large doses of ascorbic acid (2-3 g) for the prevention and treatment of a number of diseases (for example, colds).
Clinical manifestations of vitamin C deficiency. Deficiency of ascorbic acid leads to a disease called scurvy (scorbut). Scurvy, which occurs in humans when there is insufficient content of fresh fruits and vegetables in the diet, was described more than 300 years ago, from the time of long sea voyages and northern expeditions. This disease is associated with a lack of vitamin C in food. Only humans, primates and guinea pigs suffer from scurvy. The main manifestations of vitamin deficiency are caused mainly by impaired collagen formation in connective tissue. As a result, loosening of the gums, loosening of teeth, and disruption of the integrity of capillaries (accompanied by subcutaneous hemorrhages) are observed. Swelling, joint pain, and anemia occur. Anemia due to scurvy may be associated with impaired ability to use iron stores, as well as with disorders of folic acid metabolism.
18 Question
The relationship between metabolism and energy. Exergonic and endergonic reactions in the cell. Types of high-energy compounds (phosphate, thiosulfate). Structure of ATP, ATP/ADP cycle. Stages of unification of energy substrates in the body: products, energy value. Critical periods of child development and characteristics of their metabolism.
As stated, metabolism in the human body does not proceed chaotically; it is integrated and finely tuned. All transformations of organic substances, the processes of anabolism and catabolism are closely related to each other. In particular, the processes of synthesis and breakdown are interconnected, coordinated and regulated by neurohormonal mechanisms that give chemical processes the desired direction. In the human body, as in living nature in general, there is no independent metabolism of proteins, fats, carbohydrates and nucleic acids. All transformations are combined into a holistic process of metabolism. Currently, the existence of four main stages in the breakdown of carbohydrate and protein-fat molecules, which integrate the formation of energy from main food sources, has been experimentally substantiated. At stage I, polysaccharides are broken down into monosaccharides (usually hexoses); fats are broken down into glycerol and higher fatty acids, and proteins are broken down into their constituent free amino acids. It should be emphasized that these processes are mainly hydrolytic, therefore the small amount of energy released is almost entirely used by organisms as heat.
At stage II, monomeric molecules (hexoses, glycerol, fatty acids and amino acids) undergo further decomposition, during which energy-rich phosphate compounds and acetyl-CoA are formed. In particular, glycolise hexoses are broken down to pyruvic acid and further to acetyl-CoA. This process is accompanied by the formation of a limited number of energy-rich phosphate bonds through substrate phosphorylation. At this stage, higher fatty acids are similarly broken down to acetyl-CoA, while glycerol is oxidized through the glycolytic pathway to pyruvic acid and further to acetyl-CoA. For amino acids, the situation at stage II is somewhat different. With the predominant use of amino acids as an energy source (with carbohydrate deficiency or diabetes mellitus), some of them are directly converted into metabolites of the citric acid cycle (glutamate, aspartate), others indirectly through glutamate (proline, histidine, arginine), others into pyruvate and further into acetyl-CoA (alanine , serine, glycine, cysteine). Finally, a number of amino acids, in particular leucine, isoleucine, are cleaved to acetyl-CoA, and from phenylalanine-tyrosine, in addition to acetyl-CoA, oxaloacetate is formed through fumaric acid. As you can see, stage II can be called the stage of formation of acetyl-CoA, which is essentially a single (common) intermediate product of the catabolism of basic nutritional substances in cells.
At stage III, acetyl-CoA (and some other metabolites, for example α-ketoglutarate, oxaloacetate) undergo oxidation (“combustion”) in the Krebs cycle of di- and tricarboxylic acids. Oxidation is accompanied by the formation of reduced forms of NADH + H+ and FADH2.
At stage IV, electrons are transferred from reduced nucleotides to oxygen (through the respiratory chain). It is accompanied by the formation of the final product – water molecules. This electron transport is associated with ATP synthesis in the process of oxidative phosphorylation. 3. Endergonic and exergonic reactions
The direction of a chemical reaction is determined by the value of AG. If this value is negative
If it is true, the reaction proceeds spontaneously and is accompanied by a decrease in free energy. Such reactions are called exergonic. If the absolute value of AG is large, then the reaction proceeds almost to completion, and it can be considered irreversible.
If AG is positive, then the reaction will occur only when free energy is supplied from the outside; such reactions are called endergonic.
If the absolute value of AG is large, then the system is stable, and the reaction in this case practically does not occur. When AG equals zero, the system is in equilibrium (Table 6-1).
4. Conjugation of exergonic
and endergonic processes in the body
In biological systems, thermodynamically unfavorable (endergonic) reactions can occur only due to the energy of exergonic reactions. Such reactions are called energetically coupled. Many of these reactions occur with the participation of adenosine tri-
phosphate (ATP), which plays the role of a coupling factor.
Let us consider in more detail the energetics of coupled reactions using the example of glucose phosphorylation.
The reaction of phosphorylation of glucose with free phosphate to form glucose-6-phosphate is endergonic:
(1) Glucose + H3PO4 → Glucose-6-phosphate + H2O (ΔG = +13.8 kJ/mol).
For such a reaction to proceed towards the formation of glucose-6-phosphate, it must be coupled with another reaction, the value of free energy of which is greater than that required for the phosphorylation of glucose.
(2) ATP → ADP + H3PO4 (ΔG = -30.5 kJ/mol).
When processes (1) and (2) are coupled in a reaction catalyzed by hexokinase (see Section 7), glucose phosphorylation easily occurs under physiological conditions; reaction equilibrium
strongly shifted to the right, and it is almost irreversible:
(3) Glucose + ATP → Glucose-6-phosphate + ADP (ΔG = -16.7 kJ/mol).
High-energy compounds are organic compounds of living cells containing energy-rich or high-energy bonds. These compounds are formed as a result of photo- and chemosynthesis and biological oxidation. These include, for example, substances whose hydrolysis releases 2-4 times more energy than the hydrolysis of other substances. High-energy compounds include adenosine triphosphoric acid (ATP), adenosine diphosphoric acid (ADP), as well as pyrophosphate (H4P2O7), polyphosphates (polymers of metaphosphoric acid - (HPO3)n * H2O) and a number of other compounds. The most important high-energy compound is ATP. Using the energy contained in the high-energy bonds of ATP, through the action of enzymes that transfer phosphate groups, it is possible to obtain other high-energy compounds, for example, GTP (guanosine triphosphoric acid), PEP (phosphoenolpyruvic acid), etc. ATP is formed in the processes of biological oxidation and during photosynthesis. Adenosine triphosphoric acid (ATP) is a nucleotide formed by adenosine and three phosphoric acid residues. In all living organisms it acts as a universal battery and energy carrier. Under the action of special enzymes, terminal phosphate groups are cleaved off, releasing energy that goes into synthetic and other life processes.
Adenosine diphosphate (ADP) is a nucleotide formed by adenosone and two phosphoric acid residues. Participates in the energy metabolism of living organisms. ADP obtains energy by dephosphorylation of phosphoenolpyruvic acid under the action of the enzyme transphosphorylase, which transfers the high-energy bond from the acid to ADP. Uridine diphosphoric acid (UDP) and its derivatives take part in the interconversion of carbohydrates. The biosynthesis of the glycosidic bond uses uridine diphosphate glucose (UDPG), which is formed from glucose-1-phosphate and uridine triphosphate (UIP). If UDPG transfers glucose to fructose, then sucrose is formed, and if it is a dextrin chain, a polysaccharide is formed. Glycosides, glycoproteins, etc. are formed in a similar way. The interconversion of monosaccharides occurs through phosphorus esters of sugars or their uridine diphosphate derivatives (UDP derivatives). UDP derivatives of sugars are one or another sugar connected through two phosphoric acid residues to uridine.
Sugar phosphates are a source of phosphorus nutrition for plants. There may be salts of ortho-, meta- and pyrophosphoric acid and organic phosphates. The best of them are water-soluble potassium, sodium, ammonium, calcium and magnesium salts of phosphoric acid.
The energy of macroergic bonds is used to perform any work: activation of compounds (for example, glucose, so that a chain of its oxidative transformations can begin), synthesis of biopolymers (nucleic acids, proteins, polysaccharides), selective absorption of substances from the environment surrounding the cell and release of unnecessary products from the cell, muscle contraction and restoration of the active state of the body, etc. The supply of these compounds allows the body to quickly respond to changes in external conditions and perform physical work.
ATP/ADP cycle.
ATP is an energy-rich molecule because it contains two phosphoanhydride bonds (β, γ). Upon hydrolysis of the terminal phosphoanhydride bond, ATP is converted into ADP and orthophosphate Pi. In this case, the change in free energy is -7.3 kcal/mol. Under the conditions that normally exist in a cell (pH 7.0, temperature 37 °C), the actual value of ΔG0" for the hydrolysis process is about -12 kcal/mol. The free energy of ATP hydrolysis makes it possible for it to be formed from ADP due to the transfer of phosphate residue from high-energy phosphates such as phosphoenolpyruvate
Rice. 6-2. Adenosine triphosphoric acid (ATP). There are two high-energy (macroergic) bonds β and γ in the ATP molecule; they are indicated in the figure by the sign ~ (tilde).
or 1,3-bisphosphoglycerate; in turn, ATP can participate in endergonic reactions such as phosphorylation of glucose or glycerol. ATP acts as an energy donor in endergonic reactions of many anabolic processes. Some biosynthetic reactions in the body can occur with the participation of other nucleoside triphosphates, analogues of ATP; these include guanosine triphosphate (GTP), uridine triphosphate (UTP) and cytidine triphosphate (CTP). All these nucleotides, in turn, are formed by using the free energy of the terminal phosphate group of ATP. Finally, due to the free energy of ATP, various types of work are performed that underlie the vital activity of the body, for example, such as muscle contraction or active transport of substances.
Thus, ATP is the main, directly used donor of free energy in biological systems. In a cell, an ATP molecule is consumed within one minute after its formation. In humans, an amount of ATP equal to body weight is produced and destroyed every 24 hours.
The use of ATP as an energy source is possible only under the condition of continuous synthesis of ATP from ADP due to the energy of oxidation of organic compounds (Fig. 6-3). The ATP-ADP cycle is the main mechanism of energy exchange in biological systems, and ATP is the universal "energy currency".
Unification of energy substrates in the cell The main substrates of biooxidation are carbohydrates, fats and proteins, which are very different in composition. Phylogenetically, the animal body has developed a system of gradual unification (or standardization) of energy substrates, increasing the efficiency of oxidation. Conventionally, we can distinguish two stages in the unification of energy “fuel” in cells.
