Oxidation of higher fatty acids. Fatty acid oxidation disorder Fatty acid beta oxidation enzymes

2.1. Oxidation of fatty acids in cells

Higher fatty acids can be oxidized in cells in three ways:

a) by a-oxidation,

b) by b-oxidation,

c) by w-oxidation.

The processes of a- and w-oxidation of higher fatty acids occur in cell microsomes with the participation of monooxygenase enzymes and play a mainly plastic function - during these processes, the synthesis of hydroxy acids, keto acids and acids with an odd number of carbon atoms necessary for cells occurs. Thus, during a-oxidation, a fatty acid can be shortened by one carbon atom, thus turning into an acid with an odd number of “C” atoms, in accordance with the given scheme:

2.1.1. b-Oxidation of higher fatty acids The main method of oxidation of higher fatty acids, at least in relation to the total amount of compounds of this class oxidized in the cell, is the process of b-oxidation, discovered by Knoop back in 1904. This process can be defined as the process of stepwise oxidative breakdown of higher fatty acids. fatty acids, during which there is a sequential cleavage of two-carbon fragments in the form of acetyl-CoA from the carboxyl group of the activated higher fatty acid molecule.

Higher fatty acids entering the cell are activated and converted into acyl-CoA (R-CO-SKoA), and the activation of fatty acids occurs in the cytosol. The process of b-oxidation of fatty acids occurs in the mitochondrial matrix. At the same time, the inner membrane of mitochondria is impermeable to acyl-CoA, which raises the question of the mechanism of transport of acyl residues from the cytosol to the mitochondrial matrix.

Acyl residues are transported across the inner mitochondrial membrane using a special carrier, which is carnitine (CN):

In the cytosol, with the help of the enzyme external acylCoA:carnitine acyltransferase (E1 in the diagram below), the higher fatty acid residue is transferred from coenzyme A to carnitine to form acylcarnitine:

Acylcarnitinine, with the participation of a special carnitine-acylcarnitine-translocase system, passes through the membrane into the mitochondrion and in the matrix, with the help of the enzyme internal acyl-CoA: carnitine acyltransferase (E2), the acyl residue is transferred from carnitine to intramitochondrial coenzyme A. As a result, an activated residue appears in the mitochondrial matrix fatty acid in the form of acyl-CoA; the released carnitine, using the same translocase, passes through the mitochondrial membrane into the cytosol, where it can be included in a new transport cycle. Carnitine acylcarnitine translocase, built into the inner membrane of mitochondria, transfers an acylcarnitine molecule into the mitochondrion in exchange for a carnitine molecule removed from the mitochondrion.

Activated fatty acid in the mitochondrial matrix undergoes stepwise cyclic oxidation according to the following scheme:

As a result of one cycle of b-oxidation, the fatty acid radical is shortened by 2 carbon atoms, and the cleaved fragment is released as acetyl-CoA. Summary cycle equation:

During one cycle of b-oxidation, for example, during the conversion of stearoyl-CoA to palmitoyl-CoA with the formation of acetyl-CoA, 91 kcal/mol of free energy is released, but the bulk of this energy accumulates in the form of energy from reduced coenzymes, and energy loss in the form heat amounts to only about 8 kcal/mol.

The resulting acetyl-CoA can enter the Krebs cycle, where it will be oxidized to final products, or it can be used for other cell needs, for example, for the synthesis of cholesterol. Acyl-CoA, shortened by 2 carbon atoms, enters a new b-oxidation cycle. As a result of several successive cycles of oxidation, the entire carbon chain of the activated fatty acid is cleaved into "n" acetyl-CoA molecules, the value of "n" being determined by the number of carbon atoms in the original fatty acid.

The energy effect of one b-oxidation cycle can be assessed based on the fact that during the cycle 1 molecule of FADH2 and 1 molecule of NADH + H are formed. When they enter the chain of respiratory enzymes, 5 ATP molecules (2 + 3) will be synthesized. If the resulting acetyl-CoA is oxidized in the Krebs cycle, the cell will receive 12 more ATP molecules.

For stearic acid, the overall equation for its b-oxidation has the form:

Calculations show that during the oxidation of stearic acid in the cell, 148 ATP molecules will be synthesized. When calculating the energy balance of oxidation, it is necessary to exclude from this amount 2 macroergic equivalents expended during the activation of a fatty acid (during activation, ATP is broken down into AMP and 2 H3PO4). Thus, when stearic acid is oxidized, the cell will receive 146 ATP molecules.

For comparison: during the oxidation of 3 glucose molecules, which also contain 18 carbon atoms, the cell receives only 114 ATP molecules, i.e. Higher fatty acids are more beneficial energy fuel for cells compared to monosaccharides. Apparently, this circumstance is one of the main reasons that the body’s energy reserves are presented predominantly in the form of triacylglycerols rather than glycogen.

The total amount of free energy released during the oxidation of 1 mole of stearic acid is about 2632 kcal, of which about 1100 kcal is accumulated in the form of the energy of high-energy bonds of synthesized ATP molecules. Thus, approximately 40% of the total free energy released is accumulated.

The rate of b-oxidation of higher fatty acids is determined, firstly, by the concentration of fatty acids in the cell and, secondly, by the activity of external acyl-CoA: carnitine acyltransferase. The activity of the enzyme is inhibited by malonyl-CoA. We will dwell on the meaning of the last regulatory mechanism a little later, when we discuss the coordination of the processes of oxidation and synthesis of fatty acids in the cell.

Orange tonsils and accumulation of cholesterol esters in other reticuloendothelial tissues. The pathology is associated with accelerated catabolism of apo A-I. Digestion and absorption of lipids. Bile. Meaning. At the dawn of the formation of the modern doctrine of the exocrine function of the liver, when natural scientists had only the first...

The dynamics of chemical transformations occurring in cells is studied by biological chemistry. The task of physiology is to determine the total expenditure of substances and energy by the body and how they should be replenished with the help of adequate nutrition. Energy metabolism serves as an indicator of the general condition and physiological activity of the body. A unit of energy measurement commonly used in biology and...

Acids that are classified as essential fatty acids (linoleic, linolenic, arachidonic), which are not synthesized in humans and animals. With fats, a complex of biologically active substances enters the body: phospholipids, sterols. Triacylglycerols – their main function is lipid storage. They are found in the cytosol in the form of fine emulsified oily droplets. Complex fats: ...

... α,d – glucose glucose – 6 – phosphate With the formation of glucose – 6 – phosphate, the paths of glycolysis and glycogenolysis coincide. Glucose-6-phosphate occupies a key place in carbohydrate metabolism. It enters the following metabolic pathways: glucose - 6 - phosphate glucose + H3PO4 fructose - 6 - phosphate pentose breakdown pathway (enters the blood, etc. ...

And the respiratory chain, to convert the energy contained in fatty acids into the energy of ATP bonds.

Fatty acid oxidation (β-oxidation)

Elementary diagram of β-oxidation.

This path is called β-oxidation, since the 3rd carbon atom of the fatty acid (β-position) is oxidized into a carboxyl group, and at the same time the acetyl group, including C 1 and C 2 of the original fatty acid, is cleaved from the acid.

β-oxidation reactions occur in the mitochondria of most cells in the body (except nerve cells). For oxidation, fatty acids are used that enter the cytosol from the blood or appear during lipolysis of their own intracellular TAG. The overall equation for the oxidation of palmitic acid is as follows:

Palmitoyl-SCoA + 7FAD + 7NAD + + 7H 2 O + 7HS-KoA → 8Acetyl-SCoA + 7FADH 2 + 7NADH

Stages of fatty acid oxidation

Fatty acid activation reaction.

1. Before penetrating the mitochondrial matrix and being oxidized, the fatty acid must be activated in the cytosol. This is accomplished by the addition of coenzyme A to it to form acyl-S-CoA. Acyl-S-CoA is a high-energy compound. Irreversibility of the reaction is achieved by hydrolysis of diphosphate into two molecules of phosphoric acid.

Carnitine-dependent transport of fatty acids into the mitochondrion.

2. Acyl-S-CoA is not able to pass through the mitochondrial membrane, so there is a way to transport it in combination with the vitamin-like substance carnitine. The outer membrane of mitochondria contains the enzyme carnitine acyltransferase I.

Carnitine is synthesized in the liver and kidneys and then transported to other organs. In the prenatal period and in the first years of life, the importance of carnitine for the body is extremely high. The energy supply to the nervous system of the child’s body and, in particular, the brain is carried out through two parallel processes: carnitine-dependent oxidation of fatty acids and aerobic oxidation of glucose. Carnitine is necessary for the growth of the brain and spinal cord, for the interaction of all parts of the nervous system responsible for movement and muscle interaction. There are studies linking cerebral palsy and the phenomenon of “death in the cradle” to carnitine deficiency.

3. After binding to carnitine, the fatty acid is transported across the membrane by translocase. Here, on the inner side of the membrane, the enzyme carnitine acyltransferase II again forms acyl-S-CoA, which enters the β-oxidation pathway.

Sequence of reactions of β-oxidation of fatty acids.

4. The process of β-oxidation itself consists of 4 reactions, repeated cyclically. They sequentially undergo oxidation (acyl-SCoA dehydrogenase), hydration (enoyl-SCoA hydratase) and again oxidation of the 3rd carbon atom (hydroxyacyl-SCoA dehydrogenase). In the last, transferase reaction, acetyl-SCoA is cleaved from the fatty acid. HS-CoA is added to the remaining (shortened by two carbons) fatty acid, and it returns to the first reaction. This is repeated until the last cycle produces two acetyl-SCoAs.

Calculation of the energy balance of β-oxidation

When calculating the amount of ATP formed during β-oxidation of fatty acids, it is necessary to take into account:

• the amount of acetyl-SCoA formed is determined by the usual division of the number of carbon atoms in the fatty acid by 2;
• number of β-oxidation cycles. The number of β-oxidation cycles is easy to determine based on the concept of a fatty acid as a chain of two-carbon units. The number of breaks between units corresponds to the number of β-oxidation cycles. The same value can be calculated using the formula (n/2 −1), where n is the number of carbon atoms in the acid;
• number of double bonds in a fatty acid. In the first β-oxidation reaction, a double bond is formed with the participation of FAD. If a double bond is already present in the fatty acid, then there is no need for this reaction and FADN 2 is not formed. The number of unformed FADN 2 corresponds to the number of double bonds. The remaining reactions of the cycle proceed without changes;
• the amount of ATP energy spent on activation (always corresponds to two high-energy bonds).

Example. Oxidation of palmitic acid

• Since there are 16 carbon atoms, β-oxidation produces 8 molecules of acetyl-SCoA. The latter enters the TCA cycle; when it is oxidized in one turn of the cycle, 3 molecules of NADH, 1 molecule of FADH 2 and 1 molecule of GTP are formed, which is equivalent to 12 molecules of ATP (see also Methods of obtaining energy in the cell). So, 8 molecules of acetyl-S-CoA will provide the formation of 8 × 12 = 96 molecules of ATP.
• for palmitic acid, the number of β-oxidation cycles is 7. In each cycle, 1 molecule of FADH 2 and 1 molecule of NADH are formed. Entering the respiratory chain, in total they “give” 5 ATP molecules. Thus, in 7 cycles 7 × 5 = 35 ATP molecules are formed.
• There are no double bonds in palmitic acid.
• 1 molecule of ATP is used to activate the fatty acid, which, however, is hydrolyzed to AMP, that is, 2 high-energy bonds or two ATP are spent.

Thus, summing up, we get 96 + 35-2 = 129 ATP molecules are formed during the oxidation of palmitic acid.

To convert the energy contained in fatty acids into the energy of ATP bonds, there is a metabolic pathway for the oxidation of fatty acids to CO 2 and water, which is closely related to the tricarboxylic acid cycle and the respiratory chain. This path is called β-oxidation, because oxidation of the 3rd carbon atom of the fatty acid (β-position) into a carboxyl group occurs, and at the same time the acetyl group, including C 1 and C 2 of the original fatty acid, is cleaved from the acid.

Elementary diagram of β-oxidation

β-oxidation reactions occur in mitochondria most cells in the body (except nerve cells). Fatty acids that enter the cytosol from the blood or appear during lipolysis of their own intracellular TAGs are used for oxidation. The overall equation for the oxidation of palmitic acid is as follows:

Palmitoyl-SCoA + 7FAD + 7NAD + + 7H 2 O + 7HS-KoA → 8Acetyl-SCoA + 7FADH 2 + 7NADH

Stages of fatty acid oxidation

1. Before penetrating into the mitochondrial matrix and oxidizing, the fatty acid must activate in the cytosol. This is accomplished by the addition of coenzyme A to it to form acyl-SCoA. Acyl-SCoA is a high-energy compound. Irreversibility of the reaction is achieved by hydrolysis of diphosphate into two molecules of phosphoric acid.

Acyl-SCoA synthetases are found in the endoplasmic reticulum, on the outer membrane of mitochondria and within them. There is a wide range of synthetases specific for different fatty acids.

Fatty acid activation reaction

2. Acyl-SCoA is not able to pass through the mitochondrial membrane, so there is a way to transfer it in combination with a vitamin-like substance carnitine (vitamin B11). There is an enzyme on the outer membrane of mitochondria carnitine acyltransferase I.

Carnitine-dependent transport of fatty acids into the mitochondrion

Carnitine is synthesized in the liver and kidneys and then transported to other organs. In intrauterine period and in early years In life, the importance of carnitine for the body is extremely great. Energy supply to the nervous system children's the body and, in particular, the brain is carried out due to two parallel processes: carnitine-dependent oxidation of fatty acids and aerobic oxidation of glucose. Carnitine is necessary for the growth of the brain and spinal cord, for the interaction of all parts of the nervous system responsible for movement and muscle interaction. There are studies linking carnitine deficiency cerebral palsy and phenomenon" death in the cradle".

Infants, premature babies and low birth weight infants are particularly sensitive to carnitine deficiency. Their endogenous reserves are quickly depleted under various stressful situations (infectious diseases, gastrointestinal disorders, feeding disorders). Carnitine biosynthesis is insufficient, and intake from regular foods is unable to maintain sufficient levels in the blood and tissues.

3. After binding to carnitine, the fatty acid is transported across the membrane by translocase. Here, on the inner side of the membrane, the enzyme carnitine acyltransferase II again forms acyl-SCoA, which enters the β-oxidation pathway.

4. The process itself β-oxidation consists of 4 reactions repeated cyclically. They happen sequentially oxidation(acyl-SCoA dehydrogenase), hydration(enoyl-SCoA hydratase) and again oxidation 3rd carbon atom (hydroxyacyl-SCoA dehydrogenase). In the last, transferase reaction, acetyl-SCoA is cleaved from the fatty acid. HS-CoA is added to the remaining (shortened by two carbons) fatty acid, and it returns to the first reaction. This is repeated until the last cycle produces two acetyl-SCoAs.

Sequence of reactions of β-oxidation of fatty acids

Calculation of the energy balance of β-oxidation

Previously, when calculating the oxidation efficiency, the P/O coefficient for NADH was taken equal to 3.0, for FADH 2 – 2.0.

According to modern data, the value of the P/O coefficient for NADH corresponds to 2.5, for FADH 2 – 1.5.

When calculating the amount of ATP formed during β-oxidation of fatty acids, it is necessary to take into account:

• the amount of acetyl-SCoA formed is determined by the usual division of the number of carbon atoms in the fatty acid by 2.
• number β-oxidation cycles. The number of β-oxidation cycles is easy to determine based on the concept of a fatty acid as a chain of two-carbon units. The number of breaks between units corresponds to the number of β-oxidation cycles. The same value can be calculated using the formula (n/2 -1), where n is the number of carbon atoms in the acid.
• number of double bonds in a fatty acid. In the first β-oxidation reaction, a double bond is formed with the participation of FAD. If a double bond is already present in the fatty acid, then there is no need for this reaction and FADN 2 is not formed. The number of lost FADN 2 corresponds to the number of double bonds. The remaining reactions of the cycle proceed without changes.
• the amount of ATP energy spent on activation (always corresponds to two high-energy bonds).

Example. Oxidation of palmitic acid

1. Since there are 16 carbon atoms, β-oxidation produces 8 acetyl-SCoA molecules. The latter enters the TCA cycle; when it is oxidized in one turn of the cycle, 3 molecules of NADH (7.5 ATP), 1 molecule of FADH 2 (1.5 ATP) and 1 molecule of GTP are formed, which is equivalent to 10 molecules of ATP. So, 8 molecules of acetyl-SCoA will provide the formation of 8 × 10 = 80 ATP molecules.
2. For palmitic acid the number of β-oxidation cycles is 7. In each cycle, 1 molecule of FADH 2 (1.5 ATP) and 1 molecule of NADH (2.5 ATP) are produced. Entering the respiratory chain, in total they “give” 4 ATP molecules. Thus, in 7 cycles 7 × 4 = 28 ATP molecules are formed.
3. Double bonds in palmitic acid No.
4. 1 molecule of ATP is used to activate the fatty acid, which, however, is hydrolyzed to AMP, that is, it is wasted 2 macroergic connections or two ATP.
5. Thus, summing up, we get 80+28-2 =106 ATP molecules are formed during the oxidation of palmitic acid.

Knoop in 1904 put forward the hypothesis of β-oxidation of fatty acids based on experiments in feeding rabbits various fatty acids in which one hydrogen atom in the terminal methyl group (at the ω-carbon atom) was replaced by a phenyl radical (C 6 H 5 -).

Knoop suggested that the oxidation of the fatty acid molecule in body tissues occurs in the β-position; As a result, there is a sequential cutting off of two-carbon fragments from the fatty acid molecule on the side of the carboxyl group.

Fatty acids, which are part of the natural fats of animals and plants, belong to a series with an even number of carbon atoms. Any such acid, removing a pair of carbon atoms, ultimately passes through the stage of butyric acid, which, after the next β-oxidation, should give acetoacetic acid. The latter is then hydrolyzed to two molecules of acetic acid.

The theory of β-oxidation of fatty acids, proposed by Knoop, has not lost its significance to this day and is largely the basis of modern ideas about the mechanism of fatty acid oxidation.

Modern ideas about fatty acid oxidation

It has been established that the oxidation of fatty acids in cells occurs in mitochondria with the participation of a multienzyme complex. It is also known that fatty acids are initially activated with the participation of ATP and HS-KoA; CoA esters of these acids serve as substrates at all subsequent stages of enzymatic oxidation of fatty acids; The role of carnitine in the transport of fatty acids from the cytoplasm to mitochondria has also been clarified.

The process of fatty acid oxidation consists of the following main stages.

Activation of fatty acids and their penetration from the cytoplasm into mitochondria. The formation of the “active form” of a fatty acid (acyl-CoA) from coenzyme A and a fatty acid is an endergonic process that occurs through the use of ATP energy:

The reaction is catalyzed by acyl-CoA synthetase. There are several such enzymes: one of them catalyzes the activation of fatty acids containing from 2 to 3 carbon atoms, another - from 4 to 12 atoms, the third - from 12 or more carbon atoms.

As already noted, the oxidation of fatty acids (acyl-CoA) occurs in mitochondria. In recent years, it has been shown that the ability of acyl-CoA to penetrate from the cytoplasm into mitochondria increases sharply in the presence of a nitrogenous base, carnitine (γ-trimethylamino-β-hydroxybutyrate). Acyl-CoA, combining with carnitine, with the participation of a specific cytoplasmic enzyme (carnitine acyl-CoA transferase), forms acylcarnitine (an ester of carnitine and a fatty acid), which has the ability to penetrate into the mitochondria:

After acylcarnitine passes through the mitochondrial membrane, a reverse reaction occurs - the cleavage of acylcarnitine with the participation of HS-CoA and mitochondrial carnitine acyl-CoA transferase:

In this case, carnitine returns to the cell cytoplasm, and acyl-CoA undergoes oxidation in the mitochondria.

First stage of dehydrogenation. Acyl-CoA in mitochondria is primarily subject to enzymatic dehydrogenation;

in this case, acyl-CoA loses two hydrogen atoms in the α- and β-positions, turning into the CoA ester of an unsaturated acid:

There appear to be several FAD-containing acyl-CoA dehydrogenases, each of which has specificity for acyl-CoA of a specific carbon chain length.

Hydration stage. Unsaturated acyl-CoA (enoyl-CoA), with the participation of the enzyme enoyl-CoA hydratase, attaches a water molecule. As a result, β-hydroxyacyl-CoA is formed:

Second stage of dehydrogenation. The resulting β-hydroxyacyl-CoA is then dehydrogenated. This reaction is catalyzed by NAD-dependent dehydrogenases. The reaction proceeds according to the following equation:

In this reaction, β-ketoacyl-CoA interacts with coenzyme A. As a result, β-ketoacyl-CoA is cleaved and an acyl-CoA shortened by two carbon atoms and a two-carbon fragment in the form of acetyl-CoA are formed. This reaction is catalyzed by acetyl-CoA acyltransferase (or thiolase):

The resulting acetyl-CoA undergoes oxidation in the tricarboxylic acid cycle (Krebs cycle), and acyl-CoA, shortened by two carbon atoms, again repeatedly goes through the entire β-oxidation path until the formation of butyryl-CoA (4-carbon compound), which in its turn the turn is oxidized to two molecules of acetyl-CoA (see diagram).

For example, in the case of palmitic acid (C 16), 7 oxidation cycles are repeated. Let us remember that during the oxidation of a fatty acid containing n carbon atoms, n/2 - 1 cycles of β-oxidation occur (i.e., one cycle less than n/2, since the oxidation of butyryl-CoA immediately produces two molecules acetyl-CoA) and a total of n/2 molecules of acetyl-CoA will be obtained.

Therefore, the overall equation for the p-oxidation of palmitic acid can be written as follows:

Palmitoyl-CoA + 7 FAD + 7 NAD + 7H 2 O + 7HS-KoA --> 8 Acetyl-CoA + 7 FADH 2 + 7 NADH 2 .

Energy balance. With each cycle of β-oxidation, 1 molecule of FADH 2 and 1 molecule of NADH 2 are formed. The latter, in the process of oxidation in the respiratory chain and associated phosphorylation, give: FADH 2 - two ATP molecules and NADH 2 - three ATP molecules, i.e. in total, 5 ATP molecules are formed in one cycle. In the case of palmitic acid oxidation, 7 cycles of β-oxidation (16/2 - 1 = 7) occur, which leads to the formation of 5X7 = 35 ATP molecules. In the process of β-oxidation of palmitic acid, acetyl-CoA molecules are formed, each of which, burning in the tricarboxylic acid cycle, produces 12 ATP molecules, and 8 molecules will produce 12X8 = 96 ATP molecules.

Thus, in total, with complete oxidation of palmitic acid, 35 + 96 = 131 ATP molecules are formed. However, taking into account one ATP molecule spent at the very beginning on the formation of the active form of palmitic acid (palmitoyl-CoA), the total energy yield for the complete oxidation of one palmitic acid molecule under animal conditions will be 131-1 = 130 ATP molecules (note that with Complete oxidation of one glucose molecule produces only 36 ATP molecules).

It is calculated that if the change in free energy of the system (ΔG) upon complete combustion of one molecule of palmitic acid is 9797 kJ, and the energy-rich terminal phosphate bond of ATP is characterized by a value of about 34.5 kJ, then it turns out that approximately 45% of the total potential energy of palmitic acid at its oxidation in the body can be used for the resynthesis of ATP, and the remaining part is apparently lost as heat.

FATTY ACID- aliphatic carboxylic acids, many of which are found in animal and vegetable fats; in the body of animals and plants, free fatty acids and fatty acids that are part of lipids perform an extremely important function - energetic and plastic. Unsaturated fatty acids participate in the human and animal body in the biosynthesis of a special group of biologically active substances - prostaglandins (see). The content of free and ester-bound fatty acids in blood serum serves as an additional diagnostic test for a number of diseases. Liquid compounds are widely used for the preparation of various soaps, in the production of rubber and rubber products, varnishes, enamels and drying oils.

Depending on the number of carboxyl groups in the molecule, one-, two-, and polybasic liquid compounds are distinguished, and according to the degree of saturation of the hydrocarbon radical, saturated (saturated) and unsaturated (unsaturated) liquid compounds are distinguished. Based on the number of carbon atoms in the liquid acid chain They are divided into lower (C1-C3), middle (C4-C9) and higher (C10-C26) - Saturated fatty acids have a general molecular formula C n H 2 n O 2. The general formula of unsaturated fatty acids depends on the number of double or triple bonds they contain.

Rational and systematic nomenclature is used to designate housing; In addition, many housing complexes have historically established names. According to rational nomenclature, all liquid compounds are considered to be derivatives of acetic acid, in which the hydrogen atom of the methyl group in the molecule is replaced by a hydrocarbon radical. According to the systematic nomenclature, the name of the liquid mixture comes from the name of the hydrocarbon, the molecule of which is built from the same number of carbon atoms, including the carbon of the carboxyl group, as the liquid acid molecule (for example, propane - propane acid, ethane - ethane acid, hexane - hexane acid, etc.). The name of unsaturated liquid compounds indicates the number of double bonds (mono-, di-, tri-, etc.) and adds the ending “ene”. The numbering of liquid carbon atoms begins with the carbon of the carboxyl (COOH-) group and is indicated by Arabic numbers. The C-atom closest to the COOH group is designated alpha, the one next to it is designated beta, and the terminal carbon atom in the hydrocarbon radical is designated omega. The double bond in a liquid acid molecule is designated by the symbol Δ or simply given the number of the carbon atom on which the double bond is located, indicating the cis or trans configuration of the chain. Some of the most common housing complexes and their trivial, rational, and systematic names are given in Table 1.

Physical properties

Lower fatty acids are volatile liquids with a pungent odor, medium fatty acids are oils with an unpleasant rancid odor, and higher fatty acids are solid crystalline substances that are practically odorless.

Only formic acid (see), acetic acid (see) and propionic acid are mixed with water in all respects; in higher members of the liquid acid series, the solubility quickly decreases and finally becomes equal to zero. J. compounds are highly soluble in alcohol and ether.

The melting points in the homologous series of liquid crystals increase, but unevenly. Liquid crystals with an even number of C atoms melt at a higher temperature than the following liquid crystals, which have one more C atom (Table 2). In both of these series (with an even and odd number of C atoms), the difference in the melting temperatures of two successive members gradually decreases.

This peculiar difference between liquid compounds with an even and odd number of C-atoms in the molecule is manifested not only in the melting points, but to some extent in the chemical properties. and even in their biol, properties. Thus, acids with an even number of C-atoms disintegrate, according to G. Embden, during hemorrhage in the liver to acetone, but acids with an odd number of C-atoms do not decompose.

Liquid crystals are strongly associated and even at temperatures exceeding their boiling point, they show twice the mol. weight than their formula suggests. This association is explained by the occurrence of hydrogen bonds between individual liquid molecules.

Chemical properties

The chemical properties of liquid compounds are determined by the properties of their COOH groups and hydrocarbon radicals. In the COOH group, the O-H bond is weakened due to a shift in the electron density in the double C=O bond towards oxygen, and therefore the proton can be easily removed. This leads to the appearance of a stable anion:

The electron affinity of the carbonyl residue can be partially satisfied by the neighboring methylene group; the hydrogen atoms are the most active compared to the others. The dissociation constant of the COOH group of liquid compounds is 10 -4 -10 -5 M, i.e. its value is much lower than that of inorganic compounds. The strongest of the acids is formic acid. The COOH group of liquid acid has the ability to react in aqueous solutions with alkaline earth metals. Salts of higher liquid compounds with these metals are called soaps (see). Soaps have the properties of surfactants - detergents (see). Sodium soaps are solid, potassium soaps are liquid. Hydroxyl COOH groups of liquid acid can be easily replaced by halogen to form acid halides, which are widely used in organic syntheses. When replacing a halogen with a residue of another acid, liquid acid anhydrides are formed; when replacing a residue with an alcohol, their esters are formed, with ammonia - amides, and with hydrazine - hydrazides. The most common in nature are esters of the tribasic alcohol glycerol and higher fatty acids - fats (see). The hydrogen of the alpha carbon atom of liquid crystals can be easily replaced by halogen to form halogen-containing liquid compounds. Unsaturated liquid compounds can exist in the form of cis- and trans-isomers. Most natural unsaturated fatty acids have a cis configuration (see Isomerism). The degree of liquid unsaturation is determined by iodometric titration of double bonds. The process of converting unsaturated fatty acids into saturated ones is called hydrogenation; the reverse process is dehydrogenation (see Hydrogenation).

Natural fatty acids are obtained by hydrolysis of fats (their saponification) followed by fractional distillation or chromatographic separation of the liberated fatty acids. Non-natural fatty acids are obtained by oxidation of hydrocarbons; the reaction proceeds through the stage of formation of hydroperoxides and ketones.

Fatty acid oxidation

As an energy material, liquid acids are used in the process of beta oxidation. In 1904, F. Knoop put forward a hypothesis explaining the mechanism of oxidation of fatty acids in the animal body.

This hypothesis was built on the basis of establishing the nature of the final metabolic products excreted in the urine after the administration of co-phenyl substituted fatty acids to animals. In the experiments of F. Knoop, the administration of phenyl substituted fatty acids containing an even number of C-atoms to animals was always accompanied by the release of phenyl acetic acid in the urine, and those containing an odd number of C-atoms - the release of benzoic acid. Based on these data, F. Knoop suggested that the oxidation of the liquid acid molecule occurs by sequentially cutting off two-carbon fragments from it from the carboxyl group (Scheme 1):

The hypothesis of F. Knoop, called the theory of beta oxidation, is the basis of modern ideas about the mechanism of oxidation of fatty acids. The following methods and discoveries played an important role in the development of these ideas: 1) the introduction of a radioactive label (14 C) into the molecule of fatty acids. to study their exchange; 2) the establishment by Munoz and L. F. Leloir of the fact that the oxidation of fatty acids by cellular homogenates requires the same cofactors as the oxidation of pyruvate (inorganic phosphate, Mg 2+ ions, cytochrome c, ATP, and what -substrate of the Tricarboxylic acid cycle - succinate, fumarate, etc.); 3) establishing the fact that the oxidation of fatty acids, as well as the substrates of the Tricarboxylic acid cycle (see Tricarboxylic acid cycle), occurs only in the mitochondria of the cell [Lehninger (A. L. Lehninger) and Kennedy (E. P. Kennedy)]; 4) establishing the role of carnitine in the transport of fatty acids from the cytoplasm to mitochondria; 5) discovery of coenzyme A by F. Lipmann and F. Linen; 6) isolation from animal tissues in purified form of a multienzyme complex responsible for the oxidation of fat.

The process of oxidation of ferric acid in general consists of the following stages.

Free fatty acid, regardless of the length of the hydrocarbon chain, is metabolically inert and cannot undergo any transformations, including oxidation, until it is activated.

Activation of fatty acids occurs in the cytoplasm of the cell, with the participation of ATP, reduced CoA (KoA-SH) and Mg 2+ ions.

The reaction is catalyzed by the enzyme thiokinase:

As a result of this reaction, acyl-CoA is formed, which is the active form of fatty acids. Several thiokinases have been isolated and studied. One of them catalyzes the activation of fatty acids with a hydrocarbon chain length from C2 to C3, the other from C4 to C12, and the third from C10 to C22.

Transport into mitochondria. The coenzyme form of fatty acids, like free fatty acids, does not have the ability to penetrate into mitochondria, where their oxidation actually occurs.

It has been established that the transfer of the active form of fatty acids into mitochondria is carried out with the participation of the nitrogenous base carnitine. By combining with fatty acids using the enzyme acylcarnitine transferase, carnitine forms acylcarnitine, which has the ability to penetrate into the mitochondrial membrane.

In the case of palmitic acid, for example, the formation of palmityl-carnitine is represented as follows:

Inside the mitochondrial membrane, with the participation of CoA and mitochondrial palmityl-carnitine transferase, a reverse reaction occurs - the cleavage of palmityl-carnitine; in this case, carnitine returns to the cytoplasm of the cell, and the active form of palmitic acid, palmityl-CoA, passes into the mitochondria.

First oxidation stage. Inside the mitochondria, with the participation of fatty acid dehydrogenases (FAD-containing enzymes), oxidation of the active form of fatty acids begins in accordance with the theory of beta oxidation.

In this case, acyl-CoA loses two hydrogen atoms in the alpha and beta positions, turning into unsaturated acyl-CoA:

Hydration. Unsaturated acyl-CoA attaches a water molecule with the participation of the enzyme enoyl hydratase, resulting in the formation of beta-hydroxyacyl-CoA:

The second stage of fatty acid oxidation, like the first, occurs by dehydrogenation, but in this case the reaction is catalyzed by NAD-containing dehydrogenases. Oxidation occurs at the site of the beta carbon atom with the formation of a keto group at this position:

The final stage of one complete oxidation cycle is the cleavage of beta-ketoacyl-CoA by thiolysis (and not hydrolysis, as F. Knoop assumed). The reaction occurs with the participation of CoA and the enzyme thiolase. An acyl-CoA shortened by two carbon atoms is formed and one molecule of acetic acid is released in the form of acetyl-CoA:

Acetyl-CoA undergoes oxidation in the Tricarboxylic acid cycle to CO 2 and H 2 O, and acyl-CoA again goes through the entire path of beta-oxidation, and this continues until the decomposition of acyl-CoA, which is increasingly shortened by two carbon atoms will lead to the formation of the last acetyl-CoA particle (Scheme 2).

During beta oxidation, for example, palmitic acid, 7 oxidation cycles are repeated. Therefore, the overall result of its oxidation can be represented by the formula:

C 15 H 31 COOH + ATP + 8KoA-SH + 7NAD + 7FAD + 7H 2 O -> 8CH 3 CO-SKoA + AMP + 7NAD-H 2 + 7FAD-H 2 + pyrophosphate

The subsequent oxidation of 7 molecules of NAD-H 2 gives the formation of 21 molecules of ATP, the oxidation of 7 molecules of FAD-H 2 - 14 molecules of ATP and the oxidation of 8 molecules of acetyl-CoA in the Tricarboxylic acid cycle - 96 molecules of ATP. Taking into account one molecule of ATP spent at the very beginning on the activation of palmitic acid, the total energy yield for the complete oxidation of one molecule of palmitic acid in an animal organism will be 130 ATP molecules (with the complete oxidation of a glucose molecule, only 38 ATP molecules are formed). Since the change in free energy during complete combustion of one molecule of palmitic acid is 2338 kcal, and the energy-rich phosphate bond of ATP is characterized by a value of 8 kcal, it is easy to calculate that approximately 48% of the total potential energy of palmitic acid during its oxidation in the body is used to resynthesize ATP, and the remainder is apparently lost as heat.

A small amount of fatty acids in the body undergoes omega-oxidation (oxidation at the site of the methyl group) and alpha-oxidation (at the site of the second C-atom). In the first case, a dicarboxylic acid is formed, in the second - a fatty acid shortened by one carbon atom. Both types of oxidation occur in the microsomes of the cell.

Fatty acid synthesis

Since any of the oxidation reactions of fatty acids is in itself reversible, it has been suggested that the biosynthesis of fatty acids is a process reverse to their oxidation. This was believed until 1958, until it was established that in pigeon liver extracts, the synthesis of fatty acids from acetate could only occur in the presence of ATP and bicarbonate. Bicarbonate turned out to be an absolutely necessary component, although it itself was not included in the fatty acid molecule.

Thanks to the research of S. F. Wakil, F. Linen and R. V. Vagelos in the 60-70s. 20th century It was found that the actual unit of fatty acid biosynthesis is not acetyl-CoA, but malonyl-CoA. The latter is formed by carboxylation of acetyl-CoA:

It was for the carboxylation of acetyl-CoA that bicarbonate, ATP, and Mg2+ ions were required. The enzyme that catalyzes this reaction, acetyl-CoA carboxylase, contains biotin as a prosthetic group (see). Avidin, a biotin inhibitor, inhibits this reaction, as well as the synthesis of fatty acids in general.

The total synthesis of fatty acids, for example, palmitic acid, with the participation of malonyl-CoA can be represented by the following equation:

As follows from this equation, the formation of a molecule of palmitic acid requires 7 molecules of malonyl-CoA and only one molecule of acetyl-CoA.

The process of fat synthesis has been studied in detail in E. coli and some other microorganisms. The enzyme system called fatty acid synthetase in E. coli consists of 7 individual enzymes associated with the so-called. acyl transfer protein (APP). AP B was isolated in its pure form, and its primary structure was studied. Mol. the weight of this protein is 9750. It contains phosphorylated panthetheine with a free SH group. AP B does not have enzymatic activity. Its function is associated only with the transfer of acyl radicals. The sequence of reactions for the synthesis of fatty acids in E. coli can be presented as follows:

Next, the reaction cycle is repeated, beta-ketocapronyl-S-ACP with the participation of NADP-H 2 is reduced to beta-hydroxycapronyl-S-ACP, the latter undergoes dehydration to form unsaturated hexenyl-S-ACP, which is then reduced to saturated capronyl-S-ACP , having a carbon chain two atoms longer than butyryl-S-APB, etc.

Thus, the sequence and nature of reactions in the synthesis of fatty acids, starting with the formation of beta-ketoacyl-S-ACP and ending with the completion of one cycle of chain extension by two C-atoms, are reverse reactions of oxidation of fatty acids. However, the synthesis routes and oxidation of liquids do not even partially intersect.

It was not possible to detect ACP in animal tissues. A multienzyme complex containing all the enzymes necessary for the synthesis of fatty acids has been isolated from the liver. The enzymes of this complex are so tightly bound to each other that all attempts to isolate them individually have failed. The complex contains two free SH groups, one of which, as in ACP, belongs to phosphorylated panthetheine, the other to cysteine. All reactions of the synthesis of fatty acids occur on the surface or inside this multienzyme complex. Free SH groups of the complex (and possibly the hydroxyl group of the serine included in its composition) take part in the binding of acetyl-CoA and malonyl-CoA, and in all subsequent reactions the panthetheine SH group of the complex plays the same role as the SH group ACP, i.e., participates in the binding and transfer of the acyl radical:

The further course of reactions in the animal organism is exactly the same as presented above for E. coli.

Until the middle of the 20th century. it was believed that the liver is the only organ where the synthesis of fatty acids occurs. Then it was found that the synthesis of fatty acids also occurs in the intestinal wall, in lung tissue, in adipose tissue, in the bone marrow, in the l activating mammary gland, and even in the vascular wall. As for the cellular localization of synthesis, there is reason to believe that it occurs in the cytoplasm of the cell. It is characteristic that hl is synthesized in the cytoplasm of liver cells. arr. palmitic acid. As for other fatty acids, the main way of their formation in the liver is to lengthen the chain based on already synthesized palmitic acid or fatty acids of exogenous origin, received from the intestines. In this way, for example, liquid compounds containing 18, 20, and 22 C atoms are formed. The formation of fatty acids by chain elongation occurs in the mitochondria and microsomes of the cell.

The biosynthesis of fatty acids in animal tissues is regulated. It has long been known that the liver of starving animals and animals with diabetes slowly incorporates 14C-acetate into the stomach. The same thing was observed in animals injected with excess amounts of fat. It is characteristic that in liver homogenates of such animals acetyl-CoA, but not malonyl-CoA, was slowly used for the synthesis of fatty acids. This led to the assumption that the rate-limiting reaction of the process as a whole is associated with the activity of acetyl-CoA carboxylase. Indeed, F. Linen showed that long-chain acyl derivatives of CoA at a concentration of 10 -7 M inhibited the activity of this carboxylase. Thus, the accumulation of fatty acids itself has an inhibitory effect on their biosynthesis through a feedback mechanism.

Another regulating factor in the synthesis of fatty acids, apparently, is citric acid (citrate). The mechanism of action of citrate is also associated with its effect on acetyl-CoA carboxylase. In the absence of citrate, acetyl-CoA - liver carboxylase is in the form of an inactive monomer with a mol. weighing 540,000. In the presence of citrate, the enzyme turns into an active trimer with a mol. weight approx. 1,800,000 and providing a 15-16-fold increase in the rate of synthesis of fatty acids. It can therefore be assumed that the content of citrate in the cytoplasm of liver cells has a regulatory effect on the rate of synthesis of fatty acids. Finally, it is important for the synthesis of fatty acids concentration of NADPH 2 in the cell.

Metabolism of unsaturated fatty acids

Convincing evidence has been obtained that in the liver of animals, stearic acid can be converted into oleic acid, and palmitic acid into palmitooleic acid. These transformations, which occur in cell microsomes, require the presence of molecular oxygen, a reduced system of pyridine nucleotides and cytochrome b5. Microsomes can also convert monounsaturated compounds into diunsaturated ones, for example, oleic acid into 6,9-octadecadiene acid. Along with the desaturation of fatty acids in microsomes, their elongation also occurs, and both of these processes can be combined and repeated. In this way, for example, nervonic and 5, 8, 11-eicosatetraenoic acids are formed from oleic acid.

At the same time, human tissues and a number of animals have lost the ability to synthesize some polyunsaturated compounds. These include linoleic (9,12-octadecadienic), linolenic (6,9,12-octadecatrienic) and arachidonic (5, 8, 11, 14-eicosatetraenoic) compounds. These compounds are classified as essential fatty acids. With their long-term absence from food, animals experience growth retardation and characteristic lesions of the skin and hair develop. Cases of insufficiency of essential fatty acids in humans have been described. Linoleic and linolenic acids, containing two and three double bonds, respectively, as well as related polyunsaturated fatty acids (arachidonic acid, etc.) are conventionally combined into a group called “vitamin F”.

Biol, the role of essential fatty acids became clearer in connection with the discovery of a new class of physiologically active compounds - prostaglandins (see). It has been established that arachidonic acid and, to a lesser extent, linoleic acid are precursors of these compounds.

Fatty acids are part of a variety of lipids: glycerides, phosphatides (see), cholesterol esters (see), sphingolipids (see) and waxes (see).

The main plastic function of fatty acids is reduced to their participation in the composition of lipids in the construction of biol, membranes that make up the skeleton of animal and plant cells. In biol, membranes hl are found. arr. esters of the following fatty acids: stearic, palmitic, oleic, linoleic, linolenic, arachidonic and docosahexaenoic. Unsaturated fatty acids of biol lipids, membranes can be oxidized with the formation of lipid peroxides and hydroperoxides - the so-called. peroxidation of unsaturated fatty acids.

In the body of animals and humans, only unsaturated fatty acids with one double bond (for example, oleic acid) are easily formed. Polyunsaturated fatty acids are formed much more slowly, most of which are supplied to the body with food (essential fatty acids). There are special fat depots, from which, after hydrolysis (lipolysis) of fats, fatty acids can be mobilized to meet the needs of the body.

It has been experimentally shown that eating fats containing large amounts of saturated fatty acids contributes to the development of hypercholesterolemia; The use of vegetable oils containing large amounts of unsaturated fatty acids with food helps reduce cholesterol in the blood (see Fat metabolism).

Medicine pays the greatest attention to unsaturated fatty acids. It has been established that their excessive oxidation by the peroxide mechanism can play a significant role in the development of various pathols, conditions, for example, with radiation damage, malignant neoplasms, vitamin deficiency E, hyperoxia, and carbon tetrachloride poisoning. One of the products of peroxidation of unsaturated fatty acids, lipofuscin, accumulates in tissues during aging. A mixture of ethyl ethers of unsaturated fatty acids, consisting of oleic acid (approx. 15%), linoleic acid (approx. 15%) and linolenic acid (approx. 57%), the so-called. linetol (see), is used in the prevention and treatment of atherosclerosis (see) and externally for burns and radiation injuries of the skin.

In the clinic, methods for the quantitative determination of free (non-esterified) and ether-bound fatty acids are most widely used. Methods for the quantitative determination of ester-bound fatty acids are based on their transformation into the corresponding hydroxamic acids, which, interacting with Fe 3+ ions, form colored complex salts .

Normally, the blood plasma contains from 200 to 450 mg% of esterified fatty acids and from 8 to 20 mg% of non-esterified fatty acids. An increase in the content of the latter is observed in diabetes, nephrosis, after the administration of adrenaline, during fasting, and also during emotional stress . A decrease in the content of non-esterified fatty acids is observed in hypothyroidism, during treatment with glucocorticoids, and also after injection of insulin.

Individual fatty acids - see articles by their name (for example, Arachidonic acid, Arachinic acid, Caproic acid, Stearic acid, etc.). See also Fat metabolism, Lipids, Cholesterol metabolism.

Table 1. NAMES AND FORMULAS OF SOME OF THE MOST COMMON FATTY ACIDS

Zinoviev A. A. Chemistry of fats, M., 1952; Newsholm E. and Start K. Regulation of metabolism, trans. from English, M., 1977; Perekalin V.V. and Sonne S.A. Organic chemistry, M., 1973; Biochemistry and methodology of lipids, ed. by A. R. Jonson a. J.B. Davenport, N.Y., 1971; Fatty acids, ed. by K. S. Markley, pt 1-3, N. Y.-L., 1960-1964, bibliogr.; Lipid metabolism, ed. by S. J. Wakil, N. Y.-L., 1970.

A. N. Klimov, A. I. Archakov.