The biosynthesis of fatty acids involves a series of reactions that do not correspond to the process of their degradation.
In particular, special proteins - ACP (acyl carrier proteins) are mediators in the synthesis of fatty acids. In contrast, HS-KoA is used in the breakdown of a fatty acid.
Fatty acid synthesis occurs in the cytosol, and fatty acid breakdown occurs in mitochondria.
For fatty acid synthesis, the coenzyme NADP / NADPH is used, while the breakdown of the fatty acid involves the coenzyme NAD + / NADH.
Fatty acids that make up tissue lipids can be divided into short- (2-6 carbon atoms), medium- (8-12 carbon atoms) and long-chain (14-20 or more carbon atoms in the molecule). Most of the fatty acids in animal tissues are long-chain. The vast majority of fatty acids in the body contain an even number of carbon atoms in the molecule (C: 16, 18, 20), although there are longer fatty acid molecules in the fats of the nervous tissue, including 22 carbon atoms with six double bonds.
Acid with one double bond refers to monounsaturated fatty acids, while acids with two or more isolated double bonds are polyunsaturated.
table 2
Essential fatty acids in mammals
|
Acid name |
Acid structure |
Number and position of double bonds |
|
Oil |
UNCUN |
|
|
Nylon |
||
|
Caprylic |
STNUSON |
|
|
Capric |
||
|
Lauric |
С11Н21СООН |
|
|
Myristic |
Spnzsun |
|
|
Palmitic |
С15Н31СООН |
|
|
Stearic |
С17Н35СООН |
|
|
Oleinovaya |
SPNZZUNO |
|
|
Linoleic |
С17Н31СООН |
|
|
Linolenic |
SPNZZUNO |
|
|
Arachidonic |
С19Н31СООН |
4 (5, 8. 11, 14) |
Unsaturated fatty acids are usually in the cys form. Fats of plants and fish contain more polyunsaturated fatty acids in their composition, and saturated fatty acids prevail in the composition of fats of mammals and birds.
Diet fatty acids and their endogenous biosynthesis are necessary for the body to obtain energy and form hydrophobic components of biomolecules. Excess proteins and carbohydrates in the diet are actively converted into fatty acids and stored in the form of triglycerides.
Most tissues are capable of synthesizing saturated fatty acids. Quantitatively, the synthesis of fatty acids is important, primarily in the liver, intestines, adipose tissue, mammary gland, bone marrow, and lungs. If the oxidation of fatty acids occurs in the mitochondria of cells, then their synthesis takes place in the cytoplasm.
The main way of providing the body with fatty acids is their biosynthesis from small intermediary molecules, derivatives of carbohydrate catabolism, individual amino acids and other fatty acids. Usually saturated 16-carboxylic acid - palmitic - is synthesized first, and all other fatty acids are a modification of palmitic acid.
All reactions of synthesis of fatty acids are catalyzed by a multienzyme complex - synthase of fatty acids, which is located in the cytosol. Acetyl-CoA is a direct source of carbon atoms for this synthesis. The main suppliers of acetyl-CoA molecules are: degradation of amino acids, oxidation of fatty acids, pyruvate glycolysis.
Malonyl-CoA necessary for the synthesis of fatty acids comes as a result of carboxylation of acetyl-CoA, and the necessary NADPH can also be obtained in the pentose phosphate pathway.
Acetyl-CoA molecules are mainly found in mitochondria. However, the inner mitochondrial membrane is impermeable to a relatively large molecule such as acetyl-CoA. Therefore, for the transition from mitochondria to the cytoplasm, acetyl-CoA with the participation of citrate synthase interacts with oxalic-acetic acid, forming citric acid:
In the cytoplasm, citric acid is broken down under the influence of citrate lyase:
Thus, citric acid acts as a transporter for acetyl-CoA. In ruminants, instead of citric acid in the cytoplasm of the cell, acetate is used, which is formed in the rumen from polysaccharides, which is converted into acetyl-CoA in the cells of the liver and adipose tissue.
1. At the first stage of fatty acid biosynthesis, acetyl-CoA interacts with a special acyl-carrying protein (HS-ACP) containing vitamin B 3 and a sulfhydryl group (HS), resembling the structure of coenzyme A:
2. An indispensable intermediate in the synthesis is malonyl-CoA, which is formed in the reaction of carboxylation of acetyl-CoA with the participation of ATP and a biotin-containing enzyme, acetyl-CoA carboxylase:
Biotin (vitamin H) as a carboxylase coenzyme is covalently linked to an apoenzyme to carry a one-carbon fragment. Acetyl CoA carboxylase is a multifunctional enzyme that regulates the rate of fatty acid synthesis. Insulin stimulates fatty acid synthesis by activating carboxylase, while epinephrine and glucagon have the opposite effect.
3. The resulting malonyl-S-KoA interacts with HS-ACP with the participation of the enzyme malonyl transacylase:
4. In the following condensation reaction under the influence of the enzyme acyl-malonyl-B-ACP-synthase, malonyl-B-ACP and acetyl-B-ACP interact with the formation of acetoacetyl-B-ACP:
5. Acetoacetyl-B-ACP with the participation of NADP + -dependent reductase is reduced to form p-hydroxylbutyryl-B-ACP:
7. In the following reaction, crotonyl-B-APB is reduced by NADP + -dependent reductase with the formation of butyryl-B-APB:
In the case of the synthesis of palmitic acid (C: 16), it is necessary to repeat six more reaction cycles, the beginning of each will be the addition of the malonyl-B-ACP molecule to the carboxyl end of the synthesized fatty acid chain. Thus, by attaching one molecule of malonyl-B-ACP, the carbon chain of the synthesized palmitic acid increases by two carbon atoms.
8. Synthesis of palmitic acid is completed by hydrolytic cleavage of HS-ACP from palmityl-B-ACP with the participation of the deacylase enzyme:
The synthesis of palmitic acid is the basis for the synthesis of other fatty acids, including monounsaturated acids (oleic, for example). Free palmitic acid is converted to palmityl-S-KoA with the participation of thiokinase. Palmytyl-S-KoA in the cytoplasm can be used in the synthesis of simple and complex lipids, or enter mitochondria with the participation of carnitine for the synthesis of fatty acids with a longer carbon chain.
In mitochondria and in the smooth endoplasmic reticulum, there is a system of fatty acid lengthening enzymes for the synthesis of acids with 18 or more carbon atoms by lengthening the carbon chain of fatty acids from 12 to 6 carbon atoms. When propionyl-S-KoA is used instead of acetyl-S-KoA, the synthesis results in an odd-numbered fatty acid.
In total, the synthesis of palmitic acid can be represented by the following equation:
Acetyl-S-KoA in the cytoplasm in this synthesis serves as a source of carbon atoms of the palmitic acid molecule. ATP is required for the activation of acetyl-S-KoA, while NADPH + H + is an essential reducing agent. NADPH + + H + in the liver is formed in the reactions of the pentose phosphate pathway. Fatty acid synthesis occurs only in the presence of these basic components in the cell. Consequently, the biosynthesis of fatty acids requires glucose, which supplies the process with acetyl radicals, C0 2 and H 2 in the form of NADPH 2.
All enzymes of fatty acid biosynthesis, including HS-ACP, are in the cytoplasm of the cell in the form of a multienzyme complex called fatty acid synthetase.
The synthesis of oleic (unsaturated) acid with one double bond occurs due to the reaction of saturated stearic acid with NADPH + H + in the presence of oxygen:
In hepatocytes and in the mammary gland of lactating animals, NADPH 2, necessary for the synthesis of fatty acids, is provided by the pentose phosphate pathway. If in most eukaryotes the synthesis of fatty acids occurs exclusively in the cytoplasm, then the synthesis of fatty acids in photosynthetic plant cells takes place in the stroma of chloroplasts.
Polyunsaturated fatty acids - linoleic (C 17 H 31 COOH), linolenic (C 17 H 29 COOH), having double bonds near the methyl end of the carbon chain, are not synthesized in mammals due to the lack of necessary enzymes (desaturases) that ensure the formation of unsaturated bonds in molecule. However, arachidonic acid (C 19 H 31 COOH) can be synthesized from linoleic acid. In turn, arachidonic acid is a precursor in the synthesis of prostaglandins. Note that plants are capable of synthesizing double bonds at positions 12 and 15 of the carbon chain with the participation of necessary enzymes in the synthesis of linoleic and linolenic acids.
The main role of all polyunsaturated fatty acids is probably to provide flow properties in biological membranes. This is confirmed by the fact that lower organisms have the ability to change the composition of fatty acids of phospholipids due to their fluidity, for example, at different ambient temperatures. This is achieved by increasing the proportion of double bond fatty acids or by increasing the degree of unsaturation of the fatty acids.
The methylene carbon of any double bond in the structure of a polyunsaturated fatty acid is very sensitive to hydrogen removal and oxygen fixation with the formation of free radicals. The hydroperoxide molecules thus formed form dialdehydes mainly in the form of malondialdehyde. The latter is capable of causing cross-linking, leading to cytotoxicity, mutagenicity, membrane disruption and enzyme modification. Polymerization of malonic aldehyde forms the insoluble pigment lipofuscin, which accumulates in some tissues with age.
Interest in polyunsaturated fatty acids at the biochemical level is associated with studies that indicate that diets with a high level of polyunsaturated fatty acids in relation to the level of saturated fatty acids help lower cholesterol levels in the body.
In the body of a starving animal, with the subsequent presence of a diet with a high level of carbohydrates and a low level of fat, the activity of acetyl-CoA carboxylase is significantly increased due to covalent modification and the synthesis of fatty acids for several days. This is an adaptive control of the regulation of fat metabolism. The synthesis and oxidation of fatty acids in the body are interdependent processes. When an animal is starving, the level of free fatty acids in the blood increases due to an increase in lipase activity of fat cells under the influence of hormones such as adrenaline, glucagon. The biosynthesis of fatty acids, converting NADPH + H + molecules into NADP ~, causes the breakdown of glucose via the pentose phosphate pathway. Thus, glucose is indispensable in the biosynthesis of fatty acids, supplying not only acetyl radicals, but also coenzymes in the form of NADPH + H +.
Free fatty acids bind to serum albumin, which are the main transporters of non-esterified fatty acids. In combination with albumin, fatty acids represent an active transport source of energy for various tissues at a certain period of time. However, the nervous tissue, which receives almost all of its energy from glucose, is not able to use the fatty acids associated with albumin for energy.
The concentration of free fatty acids in the blood is relatively constant (0.6 mM). Their half-life is only two minutes. The liver intensively involves fatty acids in the synthesis of triglycerides, binding them to low density lipoproteins (LDL), which enter the blood circulation. LDL cholesterol transports blood plasma cholesterol to various tissues, the walls of blood vessels.
Previously, it was assumed that the processes of cleavage are the reversal of the processes of synthesis, including the synthesis of fatty acids was considered as a process opposite to their oxidation.
It has now been established that the mitochondrial system of fatty acid biosynthesis, which includes a slightly modified sequence of the β-oxidation reaction, only lengthens the medium-chain fatty acids already existing in the body, while the complete biosynthesis of palmitic acid from acetyl-CoA is actively proceeding outside mitochondria on a completely different path.
Let's consider some important features of the fatty acid biosynthesis pathway.
1. Synthesis occurs in the cytosol, in contrast to the decay that occurs in the mitochondrial matrix.
2. Intermediates of fatty acid synthesis are covalently linked to sulfhydryl groups of acyl transfer protein (ACP), while intermediate products of fatty acid cleavage are linked to coenzyme A.
3. Many enzymes for the synthesis of fatty acids in higher organisms are organized into a multienzyme complex called fatty acid synthetase. In contrast, enzymes that catalyze the breakdown of fatty acids seem to be reluctant to associate.
4. The growing fatty acid chain is lengthened by the sequential addition of two-carbon components derived from acetyl-CoA. Malonyl-APB serves as an activated donor of bicarbon components at the elongation stage. The elongation reaction is triggered by the release of CO 2.
5. The role of a reducing agent in the synthesis of fatty acids is played by NADPH.
6. Mn 2+ also participates in the reactions.
7. Elongation under the action of the fatty acid synthetase complex stops at the stage of palmitate formation (C 16). Further elongation and introduction of double bonds are carried out by other enzyme systems.
Formation of malonyl coenzyme A
Fatty acid synthesis begins with the carboxylation of acetyl-CoA to malonyl-CoA. This irreversible reaction is a crucial step in the synthesis of fatty acids.
The synthesis of malonyl-CoA is catalyzed by acetyl CoA carboxylase and is carried out at the expense of the energy of the ATR. The source of CO 2 for the carboxylation of acetyl-CoA is bicarbonate.
Rice. Synthesis of malonyl-CoA
Acetyl CoA carboxylase contains as a prosthetic group biotin.
Rice. Biotin
The enzyme consists of a variable number of identical subunits, each of which contains biotin, biotincarboxylase, carboxybiotin transfer protein, transcarboxylase, as well as the regulatory allosteric center, i.e. represents polyenzyme complex. The carboxyl group of biotin is covalently attached to the ε-amino group of the lysine residue of the carboxybiotin transfer protein. Carboxylation of the biotin component in the formed complex is catalyzed by the second subunit, biotin carboxylase. The third component of the system, transcarboxylase, catalyzes the transfer of activated CO 2 from carboxybiotin to acetyl-CoA.
Biotin enzyme + ATP + HCO 3 - ↔ CO 2 ~ Biotin enzyme + ADP + Pi,
CO 2 ~ Biotin-enzyme + Acetyl-CoA ↔ Molonyl-CoA + Biotin-enzyme.
The length and flexibility of the bond between biotin and the protein carrying it make it possible for the activated carboxyl group to move from one active center of the enzyme complex to another.
In eukaryotes, acetyl CoA carboxylase exists as a protomer devoid of enzymatic activity (450 kDa) or as an active filamentous polymer. Their interconversion is regulated allosterically. The key allosteric activator is citrate, which shifts the equilibrium towards the active fibrous form of the enzyme. Optimal orientation of biotin with respect to substrates is achieved in fibrous form. In contrast to citrate, palmitoyl-CoA shifts the equilibrium towards the inactive protomeric form. Thus, palmitoyl-CoA, the end product, inhibits the first critical step in fatty acid biosynthesis. The regulation of acetyl CoA carboxylase in bacteria differs sharply from that in eukaryotes, since in them fatty acids are primarily precursors of phospholipids, and not a reserve fuel. Here citrate has no effect on bacterial acetyl CoA carboxylase. The activity of the transcarboxylase component of the system is regulated by guanine nucleotides, which coordinate the synthesis of fatty acids with the growth and division of bacteria.
The building block for the synthesis of fatty acids in the cytosol of the cell is acetyl-CoA, which is formed in two ways: either as a result of oxidative decarboxylation of pyruvate. (see Fig. 11, Stage III), or as a result of b-oxidation of fatty acids (see Fig. 8).
Figure 11 - Scheme of the conversion of carbohydrates into lipids
Recall that the conversion of pyruvate formed during glycolysis into acetyl-CoA and its formation during β-oxidation of fatty acids occurs in mitochondria. The synthesis of fatty acids takes place in the cytoplasm. The inner mitochondrial membrane is impermeable to acetyl-CoA. Its entry into the cytoplasm is carried out by the type of facilitated diffusion in the form of citrate or acetylcarnitine, which are converted in the cytoplasm into acetyl-CoA, oxaloacetate or carnitine. However, the main route of transfer of acetyl-coA from mitochondria to the cytosol is citrate (see Fig. 12).
Initially, intramitochondrial acetyl-CoA reacts with oxaloacetate to form citrate. The reaction is catalyzed by the enzyme citrate synthase. The resulting citrate is transported across the mitochondrial membrane into the cytosol using a special tricarboxylate transport system.
In the cytosol, citrate reacts with HS-CoA and ATP, again decomposes into acetyl-CoA and oxaloacetate. This reaction is catalyzed by ATP citrate lyase. Already in the cytosol, oxaloacetate, with the participation of the cytosolic dicarboxylate-transporting system, returns to the mitochondrial matrix, where it is oxidized to oxaloacetate, thereby completing the so-called shuttle cycle:
Figure 12 - Scheme of the transfer of acetyl-CoA from mitochondria to the cytosol
The biosynthesis of saturated fatty acids occurs in the direction opposite to their b-oxidation, the build-up of hydrocarbon chains of fatty acids is carried out due to the sequential addition of a two-carbon fragment (C 2) - acetyl-CoA to their ends (see Fig. 11, stage IV.).
The first reaction of fatty acid biosynthesis is the carboxylation of acetyl-CoA, which requires CO 2, ATP, and Mn ions. This reaction is catalyzed by the enzyme acetyl-CoA - carboxylase. The enzyme contains biotin (vitamin H) as a prosthetic group. The reaction proceeds in two stages: 1 - carboxylation of biotin with the participation of ATP and II - transfer of the carboxyl group to acetyl-CoA, as a result of which malonyl-CoA is formed:
Malonyl-CoA is the first specific product of fatty acid biosynthesis. In the presence of an appropriate enzyme system, malonyl-CoA is rapidly converted to fatty acids.
It should be noted that the rate of fatty acid biosynthesis is determined by the sugar content in the cell. An increase in the concentration of glucose in the adipose tissue of humans and animals and an increase in the rate of glycolysis stimulates the synthesis of fatty acids. This indicates that fat and carbohydrate metabolism are closely interrelated with each other. An important role here is played by the carboxylation reaction of acetyl-CoA with its transformation into malonyl-CoA, catalyzed by acetyl-CoA carboxylase. The activity of the latter depends on two factors: the presence of high molecular weight fatty acids and citrate in the cytoplasm.
The accumulation of fatty acids has an inhibitory effect on their biosynthesis, i.e. inhibit carboxylase activity.
A special role is played by citrate, which is an activator of acetyl-CoA carboxylase. Citrate at the same time plays the role of a connecting link of carbohydrate and fat metabolism. In the cytoplasm, citrate has a double effect in stimulating the synthesis of fatty acids: firstly, as an activator of acetyl-CoA carboxylase and, secondly, as a source of acetyl groups.
A very important feature of the synthesis of fatty acids is that all intermediate synthesis products are covalently linked to an acyl-transfer protein (HS-ACP).
HS-ACP is a low-molecular-weight protein that is thermally stable, contains an active HS-group and contains pantothenic acid (vitamin B 3) in its prosthetic group. The function of HS-ACP is similar to that of enzyme A (HS-CoA) in b-oxidation of fatty acids.
In the process of building a chain of fatty acids, intermediate products form ester bonds with ABP (see Fig. 14):
The fatty acid chain lengthening cycle includes four reactions: 1) condensation of acetyl-ACP (C 2) with malonyl-ACP (C 3); 2) recovery; 3) dehydration; and 4) second reduction of fatty acids. In fig. 13 shows a scheme for the synthesis of fatty acids. One cycle of fatty acid chain extension involves four consecutive reactions.
Figure 13 - Scheme of the synthesis of fatty acids
In the first reaction (1) - condensation reaction - acetyl and malonyl groups interact with each other to form acetoacetyl-ABP with simultaneous release of CO 2 (C 1). This reaction is catalyzed by the condensing enzyme b-ketoacyl-ABP synthetase. CO 2 cleaved from malonyl-ACP is the same CO 2 that took part in the carboxylation reaction of acetyl-ACP. Thus, as a result of the condensation reaction, a four-carbon compound (C 4) is formed from two- (C 2) and three-carbon (C 3) components.
In the second reaction (2), a reduction reaction catalyzed by b-ketoacyl-ACP reductase, acetoacetyl-ACP is converted to b-hydroxybutyryl-ACP. The reducing agent is NADPH + H +.
In the third reaction (3) of cycle-dehydration - a water molecule is split off from b-hydroxybutyryl-ACP with the formation of crotonyl-ACP. The reaction is catalyzed by b-hydroxyacyl-ACP-dehydratase.
The fourth (final) reaction (4) of the cycle is the reduction of crotonyl-ACP to butyryl-ACP. The reaction proceeds under the action of enoyl-ACP reductase. The role of the reducing agent here is played by the second molecule NADPH + H +.
Then the cycle of reactions is repeated. Let us assume that palmitic acid (C 16) is being synthesized. In this case, the formation of butyryl-ACP is completed only in the first of 7 cycles, in each of which the beginning is the addition of the molonyl-ACP (C 3) molecule - reaction (5) to the carboxyl end of the growing fatty acid chain. This cleaves the carboxyl group in the form of CO 2 (C 1). This process can be represented as follows:
С 3 + С 2 ® С 4 + С 1 - 1 cycle
С 4 + С 3 ® С 6 + С 1 - 2 cycle
С 6 + С 3 ® С 8 + С 1-3 cycle
С 8 + С 3 ® С 10 + С 1 - 4 cycle
С 10 + С 3 ® С 12 + С 1 - 5 cycle
С 12 + С 3 ® С 14 + С 1 - 6 cycle
С 14 + С 3 ® С 16 + С 1 - 7 cycle
Not only higher saturated fatty acids can be synthesized, but also unsaturated ones. Monounsaturated fatty acids are formed from saturated ones as a result of oxidation (desaturation) catalyzed by acyl-CoA oxygenase. Unlike plant tissues, animal tissues have a very limited ability to convert saturated fatty acids into unsaturated ones. It was found that the two most common monounsaturated fatty acids - palmitooleic and oleic - are synthesized from palmitic and stearic acids. In the body of mammals, including humans, linoleic (C 18: 2) and linolenic (C 18: 3) acids cannot be formed, for example, from stearic acid (C 18: 0). These acids are classified as essential fatty acids. Essential fatty acids also include arachidic acid (C 20: 4).
Along with desaturation of fatty acids (formation of double bonds), their elongation (elongation) also occurs. Moreover, both of these processes can be combined and repeated. Elongation of the fatty acid chain occurs by sequential addition of bicarbon fragments to the corresponding acyl-CoA with the participation of malonyl-CoA and NADPH + H +.
Figure 14 shows the pathways for the conversion of palmitic acid in desaturation and elongation reactions.
Figure 14 - Scheme of the conversion of saturated fatty acids
into unsaturated
The synthesis of any fatty acid is completed by the cleavage of HS-ACP from acyl-ACP under the influence of the deacylase enzyme. For example:
The resulting acyl-CoA is the active form of the fatty acid.
Since the ability of animals and humans to store polysaccharides is rather limited, glucose, obtained in quantities that exceed the immediate energy requirements and "storage capacity" of the body, can be a "building material" for the synthesis of fatty acids and glycerol. In turn, fatty acids, with the participation of glycerol, are converted into triglycerides, which are deposited in adipose tissues.
The biosynthesis of cholesterol and other sterols is also an important process. Although in quantitative terms, the pathway of cholesterol synthesis is not so important, it is of great importance due to the fact that numerous biologically active steroids are formed from cholesterol in the body.
Synthesis of higher fatty acids in the body
At present, the mechanism of the biosynthesis of fatty acids in the body of animals and humans, as well as the enzyme systems that catalyze this process, have been sufficiently studied. The synthesis of fatty acids in tissues takes place in the cytoplasm of the cell. In mitochondria, on the other hand, the lengthening of the existing chains of fatty acids 1 occurs.
1 Experiments in vitro have shown that isolated mitochondria have a negligible ability to incorporate labeled acetic acid into long-chain fatty acids. For example, it was found that palmitic acid is synthesized in the cytoplasm of liver cells, and in the mitochondria of liver cells on the basis of palmitic acid cells already synthesized in the cytoplasm or on the basis of fatty acids of exogenous origin, i.e., those received from the intestine, fatty acids containing 18, 20 and 22 carbon atoms. In this case, the reactions of synthesis of fatty acids in mitochondria are essentially reverse reactions of oxidation of fatty acids.
The extramitochondrial synthesis (basic, main) of fatty acids in its mechanism differs sharply from the process of their oxidation. The building block for the synthesis of fatty acids in the cytoplasm of the cell is acetyl-CoA, which is mainly derived from the mitochondrial acetyl-CoA. It has also been established that the presence of carbon dioxide or bicarbonate ion in the cytoplasm is important for the synthesis of fatty acids. In addition, it was found that citrate stimulates the synthesis of fatty acids in the cytoplasm of the cell. It is known that acetyl-CoA formed in mitochondria during oxidative decarboxylation cannot diffuse into the cytoplasm of the cell, because the mitochondrial membrane is impermeable to this substrate. It was shown that mitochondrial acetyl-CoA interacts with oxaloacetate, resulting in the formation of citrate, which freely penetrates into the cytoplasm of the cell, where it is degraded to acetyl-CoA and oxaloacetate:
Therefore, in this case, citrate acts as a carrier of the acetyl radical.
There is another way of transfer of intramitochondrial acetyl-CoA into the cytoplasm of the cell. This is the carnitine pathway. It was mentioned above that carnitine plays the role of a carrier of acyl groups from the cytoplasm to mitochondria during the oxidation of fatty acids. Apparently, it can perform this role in the reverse process, i.e., in the transfer of acyl radicals, including the acetyl radical, from mitochondria into the cytoplasm of the cell. However, when it comes to the synthesis of fatty acids, this pathway for the transfer of acetyl-CoA is not the main one.
The most important step in understanding the process of fatty acid synthesis was the discovery of the enzyme acetyl-CoA carboxylase. This complex biotin-containing enzyme catalyzes the ATP-dependent synthesis of malonyl-CoA (HOOC-CH 2 -CO-S-CoA) from acetyl-CoA and CO 2.
This reaction takes place in two stages:
It was found that citrate acts as an activator of the acetyl-CoA-carboxylase reaction.
Malonyl-CoA is the first specific product of fatty acid biosynthesis. In the presence of an appropriate enzymatic system, malonyl-CoA (which in turn is formed from acetyl-CoA) is rapidly converted to fatty acids.
The enzyme system that synthesizes higher fatty acids consists of several enzymes that are linked in a certain way.
Currently, the process of synthesis of fatty acids has been studied in detail in E. coli and some other microorganisms. A multi-enzyme complex called fatty acid synthetase, in E. coli, consists of seven enzymes associated with a so-called acyl-transfer protein (ACP). This protein is relatively thermostable, has free HS-rpynny and is involved in the synthesis of higher fatty acids at almost all its stages. The relative molecular weight of APB is about 10,000 daltons.
Below is the sequence of reactions that occur during the synthesis of fatty acids:
Then the cycle of reactions is repeated. Suppose that palmitic acid (C 16) is being synthesized; in this case, the formation of butyryl-ACP ends only in the first of seven cycles, in each of which the beginning is the attachment of the malonyl-ACP molecule to the carboxyl end of the growing fatty acid chain. This cleaves off the HS-ACP molecule and the distal carboxyl group of malonyl-ACP in the form of CO 2. For example, butyryl-APB formed in the first cycle interacts with malonyl-APB:
The synthesis of fatty acids ends with the cleavage of HS-ACP from acyl-ACP under the influence of the deacylase enzyme, for example:
The overall equation for the synthesis of palmitic acid can be written as follows:
Or, given that the formation of one molecule of malonyl-CoA from acetyl-CoA requires one molecule of ATP and one molecule of CO 2, the total equation can be represented as follows:
The main stages of fatty acid biosynthesis can be represented in the form of a diagram.
Compared with β-oxidation, the biosynthesis of fatty acids has a number of characteristic features:
- the synthesis of fatty acids is mainly carried out in the cytoplasm of the cell, and oxidation is carried out in the mitochondria;
- participation in the biosynthesis of fatty acids malonyl-CoA, which is formed by binding CO 2 (in the presence of a biotin enzyme and ATP) with acetyl-CoA;
- at all stages of the synthesis of fatty acids, an acyl transfer protein (HS-APB) is involved;
- the need for the synthesis of fatty acids of the coenzyme NADPH 2. The latter in the body is formed partly (by 50%) in the reactions of the pentose cycle (hexose-monophosphate "shunt"), partly as a result of the reduction of NADP with malate (malic acid + NADP-pyruvic acid + CO 2 + NADPH 2);
- the restoration of the double bond in the enoyl-ACP-reductase reaction occurs with the participation of NADPH 2 and an enzyme, the prosthetic group of which is a flavin mononucleotide (FMN);
- in the process of synthesis of fatty acids, hydroxy derivatives are formed, related in their configuration to the D-series of fatty acids, and during the oxidation of fatty acids - hydroxy derivatives of the L-series.
Formation of unsaturated fatty acids
In mammalian tissues, unsaturated fatty acids are present, which can be attributed to four families, differing in the length of the aliphatic chain between the terminal methyl group and the nearest double bond:
It has been established that the two most common monounsaturated fatty acids - palmitooleic and oleic - are synthesized from palmitic and stearic acids. The double bond in the molecule of these acids is introduced into the microsomes of liver cells and adipose tissue with the participation of specific oxygenase and molecular oxygen. In this reaction, one oxygen molecule is used as an acceptor of two pairs of electrons, one pair of which belongs to the substrate (Acyl-CoA), and the other to NADPH 2:
At the same time, the tissues of humans and a number of animals are unable to synthesize linoleic and linolenic acids, but must receive them with food (the synthesis of these acids is carried out by plants). In this regard, linoleic and linolenic acids, containing respectively two and three double bonds, are called essential fatty acids.
All other polyunsaturated acids found in mammals are formed from four precursors (palmitooleinoid, oleic, linoleic and linolenic kyolot) by further chain lengthening and / or the introduction of new double bonds. This process takes place with the participation of mitochondrial and microsomal enzymes. For example, the synthesis of arachidonic acid occurs according to the following scheme:
The biological role of polyunsaturated fatty acids has been largely clarified in connection with the discovery of a new class of physiologically active compounds - prostaglandins.
Triglyceride biosynthesis
There is reason to believe that the rate of biosynthesis of fatty acids is largely determined by the rate of formation of triglycerides and phospholipids, because free fatty acids are present in tissues and blood plasma in small amounts and do not normally accumulate.
The synthesis of triglycerides occurs from glycerol and fatty acids (mainly stearic, palmitic and oleic). The pathway of triglyceride biosynthesis in tissues proceeds through the formation of glycerol-3-phosphate as an intermediate. In the kidneys, as well as in the intestinal wall, where the activity of the enzyme glycerol kinase is high, glycerol is phosphorylated by ATP to form glycerol-3-phosphate:
In adipose tissue and muscles, due to the very low activity of glycerol kinase, the formation of glycerol-3-phosphate is mainly associated with glycolysis or glycogenolysis 1. 1 In cases where the glucose content in the adipose tissue is low (for example, during fasting), only a small amount of glycerol-3-phosphate is formed and the free fatty acids released during lipolysis cannot be used for the resynthesis of triglycerides, therefore fatty acids leave the adipose tissue ... On the contrary, the activation of glycolysis in adipose tissue promotes the accumulation of triglycerides in it, as well as the fatty acids included in their composition. It is known that in the process of glycolytic decomposition of glucose, dioxyacetone phosphate is formed. The latter, in the presence of cytoplasmic NAD-dependent glycerol phosphate dehydrogenase, is capable of converting into glycerol-3-phosphate:
In the liver, both pathways for the formation of glycerol-3-phosphate are observed.
Formed, in one way or another, glycerol-3-phosphate is acylated by two molecules of the CoA-derivative of a fatty acid (ie, "active" forms of a fatty acid) 2. 2 In some microorganisms, for example, in E. coli, the donor of the acyl group is not CoA-proxy, but ACP-derivatives of fatty acids. As a result, phosphatidic acid is formed:
Note that although phosphatidic acid is present in cells in extremely small amounts, it is a very important intermediate product common to the biosynthesis of triglycerides and glycerophospholipids (see diagram).
If triglycerides are being synthesized, then phosphatidic acid is dephosphorylated using a specific phosphatase (phosphatidate phosphatase) and 1,2-diglyceride is formed:
The biosynthesis of triglycerides is completed by the esterification of the resulting 1,2-diglyceride with a third acyl-CoA molecule:
Biosynthesis of glycerophospholipids
The synthesis of the most important glycerophospholipids is localized mainly in the endoplasmic reticulum of the cell. First, phosphatidic acid, as a result of a reversible reaction with cytidine triphosphate (CTP), is converted into cytidine diphosphate diglyceride (CDP-diglyceride):
Then, in subsequent reactions, each of which is catalyzed by a corresponding enzyme, cytidine monophosphate is displaced from the CDP-diglyceride molecule by one of two compounds - serine or inositol, forming phosphatidylserine or phosphatidylinositol, or 3-phosphatidyl-glycerol-1-phosphate. As an example, we give the formation of phosphatidylserine:
In turn, phosphatidylserine can be decarboxylated to form phosphatidylethanolamine:
Phosphatidl ethanolamine is a precursor of phosphatidylcholine. As a result of the sequential transfer of three methyl groups from three molecules of S-adenosylmethionine (a donor of methyl groups) to the amino group of the ethanolamine residue, phosphatidylcholine is formed:
There is another way for the synthesis of phosphatidylethanolamine and phosphatidylcholine in animal cells. This pathway also uses CTP as a carrier, but not phosphatidic acid, but phosphorylcholine or phosphorylethanolamine (scheme).
Cholesterol biosynthesis
Back in the 60s of this century, Bloch et al. in experiments using acetate labeled with 14 C at the methyl and carboxyl groups, he showed that both carbon atoms of acetic acid are included in liver cholesterol in approximately equal amounts. In addition, it has been shown that all of the carbon atoms of cholesterol are derived from acetate.
Later, thanks to the works of Linen, Redney, Polyak, Kornforth, A. N. Klimov and other researchers, the main details of the enzymatic synthesis of cholesterol, numbering more than 35 enzymatic reactions, were clarified. In the synthesis of cholesterol, three main stages can be distinguished: the first is the conversion of active acetate to mevalonic acid, the second is the formation of squalene from mevalonic acid, and the third is the cyclization of squalene to cholesterol.
First, consider the step of converting active acetate to mevalonic acid. The initial stage in the synthesis of mevalonic acid from acetyl-CoA is the formation of acetoacetyl-CoA through a reversible thiolase reaction:
Then the subsequent condensation of acetoacetyl-CoA with the third molecule of acetyl-CoA with the participation of hydroxymethylglutaryl-CoA synthase (HMG-CoA synthase) gives the formation of β-hydroxy-β-methylglutaryl-CoA:
Note that we have already considered these first stages of the synthesis of mevalonic acid when we talked about the formation of ketone bodies. Further, β-hydroxy-β-methylglutaryl-CoA under the influence of NADP-dependent hydroxymethylglutaryl-CoA reductase (HMG-CoA reductase) as a result of the reduction of one of the carboxyl groups and the elimination of HS-KoA is converted into mevalonic acid:
The HMG-CoA reductase reaction is the first practically irreversible reaction in the cholesterol biosynthesis chain and it proceeds with a significant loss of free energy (about 33.6 kJ). It was found that this reaction limits the rate of cholesterol biosynthesis.
Along with the classical biosynthesis pathway for mevalonic acid, there is a second pathway, in which β-hydroxy-β-methylglutaryl-CoA is not formed as an intermediate substrate, but β-hydroxy-β-methylglutarnl-S-ACP. The reactions of this pathway are apparently identical to the initial stages of fatty acid biosynthesis up to the formation of acetoacetyl-S-ACP. Acetyl-CoA-carboxylase, an enzyme that converts acetyl-CoA into malonyl-CoA, takes part in the formation of mevalonic acid by this pathway. The optimal ratio of malonyl-CoA and acetyl-CoA for the synthesis of mevalonic acid: two molecules of acetyl-CoA per one molecule of malonyl-CoA.
The participation of malonyl-CoA, the main substrate of fatty acid biosynthesis, in the formation of mevalonic acid and various polyisoprenoids has been shown for a number of biological systems: pigeon and rat liver, rabbit mammary gland, and acellular yeast extracts. This pathway of biosynthesis of mevalonic acid is observed mainly in the cytoplasm of liver cells. In this case, hydroxymethylglutaryl-CoA reductase, found in the soluble fraction of rat liver and not identical to the microsomal enzyme in terms of a number of kinetic and regulatory properties, plays a significant role in the formation of mevalonate. It is known that microsomal hydroxymethylglutaryl-CoA reductase is the main link in the regulation of the pathway of mevalonic acid biosynthesis from acetyl-CoA with the participation of acetoacetyl-CoA-thiolase and HMG-CoA synthase. Regulation of the second pathway of mevalonic acid biosynthesis under a number of influences (fasting, feeding with cholesterol, administration of a surfactant - newt WR-1339) differs from the regulation of the first pathway, in which microsomal reductase is involved. These data indicate the existence of two autonomous systems for the biosynthesis of mevalonic acid. The physiological role of the second pathway has not been fully studied. It is believed that it is of certain importance not only for the synthesis of non-steroidal substances, such as the side chain of ubiquinone and the unique base N 6 (Δ 2 -isopentyl) -adenosine of some tRNAs, but also for the biosynthesis of steroids (A.N. Klimov, E D. Polyakova).
In the second stage of the cholesterol sitesis, mevalonic acid is converted to squalene. The second stage reactions begin with the phosphorylation of mevalonic acid with ATP. As a result, a 5 "-pyrophosphoric ester is formed, and then a 5" -pyrophosphoric ester of mevalonic acid:
5 "-pyrophosphomevalonic acid, as a result of the subsequent phosphorylation of the tertiary hydroxyl group, forms an unstable intermediate product - 3" -phospho-5 "-pyrophosphomevalonic acid, which, decarboxylating and losing phosphoric acid, is converted to isopentenyl pyrophosphate. The latter is isomerized to dimethylallylpyrophosphate.
Then, these two isomeric isopentenyl pyrophosphates (dimethylallyl pyrophosphate and isopentenyl pyrophosphate) condense to release pyrophosphate and form geranyl pyrophosphate. Isopentenyl pyrophosphate rejoins geranyl pyrophosphate, resulting in farnesyl pyrophosphate.
Synthesis of palmitic acid (C16) from Acetyl-CoA.
1) It flows in the cytoplasm of liver cells and adipose tissue.
2) Value: for the synthesis of fats and phospholipids.
3) It proceeds after eating (during the absorption period).
4) Formed from acetyl-CoA obtained from glucose (glycolysis → OPVA → Acetyl-CoA).
5) In the process, 4 reactions are sequentially repeated:
condensation → recovery → dehydration → recovery.
At the end of each LCD cycle lengthens by 2 carbon atoms.
Donor 2C - malonil-CoA.
6) NADPH + H + takes part in two reduction reactions (50% comes from PPP, 50% from MALIK enzyme).
7) Only the first reaction proceeds directly in the cytoplasm (regulatory).
The remaining 4 are cyclic - on a special palmitate synthase complex (synthesis of only palmitic acid)
8) A regulatory enzyme functions in the cytoplasm - Acetyl-CoA-carboxylase (ATP, vit. H, biotin, IV class).
The structure of the palmitate synthase complex
Palmitate synthase is an enzyme consisting of 2 subunits.
Each consists of one PPC with 7 active centers.
Each active center catalyzes its own reaction.
Each PPC contains an acyl-transfer protein (ACP), on which the synthesis takes place (contains phosphopantetonate).
Each subunit has an HS group. In one, the HS-group belongs to cysteine, in the other to phosphopantothenic acid.
Mechanism
1) Acetyl-Coa obtained from carbohydrates cannot enter the cytoplasm, where FA synthesis takes place. It comes out through the first reaction of the TCA - the formation of citrate.
2) In the cytoplasm, citrate breaks down into Acetyl-Coa and oxaloacetate.
3) Oxaloacetate → malate (CTA reaction in the opposite direction).
4) Malate → pyruvate, which is used in ODPVK.
5) Acetyl-CoA → FA synthesis.
6) Acetyl-CoA under the action of acetyl-CoA-carboxylase is converted into malonyl-CoA.
Activation of the enzyme acetyl-CoA carboxylase:
a) by enhancing the synthesis of subunits under the action of insulin - three tetramers are synthesized separately
b) under the action of citrate, three tetramers combine, and the enzyme is activated
c) during fasting, glucagon inhibits the enzyme (by phosphorylation), fat synthesis does not occur
7) one acetyl CoA from the cytoplasm is transferred to the HS-group (from cysteine) of palmitate synthase; one malonyl-CoA per HS-group of the second subunit. Further on palmitate synthase occur:
8) their condensation (acetyl CoA and malonyl-CoA)
9) recovery (donor - NADPH + H + from PPP)
10) dehydration
11) recovery (donor - NADPH + H + from MALIK-enzyme).
As a result, the acyl radical increases by 2 carbon atoms.
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Mobilization of fats
During fasting or prolonged physical activity, glucagon or adrenaline is released. They activate TAG lipase in adipose tissue, which is located in adipocytes and is called tissue lipase(hormone sensitive). It breaks down fats in adipose tissue into glycerol and fatty acids. Glycerol goes to the liver for gluconeogenesis. FAs enter the bloodstream, bind with albumin and enter organs and tissues, are used as a source of energy (by all organs, besides the brain which uses glucose and ketone bodies during fasting or prolonged exercise).
For the heart muscle, fatty acids are the main source of energy.
β-oxidation
β-oxidation- the process of splitting fatty acids in order to extract energy.
1) Specific pathway of FA catabolism to acetyl-CoA.
2) It flows in the mitochondria.
3) Includes 4 repetitive reactions (i.e. conditionally cyclic):
oxidation → hydration → oxidation → cleavage.
4) At the end of each cycle, the FA is shortened by 2 carbon atoms in the form of acetyl-CoA (entering the CTC).
5) 1 and 3 reactions - oxidation reactions, associated with CPE.
6) Vit. B 2 - coenzyme FAD, vit. PP - NAD, pantothenic acid - HS-KoA.
Mechanism of FA transfer from cytoplasm to mitochondria.
1. FAs must be activated before entering the mitochondria.
Only activated FA = acyl-CoA can be transported across the lipid double membrane.
The carrier is L-carnitine.
The regulatory enzyme of β-oxidation is carnitine acyltransferase-I (KAT-I).
2. CAT-I transfers fatty acids to the intermembrane space.
3. Under the action of CAT-I, acyl-CoA is transferred to the L-carnitine transporter.
Acylcarnitine is formed.
4. With the help of a translocase built into the inner membrane, acylcarnitine is transported into the mitochondria.
5. In the matrix, under the action of CAT-II, FA is cleaved from carnitine and enters into β-oxidation.
Carnitine returns back to the intermembrane space.
Β-oxidation reactions
1. Oxidation: FA is oxidized with the participation of FAD (enzyme acyl-CoA-DH) → enoyl.
FAD enters the CPE (p / o = 2)
2. Hydration: enoyl → β-hydroxyacyl-CoA (enzyme enoyl hydratase)
3. Oxidation: β-hydroxyacyl-CoA → β-ketoacyl-CoA (with the participation of NAD, which enters the CPE and has p / o = 3).
4. Cleavage: β-ketoacyl-CoA → acetyl-CoA (thiolase enzyme, with the participation of HS-KoA).
Acetyl-CoA → CTA → 12 ATP.
Acyl-CoA (C-2) → next β-oxidation cycle.
Energy calculation in β-oxidation
For example, meristic acid (14C).
We calculate how much acetyl-CoA the fatty acid decomposes
½ n = 7 → TCA (12ATP) → 84 ATP.
We count how many cycles they decompose
(1/2 n) -1 = 6.5 (2 ATP in 1 reaction and 3 ATP in 3 reactions) = 30 ATP
· Subtract 1 ATP spent on the activation of fatty acids in the cytoplasm.
Total - 113 ATP.
Synthesis of ketone bodies
Almost all of the acetyl-CoA enters the CTK. A small part is used for the synthesis of ketone bodies = acetone bodies.
Ketone bodies- acetoacetate, β-hydroxybutyrate, acetone (for pathology).
The normal concentration is 0.03-0.05 mmol / l.
Are synthesized only in the liver from acetyl-CoA obtained by β-oxidation.
Used as a source of energy by all organs except the liver (no enzyme).
With prolonged fasting or diabetes mellitus, the concentration of ketone bodies can increase tenfold, because under these conditions, liquid crystals are the main source of energy. Under these conditions, intense β-oxidation proceeds, and all acetyl-CoA does not have time to be utilized in the CTC, because:
Lack of oxaloacetate (it is used in gluconeogenesis)
· As a result of β-oxidation, a lot of NADH + H + is formed (in 3 reactions), which inhibits isocitrate-DH.
Consequently, acetyl-CoA is used for the synthesis of ketone bodies.
Because ketone bodies are acids, they cause a shift in acid-base balance. Acidosis occurs (due to ketonemia).
They do not have time to be disposed of and appear in the urine as a pathological component → keturia... Also, there is a smell of acetone from the mouth. This state is called ketosis.
Cholesterol metabolism
Cholesterol(Xc) is a monohydric alcohol based on the cyclopentane perhydrophenanthrene ring.
27 carbon atoms.
The normal concentration of cholesterol is 3.6-6.4 mmol / l, no higher than 5 is allowed.
To build membranes (phospholipids: Xc = 1: 1)
Synthesis of gallstones
Synthesis of steroid hormones (cortisol, progesterone, aldosterone, calcitriol, estrogen)
· In the skin under the influence of UV it is used for the synthesis of vitamin D3 - cholecalciferol.
The body contains about 140 g of cholesterol (mainly in the liver and brain).
The daily requirement is 0.5-1 g.
Contained only in animal products (eggs, butter, cheese, liver).
Xc is not used as a source of energy, because its ring is not cleaved to CO 2 and H 2 O and ATP is not released (no enzyme).
Excess Chs is not excreted, not deposited, deposited in the wall of large blood vessels in the form of plaques.
The body synthesizes 0.5-1 g of Chs. The more it is consumed with food, the less it is synthesized in the body (normal).
Xc in the body is synthesized in the liver (80%), intestines (10%), skin (5%), adrenal glands, gonads.
Even vegetarians can have high cholesterol levels. only carbohydrates are needed for its synthesis.
Cholesterol biosynthesis
It proceeds in 3 stages:
1) in the cytoplasm - before the formation of mevalonic acid (similar to the synthesis of ketone bodies)
2) in EPR - to squalene
3) in EPR - to cholesterol
About 100 reactions.
The regulatory enzyme is β-hydroxymethylglutaryl-CoA reductase (HMG reductase). Cholesterol-lowering statins inhibit this enzyme.)
Regulation of HMG reductase:
a) Inhibited by the principle of negative feedback by excess dietary cholesterol
b) Enzyme synthesis (estrogen) may increase or decrease (cholesterol and gallstones)
c) The enzyme is activated by insulin by dephosphorylation
d) If there is a lot of enzyme, then the excess can be cleaved by proteolysis
Cholesterol is synthesized from acetyl-CoA, derived from carbohydrates(glycolysis → ODPVK).
The resulting cholesterol in the liver is packed together with fat in VLDL unresolved. VLDL has an apoprotein B100, enters the bloodstream and, after the attachment of apoproteins C-II and E, turns into mature VLDL, which enters the LP-lipase. LDL lipase removes fats from VLDL (50%), leaving LDL, which consists of 50-70% cholesterol esters.
Supplies cholesterol to all organs and tissues
· In cells there are receptors in B100, by which they recognize LDL and absorb it. Cells regulate the supply of cholesterol by increasing or decreasing the number of B100 receptors.
In diabetes mellitus, B100 glycosylation (glucose attachment) can occur. Consequently, the cells do not recognize LDL and hypercholesterolemia occurs.
LDL can penetrate the blood vessels (atherogenic particle).
More than 50% of LDL is returned to the liver, where cholesterol is used to synthesize gallstones and inhibit its own cholesterol synthesis.
There is a defense mechanism against hypercholesterolemia:
Regulation of the synthesis of own cholesterol according to the principle of negative feedback
Cells regulate the flow of cholesterol by increasing or decreasing the number of B100 receptors
Functioning of HDL
HDL is synthesized in the liver. It is disc-shaped and contains little cholesterol.
HDL functions:
Removes excess cholesterol from cells and other lipoproteins
Supplies C-II and E to other lipoproteins
Mechanism of HDL functioning:
HDL has apoprotein A1 and LCAT (the enzyme lecithin cholesterol acyltransferase).
HDL is released into the bloodstream, and LDL approaches it.
According to A1 LDL, it is recognized that they have a lot of cholesterol, and they activate LHAT.
LCAT cleaves FAs from HDL phospholipids and transfers them to cholesterol. Esters of cholesterol are formed.
Cholesterol esters are hydrophobic, so they pass into the lipoprotein.
TOPIC 8
METHOD OF SUBSTANCES: PROTEIN EXCHANGE
Squirrels - These are high molecular weight compounds, consisting of α-amino acid residues, which are interconnected by peptide bonds.
Peptide bonds are located between the α-carboxyl group of one amino acid and the amino group of another, following it, the α-amino acid.
Functions of proteins (amino acids):
1) plastic (main function) - proteins of muscles, tissues, gems, carnitine, creatine, some hormones and enzymes are synthesized from amino acids;
2) energy
a) in case of excess intake with food (> 100 g)
b) with prolonged fasting
Peculiarity:
Amino acids, unlike fats and carbohydrates, not deposited .
The amount of free amino acids in the body is about 35 g.
Sources of protein for the body:
Food proteins (main source)
Proteins of tissues
· Synthesized from carbohydrates.
Nitrogen balance
Because 95% of all nitrogen in the body belongs to amino acids, then their exchange can be judged by nitrogen balance - the ratio of incoming nitrogen and excreted in the urine.
ü Positive - it is released less than it comes in (in children, pregnant women, during the recovery period after an illness);
ü Negative - more is released than it comes in (old age, period of prolonged illness);
ü Nitrogen balance - in healthy people.
Because proteins of food - the main source of amino acids, then they say about “ usefulness of protein nutrition ».
All amino acids are divided into:
Replaceable (8) - Ala, Gli, Ser, Pro, Glu, Gln, Asp, Asn;
· Partially replaceable (2) - Arg, Gis (synthesized slowly);
Conditionally replaceable (2) - Cis, Tyr (can be synthesized on condition receipts of irreplaceable ones - Met → Cis, Fen → Tyr);
Irreplaceable (8) - Val, Ile, Lei, Liz, Met, Tre, Hairdryer, TPF.
In this regard, proteins are allocated:
ü Complete - contain all essential amino acids
ü Defective - do not contain Met and TPF.
Digestion of proteins
Peculiarities:
1) Proteins are digested in the stomach, small intestine
2) Enzymes - peptidases (cleave peptide bonds):
a) exopeptidase - along the edges from the C-N-ends
b) endopeptidase - inside the protein
3) Enzymes of the stomach and pancreas are produced in an inactive form - enzymes(as they would digest their own tissues)
4) Enzymes are activated by partial proteolysis (cleavage of part of the PPC)
5) Some amino acids undergo rotting in the large intestine
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1. They are not digested in the oral cavity.
2. In the stomach, proteins are affected by pepsin(endopeptidase). It cleaves the bonds formed by the amino groups of aromatic amino acids (Tyr, Phen, TPF).
Pepsin is produced by the main cells as an inactive pepsinogen.
The parietal cells produce hydrochloric acid.
HCl functions:
ü Creates an optimum pH for pepsin (1.5 - 2.0)
ü Activates pepsinogen
ü Denatures proteins (facilitates enzyme action)
ü Bactericidal action
Pepsinogen activation
Pepsinogen under the action of HCl is converted into active pepsin by cleavage of 42 amino acids slowly. Then active pepsin rapidly activates pepsinogen ( autocatalytically).
Thus, in the stomach, proteins are broken down into short peptides that enter the intestines.
3. In the intestine, pancreatic enzymes act on peptides.
Activation of trypsinogen, chymotrypsinogen, proelastase, procarboxypeptidase
In the intestine, under the action of enteropeptidase, it is activated trypsinogen... Then activated from it trypsin activates all other enzymes by partial proteolysis (chymotrypsinogen → chymotrypsin, proelastase → elastase, procarboxypeptidase → carboxypeptidase).
Trypsin cleaves the bonds formed by the carboxyl groups Lys or Arg.
Chymotrypsin- between the carboxyl groups of aromatic amino acids.
Elastase- bonds formed by carboxyl groups Ala or Gly.
Carboxypeptidase cleaves carboxyl bonds from the C-terminus.
Thus, short di-, tripeptides are formed in the intestine.
4. Under the action of intestinal enzymes, they are broken down to free amino acids.
Enzymes - di-, tri-, aminopeptidase... They are not species specific.
The formed free amino acids are absorbed by the secondary active transport with Na + (against the concentration gradient).
5. Some amino acids rot.
Putrefaction - the enzymatic process of the breakdown of amino acids to low-toxic products with the release of gases (NH 3, CH 4, CO 2, mercaptan).
Meaning: to maintain the vital activity of the intestinal microflora (during rotting Tyr forms toxic products phenol and cresol, TPF - indole and skatole). Toxic products enter the liver and are rendered harmless.
Amino acid catabolism
The main path is deamination - enzymatic process of cleavage of the amino group in the form of ammonia and the formation of nitrogen-free keto acid.
Oxidative deamination
Non-oxidative (Ser, Tre)
Intramolecular (His)
Hydrolytic
Oxidative deamination (basic)
A) Direct - only for Glu, tk. for all others, enzymes are inactive.
It proceeds in 2 stages:
1) Enzymatic
2) Spontaneous
As a result, ammonia and α-ketoglutarate are formed.
Transamination functions:
ü Because the reaction is reversible, serves for the synthesis of nonessential amino acids;
ü The initial stage of catabolism (transamination is not catabolism, since the amount of amino acids does not change);
ü For the redistribution of nitrogen in the body;
ü Participates in the malate-aspartate shuttle mechanism of hydrogen transfer in glycolysis (6 reaction).
To determine the activity of ALT and AST in the clinic for the diagnosis of heart and liver diseases, the de Ritis coefficient is measured:
At 0.6 - hepatitis,
1 - cirrhosis,
10 - myocardial infarction.
Decarboxylation amino acids - an enzymatic process of cleavage of the carboxyl group in the form of CO 2 from amino acids.
As a result, biologically active substances are formed - biogenic amines.
Enzymes are decarboxylases.
Coenzyme - pyridoxal phosphate ← vit. AT 6.
After exerting an action, biogenic amines are rendered harmless in 2 ways:
1) Methylation (addition of CH 3; donor - SAM);
2) Oxidation with cleavage of the amino group in the form of NH 3 (enzyme MAO - monoamine oxidase).
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