What does the Krebs cycle affect? Krebs Cycle The Krebs cycle is a key stage in the respiration of all cells that use oxygen, the intersection of many metabolic pathways in the body

Krebs cycle

Tricarboxylic acid cycle (Krebs cycle, citrate cycle) - central part common path catabolism, a cyclic biochemical aerobic process during which the conversion of two- and three-carbon compounds formed as intermediate products in living organisms during the breakdown of carbohydrates, fats and proteins occurs into CO 2. In this case, the released hydrogen is sent to the tissue respiration chain, where it is further oxidized to water, directly participating in the synthesis of a universal energy source - ATP.

The Krebs cycle is a key stage in the respiration of all cells that use oxygen, the intersection of many metabolic pathways in the body. In addition to the significant energy role, the cycle is also assigned a significant plastic function, that is, it important source precursor molecules, from which, in the course of other biochemical transformations, compounds important for the life of the cell are synthesized, such as amino acids, carbohydrates, fatty acids, etc.

The cycle of transformation of citric acid in living cells was discovered and studied by the German biochemist Hans Krebs, for this work he (together with F. Lipmann) was awarded the Nobel Prize (1953).

Stages of the Krebs cycle

	Substrates	Products	Enzyme	Reaction type	Comment
1	Oxaloacetate + Acetyl-CoA+ H2O	Citrate + CoA-SH	Citrate synthase	Aldol condensation	limiting stage converts C4 oxaloacetate to C6
2	Citrate	cis-aconiat + H2O	aconitase	Dehydration	reversible isomerization
3	cis-aconiat + H2O	isocitrate		hydration
4	Isocitrate +	isocitrate dehydrogenase	Oxidation	NADH is formed (equivalent to 2.5 ATP)
5	Oxalosuccinate		α-ketoglutarate + CO2	decarboxylation	reversible stage C5 is formed
6	α-ketoglutarate + NAD++ CoA-SH	succinyl-CoA+ NADH+H++ CO2	alpha-ketoglutarate dehydrogenase	Oxidative decarboxylation	NADH is formed (equivalent to 2.5 ATP), regeneration of C 4 pathway (released by CoA)
7	succinyl-CoA+ GDP + Pi	succinate + CoA-SH+ GTP	succinyl coenzyme A synthetase	substrate phosphorylation	or ADP ->ATP, 1 ATP is formed
8	succinate + ubiquinone (Q)	fumarate + ubiquinol (QH 2)	succinate dehydrogenase	Oxidation	FAD is used as a prosthetic group (FAD->FADH 2 in the first stage of the reaction) in the enzyme, the equivalent of 1.5 ATP is formed
9	fumarate + H2O	L-malate	fumarase	H 2 O-addition (hydration)
10	L-malate + NAD+	oxaloacetate + NADH+H+	malate dehydrogenase	oxidation	NADH is formed (equivalent to 2.5 ATP)

The general equation for one revolution of the Krebs cycle is:

Acetyl-CoA → 2CO 2 + CoA + 8e −

Notes

Links

Wikimedia Foundation. 2010.

See what the “Krebs Cycle” is in other dictionaries:

- (citric and tricarboxylic acid cycle), a system of biochemical reactions through which most EUKARYOTIC organisms obtain their main energy as a result of the oxidation of food. Occurs in MITOCHONDRIA CELLS. Includes several chemical... ... Scientific and technical encyclopedic dictionary

Krebs cycle- The tricarboxylic acid cycle, a cycle of sequential reactions in the cells of aerobic organisms, as a result of which the synthesis of ATP molecules occurs Biotechnology topics EN Krebs cycle ... Technical Translator's Guide

Krebs cycle- - metabolic pathway leading to the complete destruction of acetyl CoA to the final products - CO2 and H2O ... Brief dictionary biochemical terms

Krebs cycle- trikarboksirūgščių ciklas statusas T sritis chemija apibrėžtis Baltymų, riebalų ir angliavandenių oksidacinio skaidymo organizme ciklas. atitikmenys: engl. citric acid cycle; Krebs cycle; tricarboxylic acid cycle rus. Krebs cycle; lemon cycle... ... Chemijos terminų aiškinamasis žodynas

Tricarboxylic acid (Krebs, citric acid) cycle The most important cyclic sequence of metabolic reactions in aerobic organisms (eu and prokaryotes), as a result of which a sequential... ... Molecular biology and genetics. Dictionary.

Same as tricarboxylic acid cycle... Natural science. Encyclopedic Dictionary

A complex cycle of reactions where enzymes act as catalysts; these reactions take place in the cells of all animals and consist in the decomposition of acetate in the presence of oxygen with the release of energy in the form of ATP (via the electron transfer chain) and... ... Medical terms

KREBS CYCLE, CITRIC ACID CYCLE- (citric acid cycle) a complex cycle of reactions where enzymes act as catalysts; these reactions take place in the cells of all animals and consist in the decomposition of acetate in the presence of oxygen with the release of energy in the form of ATP (via the transmission chain... ... Explanatory dictionary of medicine

KREBS CYCLE (tricarboxylic acid cycle- citric acid cycle) is a complex cyclic enzymatic process in which pyruvic acid is oxidized in the body to produce carbon dioxide, water and energy in the form of ATP; occupies a central position in common system… … Dictionary of botanical terms

Cycle ... Wikipedia

Krebs cycle also called tricarboxylic acid cycle, since they are formed in it as intermediate products. It is an enzymatic ring conveyor that “works” in the mitochondrial matrix.

The result of the Krebs cycle is the synthesis of a small amount of ATP and the formation of NAD H 2, which is then sent to the next stage - the respiratory chain (oxidative phosphorylation), located on the inner membrane of mitochondria.

The resulting pyruvic acid (pyruvate) enters the mitochondria, where it is ultimately completely oxidized, turning into carbon dioxide and water. This occurs first in the Krebs cycle, then during oxidative phosphorylation.

Before the Krebs cycle, pyruvate is decarboxylated and dehydrogenated. As a result of decarboxylation, a CO 2 molecule is eliminated; dehydrogenation is the elimination of hydrogen atoms. They connect to NAD.

As a result, acetic acid is formed from pyruvic acid, which is added to coenzyme A. It turns out acetyl coenzyme A(acetyl-CoA) – CH 3 CO~S-CoA containing a high-energy bond.

The conversion of pyruvate to acetyl-CoA is accomplished by a large enzymatic complex consisting of dozens of polypeptides associated with electron carriers.

The Krebs cycle begins with the hydrolysis of acetyl-CoA, which removes an acetyl group containing two carbon atoms. Next, the acetyl group is included in the tricarboxylic acid cycle.

An acetyl group attaches to oxaloacetic acid, which has four carbon atoms. As a result, citric acid, containing six carbon atoms. The energy for this reaction is supplied by the high-energy acetyl-CoA bond.

What follows is a chain of reactions in which the acetyl group bound in the Krebs cycle is dehydrogenated, releasing four pairs of hydrogen atoms, and decarboxylated to form two molecules of CO 2 . In this case, oxygen is used for oxidation, split off from two water molecules, not molecular. The process is called oxidativethdecarboxylationm. At the end of the cycle, oxaloacetic acid is regenerated.

Let's return to the citric acid stage. Its oxidation occurs through a series of enzymatic reactions in which isocitric, oxalosuccinic and other acids are formed. As a result of these reactions, at different stages of the cycle, three molecules of NAD and one FAD are reduced, GTP (guanosine triphosphate) is formed, containing a high-energy phosphate bond, the energy of which is subsequently used to phosphorylate ADP. As a result, an ATP molecule is formed.

Citric acid loses two carbon atoms to form two CO 2 molecules.

As a result of enzymatic reactions, citric acid is converted into oxaloacetic acid, which can again combine with acetyl-CoA. The cycle repeats.

In citric acid, the added acetyl-CoA residue burns to form carbon dioxide, hydrogen atoms and electrons. Hydrogen and electrons are transferred to NAD and FAD, which are acceptors for it.

The oxidation of one molecule of acetyl-CoA produces one molecule of ATP, four hydrogen atoms and two molecules of carbon dioxide. That is carbon dioxide released during aerobic respiration is formed during the Krebs cycle. In this case, molecular oxygen (O 2) is not used here; it is needed only at the stage of oxidative phosphorylation.

Hydrogen atoms are attached to NAD or FAD, in this form they then enter the respiratory chain.

One molecule of glucose produces two molecules of pyruvate and therefore two acetyl-CoA. Thus, for one molecule of glucose there are two turns of the tricarboxylic acid cycle. A total of two ATP molecules, four CO 2, and eight H atoms are formed.

It should be noted that not only glucose and the pyruvate formed from it enter the Krebs cycle. As a result of the breakdown of fats by the lipase enzyme, fatty acids are formed, the oxidation of which also leads to the formation of acetyl-CoA, the reduction of NAD, as well as FAD (flavin adenine dinucleotide).

If a cell is deficient in carbohydrates and fats, then amino acids may undergo oxidation. In this case, acetyl-CoA and organic acids are formed, which further participate in the Krebs cycle.

Thus, it does not matter what the primary source of energy was. In any case, acetyl-CoA is formed, which is a universal compound for cells.

Under anaerobic conditions, pyruvic acid (pyruvate) undergoes further transformations during alcoholic, lactic and other types of fermentations, while NADH is used to restore the final products of fermentation, regenerating into an oxidized form. The latter circumstance supports the process of glycolysis, which requires oxidized NAD +. In the presence of sufficient oxygen, pyruvate is completely oxidized to C0 2 and H 2 0 in a respiratory cycle called Krebs cycle or cycle of di- and tricarboxylic acids. All areas of this process are localized in the matrix or in the inner membrane of mitochondria.

Subsequence reactions in the Krebs cycle. The participation of organic acids in respiration has long attracted the attention of researchers. Back in 1910, the Swedish chemist T. Thunberg showed that animal tissues contain enzymes that can remove hydrogen from some organic acids (succinic, malic, citric). In 1935, A. Szent-Gyorgyi in Hungary established that adding to minced muscle tissue small quantities succinic, fumaric, malic or oxaloacetic acids sharply activates the absorption of oxygen by tissue.

Taking into account the data of Thunberg and Szent-Gyorgyi and based on his own experiments studying the interconversion of various organic acids and their effect on the respiration of the flight muscle of a pigeon, the English biochemist G. A. Krebs in 1937 proposed a diagram of the sequence of oxidation of di- and tricarboxylic acids to CO 2 through "citric acid cycle" Yes, the account of hydrogen removal. This cycle was named after him.

Directly in the cycle, pyruvate itself is oxidized, and its derivative, acetyl-CoA. Thus, the first step in the oxidative cleavage of PVK is the formation of active acetyl during oxidative decarboxylation. Oxidative decarboxylation of pyruvate is carried out with the participation of the pyruvate dehydrogenase multienzyme complex. It contains three enzymes and five coenzymes. The coenzymes are thiamine pyrophosphate (TPP), a phosphorylated derivative of vitamin B, lipoic acid, coenzyme A, FAD and NAD +. Pyruvate interacts with TPP (decarboxylase), during which CO 2 is split off and a hydroxyethyl derivative of TPP is formed (Fig. 4.2). The latter reacts with the oxidized form of lipoic acid. The disulfide bond of lipoic acid is broken and a redox reaction occurs: the hydroxyethyl group attached to one sulfur atom is oxidized to acetyl (this creates a high-energy thioester bond), and the other sulfur atom of lipoic acid is reduced. The resulting acetyl lipoic acid interacts with coenzyme A, acetyl-CoA and the reduced form of lipoic acid appear. The lipoic acid hydrogen is then transferred to FAD and then to NAD+. As a result of oxidative decarboxylation of pyruvate, acetyl-CoA, CO 2 and NADH are formed.

Further oxidation of acetyl-CoA occurs in a cyclic process. The Krebs cycle begins with the interaction of acetyl-CoA with the enol form of oxaloacetic acid. In this reaction, citric acid is formed under the action of the enzyme citrate synthase. The next step in the cycle involves two reactions and is catalyzed by the enzyme aconitase, or aconitate hydratase. In the first reaction, as a result of dehydration of citric acid, cis- aconite. In the second reaction, aconitate is hydrated and isocitric acid is synthesized. Isocitric acid, under the action of NAD- or NADP-dependent isocitrate dehydrogenase, is oxidized into an unstable compound - oxalosuccinic acid, which is immediately decarboxylated to form a-ketoglutaric acid (a-oxoglutaric acid).

α-Ketoglutarate, like pyruvate, undergoes oxidative decarboxylation. The a-ketoglutarate dehydrogenase multienzyme complex is similar to the pyruvate dehydrogenase complex discussed above. During the oxidative decarboxylation reaction of α-ketoglutarate, CO2 is released and NADH and succinyl-CoA are formed.

Like acetyl-CoA, succinyl-CoA is a high-energy thioester. However, if in the case of acetyl-CoA the energy of the thioester bond is spent on the synthesis of citric acid, the energy of succinyl-CoA can be transformed into the formation of the phosphate bond of ATP. With the participation of succinyl-CoA synthetase, succinic acid (succinate), ATP are formed from succinyl-CoA, ADP and H 3 P0 4, and the CoA molecule is regenerated. ATP is formed as a result of substrate phosphorylation.

At the next stage, succinic acid is oxidized to fumaric acid. The reaction is catalyzed by succinate dehydrogenase, the coenzyme of which is FAD. Fumaric acid under the action of fumarase or fumarate hydratase, adding H 2 0, is converted into malic acid (malate). And finally, at the last stage of the cycle, malic acid is oxidized to oxaloacetic acid by NAD-dependent malate dehydrogenase. PIKE, which spontaneously transforms into the enol form, reacts with another molecule of acetyl-CoA and the cycle repeats again.

It should be noted that most of the reactions of the cycle are reversible, but the course of the cycle as a whole is practically irreversible. The reason for this is that there are two highly exergonic reactions in the cycle - citrate synthase and succinyl-CoA synthetase.

During one revolution of the cycle, during the oxidation of pyruvate, three CO2 molecules are released, three H2O molecules are included, and five pairs of hydrogen atoms are removed. The role of H 2 O in the Krebs cycle confirms the correctness of Palladin’s equation, which postulated that respiration occurs with the participation of H 2 O, the oxygen of which is included in the oxidized substrate, and hydrogen is transferred to oxygen with the help of “respiratory pigments” (according to modern concepts - coenzymes dehydrogenases) .

It was noted above that the Krebs cycle was discovered in animal objects. Its existence in plants was first proven by the English researcher A. Chibnall (1939). Plant tissues contain all the acids involved in the cycle; all enzymes catalyzing the transformation of these acids have been discovered; It has been shown that malonate, an inhibitor of suncinate dehydrogenase, inhibits the oxidation of pyruvate and sharply reduces the absorption of 02 in respiration processes in plants. Most Krebs cycle enzymes

localized in the mitochondrial matrix; aconitase and succinate dehydrogenase are located in the inner membrane of the mitochondria.

Energy output of the Krebs cycle, its connection with nitrogen metabolism. Krebs cycle. plays an extremely important role in the metabolism of the plant organism. It serves as the final stage in the oxidation of not only carbohydrates, but also proteins, fats and other compounds. During the reactions of the cycle, the main amount of energy contained in the oxidized substrate is released, and most of this energy is not lost to the body, but is utilized during the formation of high-energy terminal phosphate bonds of ATP.

What is the energy output of the Krebs cycle? During the oxidation of pyruvate, 5 dehydrogenations take place, resulting in 3NADH, NADPH (in the case of isocitrate dehydrogenase) and FADH 2. The oxidation of each NADH (NADPH) molecule with the participation of components of the electron transport chain of mitochondria produces 3 ATP molecules, and the oxidation of FADH 2 - 2 ATP. Thus, with complete oxidation of pyruvate, 14 ATP molecules are formed. In addition, 1 ATP molecule is synthesized; in the Krebs cycle during substrate phosphorylation. Consequently, the oxidation of one pyruvate molecule can produce 15 ATP molecules. And since in the process of glycolysis two pyruvate molecules arise from a glucose molecule, their oxidation will produce 30 ATP molecules.

So, during the oxidation of glucose during respiration during the functioning of glycolysis and the Krebs cycle, a total of 38 ATP molecules are formed (8 ATP are associated with glycolysis). If we assume that the energy of the third ester and phosphate bond of ATP is 41.87 kJ/mol (10 kcal/mol), then the energy output of the glycolytic pathway of aerobic respiration is 1591 kJ/mol (380 kcal/mol).

Regulation of the Krebs cycle. Further use of acetyl-CoA formed from pyruvate depends on the energy state of the cell. When the energy requirement of the cell is low, respiratory control inhibits the work of the respiratory chain, and, consequently, the reactions of the TCA cycle and the formation of cycle intermediates, including oxaloacetate, which involves acetyl-CoA in the Krebs cycle. This results in greater use of acetyl-CoA in synthetic processes, which also consume energy.

A feature of the regulation of the TCA cycle is the dependence of all four dehydrogenases of the cycle (isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, succinate dehydrogenase, malate dehydrogenase) on the ratio /. The activity of citrate synthase is inhibited by a high concentration of ATP and its own product, citrate. Isocitrate dehydrogenase is inhibited by NADH and activated by citrate. α-Keto-glutarate dehydrogenase is suppressed by the reaction product, succinyl-CoA, and activated by adenylates. The oxidation of succinate by succinate dehydrogenase is inhibited by oxaloacetate and accelerated by ATP, ADP and reduced ubiquinone (QH 2). Finally, malate dehydrogenase is inhibited by oxaloacetate and, in a number of objects, by high levels of ATP. However, the extent to which the magnitude of the energy charge, or the level of adenine nucleotides, participates in the regulation of the activity of the Krebs cycle in plants is not fully understood.

The alternative pathway of electron transport in plant mitochondria may also play a regulatory role. Under conditions of high ATP content, when the activity of the main respiratory chain is reduced, the oxidation of substrates through an alternative oxidase (without ATP formation) continues, which maintains a low NADH/NAD + ratio and reduces ATP levels. All this allows the Krebs cycle to function.

The tricarboxylic acid cycle was first discovered by the English biochemist Krebs. He was the first to postulate the importance of this cycle for the complete combustion of pyruvate, the main source of which is the glycolytic conversion of carbohydrates. It was subsequently shown that the tricarboxylic acid cycle is a “focus” at which almost all metabolic pathways converge.

So, acetyl-CoA formed as a result of oxidative decarboxylation of pyruvate enters the Krebs cycle. This cycle consists of eight consecutive reactions (Fig. 91). The cycle begins with the condensation of acetyl-CoA with oxaloacetate and the formation of citric acid. ( As will be seen below, in the cycle it is not acetyl-CoA itself that undergoes oxidation, but a more complex compound - citric acid (tricarboxylic acid).)

Then citric acid (a six-carbon compound), through a series of dehydrogenations (removal of hydrogen) and decarboxylation (elimination of CO 2), loses two carbon atoms and again oxaloacetate (a four-carbon compound) appears in the Krebs cycle, i.e., as a result of a complete revolution of the cycle, the acetyl-CoA molecule burns to CO 2 and H 2 O, and the oxaloacetate molecule is regenerated. Below are all eight sequential reactions (stages) of the Krebs cycle.

In the first reaction, catalyzed by the enzyme citrate synthase, acetyl-CoA is condensed with oxaloacetate. As a result, citric acid is formed:

Apparently, in this reaction, citril-CoA bound to the enzyme is formed as an intermediate product. The latter is then spontaneously and irreversibly hydrolyzed to form citrate and HS-CoA.

In the second reaction of the cycle, the resulting citric acid undergoes dehydration to form cis-aconitic acid, which, by adding a water molecule, becomes isocitric acid. These reversible hydration-dehydration reactions are catalyzed by the enzyme aconitate hydratase:

In the third reaction, which appears to be the rate-limiting reaction of the Krebs cycle, isocitric acid is dehydrogenated in the presence of NAD-dependent isocitrate dehydrogenase:

(There are two types of isocitrate dehydrogenases in tissues: NAD- and NADP-dependent. It has been established that NAD-dependent isocitrate dehydrogenase plays the role of the main catalyst for the oxidation of isocitric acid in the Krebs cycle.)

During the isocitrate dehydrogenase reaction, isocitric acid is decarboxylated. NAD-dependent isocitrate dehydrogenase is an allosteric enzyme that requires ADP as a specific activator. In addition, the enzyme requires Mg 2+ or Mn 2+ ions to exhibit its activity.

In the fourth reaction, α-ketoglutaric acid is oxidatively decarboxylated to succinyl-CoA. The mechanism of this reaction is similar to the reaction of oxidative decarboxylation of pyruvate to acetyl-CoA. The α-ketoglutarate dehydrogenase complex is similar in structure to the pyruvate dehydrogenase complex. In both cases, five coenzymes take part in the reaction: TDP, lipoic acid amide, HS-CoA, FAD and NAD. In total, this reaction can be written as follows:

The fifth reaction is catalyzed by the enzyme succinyl-CoA synthetase. During this reaction, succinyl-CoA, with the participation of GDP and inorganic phosphate, is converted into succinic acid (succinate). At the same time, the formation of a high-energy phosphate bond of GTP1 occurs due to the high-energy thioester bond of succinyl-CoA:

(The resulting GTP then donates its terminal phosphate group to ADP, resulting in the formation of ATP. The formation of a high-energy nucleoside triphosphate during the succinyl-CoA synthetase reaction is an example of phosphorylation at the substrate level.)

In the sixth reaction, succinate is dehydrogenated to fumaric acid. The oxidation of succinate is catalyzed by succinate dehydrogenase, in the molecule of which the coenzyme FAD is covalently bound to the protein:

In the seventh reaction, the resulting fumaric acid is hydrated under the influence of the enzyme fumarate hydratase. The product of this reaction is malic acid (malate). It should be noted that fumarate hydratase is stereospecific - during this reaction L-malic acid is formed:

Finally, in the eighth reaction of the tricarboxylic acid cycle, under the influence of mitochondrial NAD-dependent malate dehydrogenase, L-malate is oxidized to oxaloacetate:

As you can see, in one turn of the cycle, consisting of eight enzymatic reactions, complete oxidation (“combustion”) of one molecule of acetyl-CoA occurs. For continuous operation of the cycle, a constant supply of acetyl-CoA into the system is necessary, and coenzymes (NAD and FAD), which have passed into a reduced state, must be oxidized again and again. This oxidation occurs in the electron transport system (or chain of respiratory enzymes) located in the mitochondria.

The energy released as a result of the oxidation of acetyl-CoA is largely concentrated in the high-energy phosphate bonds of ATP. Of the four pairs of hydrogen atoms, three pairs are transferred through NAD to the electron transport system; in this case, for each pair in the biological oxidation system, three ATP molecules are formed (in the process of conjugate oxidative phosphorylation), and therefore a total of nine ATP molecules. One pair of atoms enters the electron transport system through FAD, resulting in the formation of 2 ATP molecules. During the reactions of the Krebs cycle, 1 molecule of GTP is also synthesized, which is equivalent to 1 molecule of ATP. So, the oxidation of acetyl-CoA in the Krebs cycle produces 12 ATP molecules.

As already noted, 1 molecule of NADH 2 (3 molecules of ATP) is formed during the oxidative decarboxylation of pyruvate into acetyl-CoA. Since the breakdown of one molecule of glucose produces two molecules of pyruvate, when they are oxidized to 2 molecules of acetyl-CoA and the subsequent two turns of the tricarboxylic acid cycle, 30 molecules of ATP are synthesized (hence, the oxidation of one molecule of pyruvate to CO 2 and H 2 O produces 15 molecules ATP).

To this we must add 2 ATP molecules formed during aerobic glycolysis, and 4 ATP molecules synthesized through the oxidation of 2 molecules of extramitochondrial NADH 2, which are formed during the oxidation of 2 molecules of glyceraldehyde-3-phosphate in the dehydrogenase reaction. In total, we find that when 1 glucose molecule is broken down in tissues according to the equation: C 6 H 12 0 6 + 60 2 -> 6CO 2 + 6H 2 O, 36 ATP molecules are synthesized, which contributes to the accumulation of adenosine triphosphate in high-energy phosphate bonds 36 X 34.5 ~ 1240 kJ (or, according to other sources, 36 X 38 ~ 1430 kJ) free energy. In other words, of all the free energy released during aerobic oxidation of glucose (about 2840 kJ), up to 50% of it is accumulated in mitochondria in a form that can be used to perform various functions. physiological functions. There is no doubt that, energetically, the complete breakdown of glucose is more efficient process than glycolysis. It should be noted that the NADH 2 molecules formed during the conversion of glyceraldehyde-3-phosphate 2 subsequently, upon oxidation, produce not 6 ATP molecules, but only 4. The fact is that the molecules of extramitochondrial NADH 2 themselves are not able to penetrate through the membrane into the mitochondria. However, the electrons they donate can be included in the mitochondrial chain of biological oxidation using the so-called glycerophosphate shuttle mechanism (Fig. 92). As can be seen in the figure, cytoplasmic NADH 2 first reacts with cytoplasmic dihydroxyacetone phosphate to form glycerol 3-phosphate. The reaction is catalyzed by NAD-dependent cytoplasmic glycerol-3-phosphate dehydrogenase.

Acetyl-SCoA formed in the PVK dehydrogenase reaction then enters tricarboxylic acid cycle(TCA cycle, citric acid cycle, Krebs cycle). In addition to pyruvate, keto acids coming from catabolism are involved in the cycle amino acids or any other substances.

Tricarboxylic acid cycle

The cycle proceeds in mitochondrial matrix and represents oxidation molecules acetyl-SCoA in eight consecutive reactions.

In the first reaction they bind acetyl And oxaloacetate(oxaloacetic acid) to form citrate(citric acid), then isomerization of citric acid occurs to isocitrate and two dehydrogenation reactions with concomitant release of CO 2 and reduction of NAD.

In the fifth reaction GTP is formed, this is the reaction substrate phosphorylation. Next, FAD-dependent dehydrogenation occurs sequentially succinate (succinic acid), hydration fumarova acid to malate(malic acid), then NAD-dependent dehydrogenation resulting in the formation oxaloacetate.

As a result, after eight reactions of the cycle again oxaloacetate is formed .

The last three reactions constitute the so-called biochemical motif (FAD-dependent dehydrogenation, hydration and NAD-dependent dehydrogenation, it is used to introduce a keto group into the succinate structure. This motif is also present in the β-oxidation reactions of fatty acids. In the reverse order (reduction, de hydration and reduction) this motif is observed in fatty acid synthesis reactions.

Functions of the TsTK

1. Energy

• generation hydrogen atoms for the functioning of the respiratory chain, namely three molecules of NADH and one molecule of FADH2,
• single molecule synthesis GTF(equivalent to ATP).

2. Anabolic. In the TCC are formed

• heme precursor succinyl-SCoA,
• keto acids that can be converted into amino acids - α-ketoglutarate for glutamic acid, oxaloacetate for aspartic acid,
• citric acid, used for the synthesis of fatty acids,
• oxaloacetate, used for glucose synthesis.

Anabolic reactions of the TCA cycle

Regulation of the tricarboxylic acid cycle

Allosteric regulation

Enzymes catalyzing the 1st, 3rd and 4th reactions of the TCA cycle are sensitive to allosteric regulation metabolites:

Regulation of oxaloacetate availability

Main And basic The regulator of the TCA cycle is oxaloacetate, or rather its availability. The presence of oxaloacetate recruits acetyl-SCoA into the TCA cycle and starts the process.

Usually the cell has balance between the formation of acetyl-SCoA (from glucose, fatty acids or amino acids) and the amount of oxaloacetate. The source of oxaloacetate is pyruvate, (formed from glucose or alanine), obtained from aspartic acid as a result of transamination or the AMP-IMP cycle, and also from fruit acids cycle itself (succinic, α-ketoglutaric, malic, citric), which can be formed during the catabolism of amino acids or come from other processes.

Synthesis of oxaloacetate from pyruvate

Regulation of enzyme activity pyruvate carboxylase carried out with the participation acetyl-SCoA. It is allosteric activator enzyme, and without it pyruvate carboxylase is practically inactive. When acetyl-SCoA accumulates, the enzyme begins to work and oxaloacetate is formed, but, of course, only in the presence of pyruvate.

Also the majority amino acids during their catabolism, they are able to convert into metabolites of the TCA cycle, which then go into oxaloacetate, which also maintains the activity of the cycle.

Replenishment of the TCA cycle metabolite pool from amino acids

Reactions of replenishment of the cycle with new metabolites (oxaloacetate, citrate, α-ketoglutarate, etc.) are called anaplerotic.

The role of oxaloacetate in metabolism

An example of a significant role oxaloacetate serves to activate the synthesis of ketone bodies and ketoacidosis blood plasma at insufficient amount of oxaloacetate in the liver. This condition is observed during decompensation of insulin-dependent diabetes mellitus (type 1 diabetes) and during fasting. With these disorders, the process of gluconeogenesis is activated in the liver, i.e. the formation of glucose from oxaloacetate and other metabolites, which entails a decrease in the amount of oxaloacetate. The simultaneous activation of fatty acid oxidation and the accumulation of acetyl-SCoA triggers a backup pathway for the utilization of the acetyl group - synthesis of ketone bodies. In this case, blood acidification develops in the body ( ketoacidosis) with a characteristic clinical picture: weakness, headache, drowsiness, decreased muscle tone, body temperature and blood pressure.

Changes in the rate of TCA cycle reactions and the reasons for the accumulation of ketone bodies under certain conditions

The described method of regulation with the participation of oxaloacetate is an illustration of the beautiful formulation " Fats burn in the flames of carbohydrates". It implies that the "flame of combustion" of glucose leads to the appearance of pyruvate, and pyruvate is converted not only into acetyl-SCoA, but also into oxaloacetate. The presence of oxaloacetate ensures the inclusion of the acetyl group formed from fatty acids in the form of acetyl-SCoA, in the first reaction of the TCA cycle.

In the case of large-scale “combustion” of fatty acids, which is observed in muscles during physical work and in the liver fasting, the rate of entry of acetyl-SCoA into the TCA cycle will directly depend on the amount of oxaloacetate (or oxidized glucose).

If the amount of oxaloacetate in hepatocyte is not enough (there is no glucose or it is not oxidized to pyruvate), then the acetyl group will go to the synthesis of ketone bodies. This happens when long fasting And diabetes mellitus 1 type.