Tricarboxylic acid cycle

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The tricarboxylic acid cycle (TCA cycle) is Aerobic organism Ubiquitous in the body Metabolic pathway 。 In prokaryotes, it is distributed in cytoplasm, and in eukaryotes, it is distributed in mitochondria. because In this cycle, several main Intermediate metabolism The substance is an organic acid containing three carboxyl groups, such as citric acid (C6), so it is called the tricarboxylic acid cycle, also known as the citric acid cycle or TCA cycle; Or with the discoverer Hans Adolf Krebs (obtained in Britain in 1953 Nobel Prize in Physiology or Medicine ）Name the Krebs loop. The tricarboxylic acid cycle is the final metabolic pathway of the three major nutrients (sugars, lipids and amino acids), and it is also the pathway of sugars, lipids Amino acid metabolism The hub of contact.

Chinese name: Tricarboxylic acid cycle
Foreign name: The tricarboxylic acid cycle
Alias: Citric acid cycle

Field: biochemistry
Abbreviation: TCA cycle
Properties: It's sugar, fat Amino acid metabolism The hub of contact.

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definition

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The tricarboxylic acid cycle is a circulatory reaction system consisting of a series of enzymatic reactions. In this reaction process, acetyl coenzyme A (C2) and oxaloacetic acid (OAA) (C4) first condense to form citric acid (C6) containing three carboxyl groups, and then undergo four dehydrogenations (three molecule NADH+H + And 1 molecule FADH two ）, once substrate horizontal phosphorylation, and finally generate 2 molecules of CO two , and regenerate Oxaloacetic acid The cyclic reaction process.

brief introduction

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Sugar substances such as glucose or glycogen are completely oxidized under aerobic conditions to produce carbon dioxide And water, and release of the energy process known as aerobic oxidation of the sugar. It was found that there was no production of lactic acid and no accumulation of pyruvate in muscle chyme in the presence of oxygen, but energy was still released. H., a famous biochemist Kreb et al. have done a lot of research work to clarify the metabolism of pyruvate under aerobic conditions, and proposed the aerobic oxidation pathway of sugar Nobel Prize 。

The aerobic oxidation of sugar and the anaerobic fermentation of sugar have a common path, that is, glucose pyruvate, but the difference is the reaction after the formation of pyruvate. In the presence of oxygen, pyruvate Pyruvate Dehydrogenase Acetyl CoA is produced by oxidative decarboxylation under the catalysis of the system, and the latter is oxidized to CO through the tricarboxylic acid cycle two , and H two O。

Kerbs Cycle (2 sheets)

Under aerobic conditions, lactic acid, the product of muscle glycolysis, may also be converted into pyruvate. For example, blood lactic acid can be used as energy by myocardium and other tissues, which is a reaction of the human body in the recovery period after intense exercise. During this recovery time, the respiration is still accelerated and deepened, and lactic acid is oxidized again to pyruvate, which is further oxidized to water and CO two^[1] 。

Discovery process

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Dr. Krebs is here The Second World During the outbreak of the war, he was persecuted by the Nazis and had to flee to England. Although he is a very excellent doctor in Germany, in Britain, because there is no Medical license Without social recognition, he had to turn to basic medical research.

At the beginning, he chose the subject only because of his understanding of how food turns into water and carbon dioxide This topic was full of interest, so he did not hesitate to choose this topic, and began to investigate various materials of previous studies on this topic. In the report, he saw that some scholars reported that "substance A was oxidized into substance B." Another scholar said that "substance C was oxidized into substance D, and then further into substance E." Another scholar believed that "substance C was obtained from substance B. Or, it can be said, substance F became substance G." Other scholars believed that, It is "substance G is oxidized into substance A" and so on. Looking at the research reports from all directions, Krebs thought that if these scattered data were sorted out, maybe we could find Food metabolism Structure of. Just like playing a puzzle game, Krebs carefully collated these data and found that food changes in the body in the order of F, G, A, B, C, D, E. Then carefully understand the chemical substances from A to F. It is found that the chain between E and F is broken. If there is a substance X between E and F, the food cycle reaction chain will be complete. Immediately concentrate on finding substance X. Four years later, it was finally found out that substance X is now put in drinks as Sour additive Citric acid. He completed the food cycle chain and named it Citric acid cycle 。 Krebs' cycle theory explains that after food enters the citric acid cycle in the body, it circulates in the order of A, B, C, D, E, X, F, G, and finally oxidizes into carbon dioxide and water. His greatness lies not only in discovering the changes of several chemicals, but also in sorting out every living change and finding an explanation Dynamic life phenomenon Structure of. Because of this achievement, he won Nobel Prize in Physiology or Medicine 。 Citric acid cycle is also called tricarboxylic acid cycle or TCA cycle. Nutrients entering the body Glycolysis → Citric acid cycle → electron transfer and a series of respiratory effects are decomposed to generate energy.

chemical reaction

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chemical reaction

Acetyl CoA Appears in the cycle: citric acid (I) is the first product in the cycle, which is produced by Oxaloacetic acid (10) And Acetyl coenzyme A (XI) is generated by condensation reaction between acetyl groups. As mentioned above, acetyl coenzyme A is an earlier glycolysis, amino acid A product of degradation or oxidation of fatty acids.

Total chemical reaction formula

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Reaction formula

Acetyl-CoA+3NAD + +FAD+GDP+P i +3H two O→CoA-SH+3NADH+3H + +FADH two +GTP+2CO two

It is worth noting that CO two The two C's of are not derived from acetyl CoA, but from OAA.

principle

Two carbon atoms with CO two The form of leaves the loop. At the end of the cycle Oxaloacetic acid Will be generated again from Acetyl CoA We get two carbon atoms. In other words, a molecule of six carbon compound (citric acid) is decomposed into a molecule of four carbon compound (oxaloacetic acid) through multiple reactions. Oxalacetic acid will follow the same path in the next reaction to obtain two carbon atoms and become citric acid again.

The energy will be converted into GTP It is released in the form of (like ATP, it is the energy currency of cells). However, the hydrogen carrier (NADH+H and FADH) generated in the cycle two ）It will release more energy in the cell respiratory chain, which is also the main purpose of cell respiration. The citric acid cycle presupposes that Glycolysis Such processes can provide enough activated acetic acid to appear in the cycle in the form of acetyl coenzyme A. NADH +H and FADH2 They are coenzymes, which can carry protons and electrons and release them when needed.

The total energy generated in the cycle is a molecule of ATP (GTP to be precise), and Cellular respiration All four step reactions of (including Internal respiration ）One glucose molecule produces 32 molecules of ATP. Before 2002, it was always considered as 38ATP. At that time, it was believed that one FADH2 could produce two ATP and one NADH2 could produce three ATP, which was the result of idealized chemical calculation. It is measured that one FADH2 can generate 1.5 ATP and one NADH2 can generate 2.5 ATP. Please refer to Electron transfer chain And Oxidative phosphorylation 。

If carried out malate shuttle It will not reduce energy, but 32ATP. Glycerol 3-phosphate shuttle will be carried out in the brain and other parts, reducing 2 molecules of ATP, and finally net generating 30ATP. Therefore, you need to answer 32 or 30 when answering questions in biochemistry.

Cyclic process

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Tricarboxylic acid cycle

Acetyl CoA enters the cycle system consisting of a series of reactions and is oxidized to generate H ₂ O and CO ₂. Because this cycle reaction starts from the reaction between acetyl CoA and Oxaloacetic acid (oxaloacetic acid) condensation generated contains three carboxyl Therefore, it is called tricarboxylic acid cycle or citric acid cycle. Citric acid synthesis in the tricarboxylic acid cycle Enzyme catalysis The reaction of Key steps The supply of oxaloacetic acid is conducive to the smooth circulation. The detailed process is as follows:

1. Acetyl CoA enters the tricarboxylic acid cycle

Acetyl CoA has Thioester The acetyl group has enough energy to Oxaloacetic acid Aldehyde alcohol condensation. first Citrate Synthase The histidine residue of acetyl CoA acts as a base with acetyl CoA, making the methyl of acetyl CoA lose an H + , the generated carbon anion has a negative effect on oxaloacetic acid Carbonyl carbon Conduct nucleophilic attack to generate citroyl CoA intermediate, and then hydrolyze the high-energy thioester bond to release free citric acid, making the reaction irreversible to the right. The reaction is catalyzed by citrate synthase, which is a strong exothermic reaction. The synthesis of citric acid from oxaloacetic acid and acetyl CoA is an important regulation point of the tricarboxylic acid cycle. Citrate synthase is an allosteric enzyme, and ATP is an allosteric inhibitor of citrate synthase. In addition, α - ketoglutaric acid 、 NADH It can allosterically inhibit its activity, and long-chain acyl CoA can also inhibit its activity. AMP can resist the inhibition of ATP Activation 。

2、 Isocitrate formation

Citric Tertiary alcohol The base is not easy to oxidize and is converted into isocitric acid to make the tertiary alcohol become Secondary alcohol , it is easy to be oxidized, and this reaction is composed of Aconitase Catalysis is a reversible reaction.

3. First dehydrogenation—— Isocitrate dehydrogenase

Under the action of isocitrate dehydrogenase Secondary alcohol Oxidation to carbonyl Oxalosuccinic acid (oxaluccinic acid), which is rapidly decarboxylated on the surface of the same enzyme α - ketoglutaric acid (α - ketoglutamate), NADH and CO two , this reaction is Beta oxidation Decarboxylation, this enzyme needs Magnesium ion As an activator. This reaction is irreversible and a rate limiting step in the tricarboxylic acid cycle. ADP is the activator of isocitrate dehydrogenase, while ATP and NADH are inhibitors of this enzyme.

4. The second dehydrogenation - α - ketoglutarate dehydrogenase

At α- Ketoglutarate dehydrogenase Under the action of, α - ketoglutaric acid Oxidative decarboxylation produces succinyl CoA, NADH · H+and CO ₂, and the reaction process is completely similar to Pyruvate Dehydrogenase It is a catalytic oxidative decarboxylation, belonging to α - oxidative decarboxylation. Part of the energy generated by oxidation is stored in the high-energy thioester bond of succinyl coa. The α - ketoglutarate dehydrogenase system is also composed of three enzymes (α - ketoglutarate decarboxylase, lipoic acid amber Acyltransferase 、 Dihydrolipoic Dehydrogenase ）And five coenzymes (tpp, lipoic acid, hscoa, NAD+, FAD). This reaction is also irreversible. α- Ketoglutarate dehydrogenase complex It is inhibited by ATP, GTP, NADH and succinyl CoA, but it is not regulated by phosphorylation/dephosphorylation.

5、 Substrate phosphorylation Generate ATP

Diagram of substrate phosphorylation to generate ATP

stay Succinate thiokinase Succinatethiokinase Thioester Bond hydrolysis free energy It is used to synthesize gtp. In bacteria and higher organisms, ATP can be generated directly. In mammals, GTP is generated first, and then ATP is generated. At this time, succinyl CoA generates succinic acid and coenzyme A.

6. The third dehydrogenation - succinate dehydrogenase

Succinate dehydrogenase (succeeding hydrogen) catalyzes the oxidation of succinic acid to fumarates 。 This enzyme binds to Mitochondrial intima However, other enzymes in the tricarboxylic acid cycle exist Mitochondrial matrix The enzyme contains Iron sulfur center With covalently bound FAD, electrons from succinic acid pass through FAD and iron sulfur center, and then enter the electron transfer chain to O ₂, Malonic acid yes Succinic acid Is a powerful analogue of succinate dehydrogenase Competitive inhibition Therefore, it can block the tricarboxylic acid cycle.

7. Hydration of fumaric acid

Fumarase It only acts on the trans double bond of fumaric acid, while it acts on cisplatin Dioleic acid (Maleic acid) None Catalysis Therefore, it is highly stereospecific.

8. The fourth dehydrogenation - malate dehydrogenase (oxaloacetic acid regeneration)

stay Malate dehydrogenase Under the action of malicdehydrogenase, the secondary alcohol group of malic acid is dehydrogenated and oxidized to carbonyl group, forming Oxaloacetic acid NAD+is the coenzyme of dehydrogenase and receives hydrogen to become NADH · H+.

Tricarboxylic acid cycle

In this cycle, oxaloacetic acid is consumed for participating in the reaction at first, but regenerated after the cycle. So once per cycle, the net result is 1 Acetyl Pass twice Decarboxylation And is consumed. Produced by decarboxylation of organic acid in circulation carbon dioxide It is the main source of carbon dioxide in the body. There are 4 times in the tricarboxylic acid cycle dehydrogenation Reaction, the removed hydrogen atom enters in the form of NADH+H+and FADH2 respiratory chain Finally, it is transferred to oxygen to generate water, and the energy released in this process can be used to synthesize ATP. Acetyl CoA Not only from the decomposition of sugar, but also from the Catabolism They are generated in the tricarboxylic acid cycle and completely oxidized. Moreover, it can be converted into any one of the tricarboxylic acid cycles Intermediate metabolism All substances of the substance can be oxidized through the tricarboxylic acid cycle. Therefore, the tricarboxylic acid cycle is actually a common pathway for the end oxidation of organic substances such as sugar, fat and protein in vivo. The tricarboxylic acid cycle is not only a catabolic pathway, but also a biosynthesis Precursor molecules are provided. For example, oxaloacetic acid is the precursor for the synthesis of aspartic acid, α - ketoglutaric acid It is the precursor of glutamic acid synthesis. Some amino acids can also be converted into sugar through this pathway.

Cycle Summary

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Acetyl CoA+3NAD + +FAD+ADP+Pi+3H two O+CoA-SH—→2CO2+3NADH+FADH two +ATP+3H + +CoA-SH

1. Generation of CO ₂, twice in the cycle Decarboxylation reaction (reaction 3 and reaction 4) both at the same time Dehydrogenation , but the mechanism of action is different Isocitrate dehydrogenase Catalyzed β Oxidative decarboxylation The coenzyme is nad+, which first dehydrogenates the substrate Oxalosuccinic acid , and then under the cooperation of Mn2+or Mg2+, the carboxyl group is removed to generate α - ketoglutaric acid 。 α- Ketoglutarate dehydrogenase Catalysed Alpha oxidation Decarboxylation reaction and the above Pyruvate Dehydrogenase The reactions to menstruation are basically the same. It should be noted that through Decarboxylation The production of CO ₂ is a general rule for the production of CO ₂ in the body. It can be seen that the production of CO ₂ in the body is quite different from that of combustion in vitro.

Tricarboxylic acid cycle

2. Four times of dehydrogenation of the tricarboxylic acid cycle, three pairs of hydrogen atoms take NAD+as the hydrogen acceptor, and one pair of hydrogen atoms take FAD as the hydrogen acceptor, and respectively reduce to produce NADH+H+and FADH2. They pass through the mitochondria Hydrogen transmitter The energy released in this process makes adp and pi combine to generate ATP. Every 2H in the hydrogen transfer system involving NADH+H+oxidizes into a molecule of H ₂ O, generating a molecule of 2.5ATP, while the hydrogen transfer system involving FADH2 generates 1.5 molecules of ATP, plus one time in the tricarboxylic acid cycle Substrate phosphorylation If one molecule of ATP is generated, one molecule of citric acid will participate in the tricarboxylic acid cycle until 10 molecules of ATP are generated at the end of the cycle.

3. The carbon atom of acetyl group in acetyl CoA, acetyl CoA enters the cycle, and Receptor molecule Oxaloacetic acid Condensation to generate six carbon citric acid, and secondary decarboxylation in the tricarboxylic acid cycle to generate two molecules of CO ₂, which are mixed with the bicarbonacetyl carbon atom The number is equal, then Acetyl CoA The two carbons in have all been transformed into CO ₂, and part of the energy has been transformed into the energy in NADH and ATP.

4. Theoretically, the intermediate products of the tricarboxylic acid cycle can be recycled without consumption. However, because some components in the cycle can also participate in the synthesis of other substances, and other substances can also generate intermediate products through various ways, the composition of the tricarboxylic acid cycle is constantly updated.

Taking the transamination coupling urea cycle as an example, the intermediates of TCA can be used as precursors of other metabolic pathways.

for example Oxaloacetic acid ——→ Aspartate （Asp）

α－ Ketoglutaric acid ——→ glutamate （Glu）

Oxalacetic acid - → pyruvic acid ——→ alanine （Ala）

among Pyruvate carboxylase The catalytic reaction to produce oxaloacetic acid is the most important. Because the content of oxaloacetic acid directly affects the speed of circulation, constant supplementation of oxaloacetic acid is the key to smooth the tricarboxylic acid cycle. Malic acid and oxaloacetic acid generated in the tricarboxylic acid cycle can also be decarboxylated to form pyruvic acid, and then participate in the synthesis of many other substances or further oxidation.

Adjustment function

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The aerobic oxidation of sugar is divided into two stages, the first stage Glycolysis pathway The regulation of acetyl CoA has been discussed in the glycolysis section, and the regulation of a series of reactions in the second stage of oxidative decarboxylation of pyruvate to produce acetyl CoA and enter the tricarboxylic acid cycle is mainly discussed below. Pyruvate dehydrogenase complex 、 Citrate synthase 、 Isocitrate dehydrogenase And α- Ketoglutarate dehydrogenase complex This is the process Rate limiting enzyme 。

The pyruvate dehydrogenase complex receives Allosteric regulation Also affected chemical modification The enzyme complex is strongly inhibited by its catalytic products ATP, acetyl CoA and NADH Allosteric inhibition It can be enhanced by long-chain fatty acids. When acetyl CoA entering the tricarboxylic acid cycle decreases, while AMP, CoA and NAD+accumulate, the enzyme complex is activated by allosteric regulation. In addition to the above allosteric regulation, there is a second level of regulation in vertebrates, namely Enzyme protein PDH contains two subunits, one of which has a specific serine residue Phosphorylation Then, the enzyme activity is inhibited, Dephosphoric acid The phosphorylation - dephosphorylation is caused by Phosphokinase And phosphoprotein phosphatase They are catalysed respectively. They are actually the composition of pyruvate enzyme complex, that is, the previously mentioned regulatory protein. The kinase is activated by ATP allosteric. When ATP is high, PDH is phosphorylated and activated. When ATP concentration decreases, the kinase activity also decreases, and the phosphatase removes the phosphate on PDH, PDH is activated again.

Tricarboxylic acid cycle (17 sheets)

Citrate synthase Isocitrate dehydrogenase and α - ketoglutarate dehydrogenase Is mainly regulated by the Feedback suppression The tricarboxylic acid cycle is the main way for the body to produce energy. Therefore, the ratio of ATP/ADP and NADH/NAD+is the main factor Regulator 。 Increase of ATP/ADP ratio, inhibition Citrate synthase And isocitrase dehydrogenase, on the contrary, the decrease of ATP/ADP ratio can activate the above two enzymes. The increase of NADH/NAD+ratio inhibits citrate synthase and α - Ketoglutarate dehydrogenase Activity. In addition to the above ATP/ADP and NADH/NAD+, other metabolites also have an impact on the enzyme activity, such as lemon Acid inhibited citrate synthase activity, while succinyl CoA inhibited α - ketoglutarate dehydrogenase activity. In a word, the metabolic products in the tissue determine the speed of circulating reaction in order to regulate the concentration of ATP and NADH in the body and ensure the energy supply of the body.

Physiological significance of tricarboxylic acid cycle

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1. Provide energy for the body: each mole of glucose is completely oxidized to H two O and CO two 30 mol or 32 mol (glycogen generates 31~33 mol) ATP. Therefore, under general physiological conditions Histiocyte All (except red blood cells) derive energy from the aerobic oxidation of sugars. The aerobic oxidation of sugar not only has high productivity, but also gradually releases energy and stores it in ATP molecules, so the utilization rate of energy is also very high.

2. The tricarboxylic acid cycle is the common oxidation pathway of three major nutrients: acetyl CoA, not only the product of oxidative decomposition of sugar, but also fatty acids and Amino acid metabolism Therefore, the tricarboxylic acid cycle is actually the common main way for the three organic substances to oxidize and supply energy in the body. It is estimated that 2/3 of the organic matter in the human body is decomposed through the tricarboxylic acid cycle.

3. The tricarboxylic acid cycle is the hub of the three major metabolic links: α - ketoglutaric acid, pyruvic acid and oxaloacetic acid produced during the aerobic oxidation of sugar can be converted into corresponding amino acids when combined with ammonia; These amino acids can be converted into corresponding keto acids and enter the aerobic oxidation pathway of sugar. At the same time, glycerol produced by lipid catabolism and acetyl CoA produced by fatty acid metabolism can also enter the aerobic oxidation pathway of sugar for metabolism^[2] 。

Biological significance

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The biological significance of TCA can be discussed in two aspects: 1. energy metabolism; 2. Material metabolism.

1. The tricarboxylic acid cycle is the most effective way for the body to oxidize sugar or other substances to obtain energy. In sugar metabolism, sugar is oxidized in this way to produce the most energy. When each molecule of glucose is oxidized to H2O and CO2, it can produce 32 molecules of ATP or 30 molecules of ATP.

2. The tricarboxylic acid cycle is the hub for the metabolism, connection and transformation of sugars, lipids, proteins and even nucleic acids.

(1) Intermediate products of this cycle (e.g Oxaloacetic acid α - ketoglutaric acid) is the raw material for the synthesis of sugars, amino acids, fats, etc. Among them, OAA can be decarboxylated into PEP, participate in gluconeogenesis, and re synthesize energy in the organism. AcetylCOA can synthesize malonyl ACP and participate in the synthesis of palmitic acid. OAA can carry out transamination with the participation of transaminase to generate Asp, participate in urea cycli, and synthesize arginine substituted succinic acid and other urea precursors. Some of the metabolites can also participate in the synthesis of purine and pyrimidine, and even the synthesis of porphyrin ring hemoglobin synthesis.

(2) TCA is the common way for the complete oxidative decomposition of sugars, proteins and fats: protein hydrolysates (such as glutamic acid, aspartic acid, alanine and other deamination or transamination carbon frames) can be completely oxidized through the tricarboxylic acid cycle to generate a lot of energy; The fatty acid, the product of fat decomposition, is oxidized by β - to form acetyl CoA and glycerol. Glycerin also generates acetyl CoA through the EMP pathway, and finally it is completely oxidized through the tricarboxylic acid cycle. All pathways of sugar metabolism finally generate Pyruvate, dehydrogenate to acetyl CoA, and participate in TCA.

To sum up, the tricarboxylic acid cycle is linked to the metabolism of three substances and is also the hub of energy metabolism.

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