Carbohydrate metabolism

The storage form of sugar in the body

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This entry is made by Compilation and application of scientific encyclopedia entries of "Science Popularization China" to examine.

Sugar is a kind of polyhydroxy aldehyde or polyhydroxy ketone and its derivatives Organic compound , carbohydrate metabolism refers to a series of complex chemical reactions in the body such as glucose (Glc), glycogen (Gn), etc. The main forms of sugar in human body are glucose (Glc) and Glycogen (glycogen，Gn)。

Glucose is the transport form of sugar in the blood and plays a major role in the metabolism of glucose in the body; Glycogen is glucose POLYMER , including Hepatic glycogen 、 Muscle glycogen and Renal glycogen Etc. is the storage form of sugar in the body. Both glucose and glycogen can be oxidized to provide energy in the body. Sugar in food is the main source of sugar in the body. It is ingested by the human body, digested into monosaccharide and absorbed, and then transported to various tissues and cells through blood for anabolism and catabolism. Glycogenic Metabolic pathway Oxygen free, mainly glucose Zymolysis , aerobic oxidation Pentose phosphate pathway , glucuronic acid pathway, polyol pathway, glycogen synthesis and Glycogen decomposition 、 Gluconeogenesis And other hexose metabolism.

Chinese name: Carbohydrate metabolism
Foreign name: carbohydrate metabolism
Type: Biological metabolism

Approach: Uronic acid pathway, polyol pathway, etc
Object: blood sugar
Occurrence conditions: catalyzer
Place of occurrence: human tissue

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brief introduction

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Sugar metabolism can be divided into catabolism and anabolism. The basic processes of sugar metabolism in organisms are similar. The catabolism of sugar refers to the process in which sugars are decomposed into small molecules. After a series of decomposition reactions, sugar releases a lot of energy for life activities. At the same time, some intermediates formed in the decomposition process can also be used as raw materials (as carbon frames) for the synthesis of lipid, protein, nucleic acid and other biomacromolecules. The catabolism of sugar can be divided into anaerobic metabolism and aerobic metabolism. In the absence of oxygen, the decomposition of sugar is usually incomplete, which releases less energy and produces various metabolites; Under aerobic conditions, sugar can be completely oxidized, eventually generating carbon dioxide and water, and releasing a lot of energy. Sugar anabolism refers to the process in which organisms convert some small molecule non sugar substances into sugars or synthesize monosaccharides into oligosaccharides and polysaccharides. This process requires energy supply. Sugar metabolism also includes the absorption of sugar by organisms and the excretion of metabolites. As far as microorganisms are concerned, these processes are completed through cell membranes. This chapter will focus on the catabolism of sugar^[1] 。

blood sugar

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Glucose in blood, called blood sugar Blood glucose concentration in the body is an important indicator reflecting the state of glucose metabolism in the body. Under normal circumstances, the blood sugar concentration is relatively constant. The fasting plasma glucose concentration of normal people is 3.9 ～ 6.1mmol/L（ glucose oxidase Law). Fasting plasma glucose concentration higher than 7.0 mmol/L is called hyperglycemia, and lower than 3.9 mmol/L is called hypoglycemia. To maintain a relatively constant blood sugar concentration, it is necessary to maintain a dynamic balance between the source and destination of blood sugar.

Blood glucose metabolism

Source of blood sugar: ① sugar in food is the main source of blood sugar; ② Liver glycogen decomposition is the direct source of fasting blood glucose; ③ Non sugar substances such as glycerol, lactic acid and raw sugar amino acids generate glucose through gluconeogenesis, which is used as the source of blood sugar in long-term hunger.

The route of blood sugar: ① oxidative decomposition provides energy in various tissues, which is the main route of blood sugar; ② Glycogen synthesis in liver, muscle and other tissues; ③ Transformed into other sugars and their derivatives, such as ribose, amino sugar and uronic acid; ④ Transformed into non sugar substances, such as fat, non essential amino acids, etc.; ⑤ When the blood sugar concentration is too high, it is discharged from urine. The blood glucose concentration is more than 8.9~10.00mmol/(160-180mg/dl), more than Renal tubule Reabsorption capacity, diabetes occurs. The blood glucose concentration at the beginning of diabetes is called renal glucose threshold. Diabetes occurs ideally, often in diabetes patient.

Blood glucose regulation

The blood sugar concentration of normal human body is maintained at a relatively constant level, which is very important to ensure the utilization of various tissues and organs of the human body, especially the brain tissue, which almost relies on glucose for energy supply to carry out neural activities. Insufficient blood sugar supply will damage neural function, so it is extremely important to maintain the blood sugar concentration at a relatively stable normal level.

There is a fine mechanism to regulate the dynamic balance of blood glucose sources and routes in the normal human body. To keep the blood glucose concentration relatively constant Nervous system, hormone and Tissue and organ The result of co adjustment.

Data related to sugar metabolism

The nervous system regulates the concentration of blood glucose mainly through the hypothalamus and autonomic nervous system to regulate the secretion of related hormones. Hormones regulate blood glucose concentration mainly through insulin , glucagon, adrenaline Glucocorticoid 、 growth hormone And thyroid hormones cooperate and antagonize each other to maintain a constant blood glucose concentration. Hormones regulate blood glucose concentration.

The liver is the most important organ for regulating blood glucose concentration. Blood glucose concentration and glucose transporters on cell membrane of each tissue are two main factors affecting organ level regulation. At this time, the glucose transporter family on cell membrane has GLUT1-5, which is a two-way transporter. Under the condition of normal blood glucose concentration, each tissue cell takes glucose as energy source through GLUT1 and GLUT3 on the cell membrane; When the blood glucose concentration is too high, GLUT2 on the hepatocyte membrane plays a role, quickly ingests excessive glucose into the hepatocytes, and reduces the blood glucose concentration through the synthesis of liver glycogen; High blood sugar concentration will stimulate insulin secretion, resulting in liver, muscle and adipose tissue The amount of GLUT4 on the cell membrane increases rapidly, accelerating the absorption of glucose in the blood, synthesizing muscle glycogen or converting it into fat for storage. When the blood sugar concentration is low, the liver passes through Glycogen decomposition and Gluconeogenesis Increase blood sugar concentration.

Understanding the body's ability to regulate blood glucose concentration from in vitro experiments can be achieved by Glucose tolerance test (glucose tolerance test, GTT). In normal people, due to the fine regulation mechanism, the normal blood glucose concentration on an empty stomach is 3.8-6.1 mmol/L, and the blood glucose concentration is less than 7.8 mmol/L 2 hours after oral or intravenous glucose injection. Patients with impaired glucose tolerance generally have fasting glucose concentration<7.0 mmol/L, the highest concentration after oral or intravenous glucose injection 0.5-1 hours<11.1 mmol/L, and 2-hour glucose concentration ≥ 7.8 mmol/L and<11.1 mmol/L, which are called subclinical or asymptomatic diabetes mellitus. Glucose tolerance test is of great significance in the early diagnosis of such patients. The typical glucose tolerance test of diabetic patients is: the fasting blood glucose concentration is 6.1-7.0 mmol/L, and the blood glucose concentration is 7.8-11.1 mmol/L 2 hours after oral or intravenous glucose injection, indicating that the patient's ability to regulate blood glucose concentration is reduced. It is suggested clinically to detect fasting blood glucose concentration and 2-hour postprandial blood glucose concentration to simplify the glucose tolerance test process.

Digestion and absorption

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The sugar in food is mainly starch, and some disaccharide and monosaccharide 。 Polysaccharides and disaccharides must be hydrolyzed into monosaccharides by enzyme catalysis before they can be absorbed.

Starch in food passes α in saliva- amylase It catalyzes the hydrolysis of α - 1,4-glycosidic bond in starch, and the product is glucose malt dust Maltose oligosaccharide and dextrin. Because food stays in the mouth for a short time, the main digestive part of starch is in the small intestine. The small intestine contains pancreatic secreting Alpha amylase , Catalytic Starch hydrolysis Maltose, maltotriose, α - critical dextrin and isomaltose containing branches. There is α - dextrinase on the brush border of small intestinal mucosa, which Enzyme catalysis α- Ultimate dextrin α - 1,4-glycosidic bond and α - 1,6-glycosidic bond of α - dextrin are hydrolyzed to glucose; There are also Maltase Maltose and maltose can be hydrolyzed to glucose. Small intestinal mucosa Sucrase and lactase , the former decomposes sucrose into glucose and fructose, and the latter will lactose It is decomposed into glucose and galactose. Some adults suffer from lactose digestion and absorption disorders after consuming milk due to the lack of lactase, resulting in abdominal distention, diarrhea and other symptoms.

Carbohydrate metabolism

After sugar is digested into monosaccharides, the main absorption site is the upper part of the small intestine. The uptake of hexose, especially glucose, by intestinal epithelial cells is a Na+dependent energy consuming initiative Ingestion There are specific carriers involved in the process: on the brush border of small intestinal epithelial cells, there are Na+- glucose co transporters that bind to the cell membrane concentration gradient When entering the small intestinal epithelial cells, glucose is transferred into the cells along with Na+, which is a reverse concentration gradient transport for glucose. The energy of this process is determined by the concentration gradient of Na+（ Chemical potential energy ）Provided, it is sufficient to transport glucose from low concentration to high concentration. When the glucose concentration in small intestinal epithelial cells increases to a certain extent, the glucose passes through the unidirectional glucose transporter on the basal surface of small intestinal epithelial cells along the concentration gradient Passive diffusion Into the blood. Increased Na+passing through intestinal epithelial cells Sodium potassium pump （Na+-K+ ATPase ）, using the energy provided by ATP, it is pumped out of the intestinal epithelial cells from the basal surface and into the blood, thus reducing the concentration of Na+in the intestinal epithelial cells and maintaining Brush margin The concentration gradient of Na+on both sides enables glucose to be transported continuously.

Anaerobic enzymolysis

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Anaerobic enzymolysis

When the body is in a situation of relative hypoxia (such as strenuous exercise), the process of glucose or glycogen decomposing into lactic acid and generating energy is called anaerobic glycolysis. This metabolic process is common in skeletal muscle during exercise, because it is associated with yeast Alcoholic fermentation It is very similar, so it is also called Glycolysis 。 Reaction process

A series of enzymes involved in glycolysis reaction exist in the cytoplasm, so all the reaction processes of glycolysis are carried out in the cytoplasm. According to the reaction characteristics, the whole process can be divided into four stages:

Monohexose phosphorylation:

1. Glucose-6-phosphate (G-6-P)

⑴ It is hexokinase (HK) that catalyzes glucose to generate G-6-P. ATP provides phosphate group and Mg2+acts as activator. The Δ G "0=-16.7KJ/mol of this reaction is basically an irreversible reaction. Hexokinase is a glycolysis process key enzyme one of.

Hexokinase is widely found in various tissues, with Km of 0.1mmol/L and high affinity for glucose. Four hexokinases have been found in mammals isozyme Type Ⅰ - Ⅳ. Type IV enzyme only exists in the liver and is highly specific to glucose, also known as Glucokinase (glucokinase, GK), GK has a Km of 10mmol/L for glucose and a low affinity for glucose. The existence of this characteristic makes the enzymatic reaction catalyzed by GK strengthen only after a large amount of glucose digested and absorbed enters the liver after eating. The glycogen generated is stored in the liver and plays an important role in maintaining the constant blood sugar concentration.

⑵ The decomposition path starting from glycogen is that glycogen phosphorylase It becomes glucose 1-phosphate (G-1-P) under the action of, and then becomes G-6-P.

Carbohydrate metabolism

⑶ G-6-P is an important intermediate metabolite, which is the junction point of many sugar metabolism pathways (anaerobic fermentation, aerobic oxidation, pentose phosphate pathway, glycogen synthesis, glycogen decomposition).

⑷ After glucose enters the cell, it undergoes a series of phosphorylation, which aims to: the phosphorylated compound has increased polarity and cannot freely enter and exit the cell membrane, so it is not easy for glucose phosphorylation to escape from the outside of the cell, and the reaction is limited to the cytoplasm; At the same time, the energy released from ATP is stored in glucose 6-phosphate; In addition, compounds with phosphate groups can not only reduce the activation energy of enzymatic reaction, but also improve the specificity of enzymatic reaction.

2. G-6-P generates fructose-6-phosphate (F-6-P)

This reaction occurs in hexose phosphate isomerase Catalyzed by, it is an aldehyde ketone isomerization change.

3. Fructose-6-phosphate generates 1,6- Fructose diphosphate (Fructose l，6 bisphosphate，F-1，6-BP)

The enzymes that catalyze this reaction are 6-phosphate fructose kinase 1 (6-phosphofructokinase1, PFK 1), this is Glycolysis pathway ATP and Mg2+are required to participate in the second phosphorylation reaction of, Δ G "0=-14.2KJ/mol, and the reaction is irreversible.

Fructose-6-phosphate kinase 1 is the main rate limiting enzyme in the process of glycolysis and the main regulating point in the process of glycolysis.

So far, glycolysis has completed the first stage of metabolism. The main feature of this stage is the phosphorylation of glucose, accompanied by energy consumption. If glycolysis starts from the phosphorylation of glucose, 2 molecules of ATP will be consumed for each molecule of F-1 and 6-BP generated; If phosphorylation starts from glycogen, one molecule of ATP will be consumed for each molecule of F-1 and 6-BP generated. In this stage, there are two irreversible reactions, starting with glucose and starting with two key enzymes Hexokinase And 6-phosphofructose kinase 1; From glycogen, it is catalyzed by two key enzymes, phosphorylase and 6-phosphate fructose kinase 1, which are the regulating points of glycolysis process.

（2） 1 molecule hexose phosphate splits into 2 molecules triose phosphate

F-1,6-BP is cleaved into 2-molecule triose phosphate, which is catalyzed by aldolase and reversible. 3-phosphoric acid Glyceraldehyde and Dihydroxyacetone phosphate The two are isomers of each other and can be converted to each other under the catalysis of triose phosphate isomerase. When glyceraldehyde 3-phosphate continues to react, dihydroxyacetone phosphate can be continuously converted to glyceraldehyde 3-phosphate, so that 1 molecule F-1, 6-BP can generate 2 molecules of glyceraldehyde 3-phosphate.

（3） Two molecules of triose phosphate are oxidized to two molecules pyruvic acid

Dehydrogenation and oxidation of 1.3 glyceraldehyde phosphate to 1,3-diphosphoglycerate

This reaction consists of 3-glycerophosphate Aldehyde dehydrogenase Catalytic dehydrogenation, phosphoric acid addition coenzyme Is NAD+, and the hydrogen removed from the reaction is delivered to NAD+to become NADH+H+; The energy released during the reaction is stored in the generated mixed anhydride consisting of the carboxylic acid at position 1 of 1,3-diphosphoglyceride and phosphoric acid. This high-energy phosphoric acid group can transfer energy to ADP to form ATP.

2.1, 3-diphosphoglycerate conversion 3-phosphoglycerate

This reaction is catalyzed by 3-phosphoglycerate kinase to produce 1 molecule ATP, which is the first time ATP is generated during anaerobic fermentation. Because it is 1 molecule of glucose that produces 2 molecules of 1,3-diphosphoglycerate, 1 molecule of glucose can produce 2 molecules of ATP in this process. ATP is generated by Substrate horizontal phosphorylation （

3.3-Phosphoglycerate to 2-phosphoglycerate

This reaction is generated by Phosphoglycerate mutase Catalysis, the phosphate group is transferred from 3-position to 2-position.

4. 2-Phosphoglycerate dehydration generation Phosphoenolpyruvate (phosphoenolpyruvate，PEP)

This dehydration reaction is composed of Enolase Catalyzed by Mg2+as activator. During the reaction, the energy within the molecule is redistributed to form phosphoenolpyruvate containing high-energy phosphate groups.

5. Phosphoenolpyruvate to pyruvate

This reaction is catalyzed by pyruvate kinase (PK), and Mg2+acts as an activator to produce 1 molecule of ATP, ΔG'0=-61.9KJ/mol， Under physiological conditions, this reaction is irreversible. Pyruvate kinase It's also oxygen free Zymolysis Key enzymes and regulation points in the process.

Carbohydrate metabolism

This is the second time that ATP is generated during anaerobic fermentation, and the production mode is also substrate level phosphorylation. Since 1 molecule of glucose produces 2 molecules of pyruvate, 1 molecule of glucose can produce 2 molecules of ATP in this process.

The second stage of the reaction is characterized by the generation of energy. The energy generation in anaerobic fermentation process is mainly in the process of dehydrogenation of glyceraldehyde 3-phosphate to 1,3-diphosphoglyceride and the conversion of phosphoenolpyruvate to pyruvate. A total of four molecules of ATP are generated, all in the form of substrate level phosphorylation. In this stage Pyruvate kinase It is another key enzyme and regulation point in the glycolysis process.

（4） Reduction of 2-molecule pyruvate to 2-molecule lactic acid

In the absence of oxygen, pyruvic acid is reduced to lactic acid. This reaction is generated by lactate dehydrogenase Catalysis, there are many kinds of lactate dehydrogenase isozyme The skeletal muscle mainly contains LDH5, which has a high affinity with pyruvate and is conducive to the reduction of pyruvate to lactic acid. The coenzyme of LDH5 is NAD+. NADH+H+required for reduction reaction is 3-phosphoric acid Glyceraldehyde It is produced during dehydrogenation and becomes NAD+after dehydrogenation as a hydrogen donor, and then acts as the coenzyme of glyceraldehyde 3-phosphate dehydrogenase. Therefore, NAD+shuttles back and forth, playing the role of hydrogen transfer, making the anaerobic fermentation process continue. Under aerobic conditions, NADH+H+produced by dehydrogenation of glyceraldehyde 3-phosphate passes through the cytoplasm Shuttle system get into mitochondrion through Electron transfer chain Transfer to generate water and release energy at the same time.

Energy change

One molecule of glucose is converted into two molecules of lactic acid under the condition of hypoxia, and with the generation of energy, two molecules of ATP are generated net; Glycogen starts the glycolysis of 1 molecule of glucose unit into lactic acid, and net production of 3 molecules of ATP.

Physiological significance

（1） The main physiological function is to rapidly provide energy in the event of hypoxia

（2） Under normal circumstances, it provides some energy for some cells

（3） Glycolysis is the pre process of aerobic oxidation of sugar, and some of its intermediate metabolites are precursors of synthesis of lipids, amino acids, etc.

Glycolysis regulation

There are three irreversible reactions in the glycolysis pathway: those catalyzed by hexokinase (glucokinase), 6-phosphate fructose kinase 1 and pyruvate kinase, respectively. They are Anaerobic glycolysis Among the three regulatory points of the pathway, the activity of 6-phosphofructokinase-1 is the main regulatory point of the pathway.

（1） Allosteric regulation of hexokinase activity

The Km of hexokinase in skeletal muscle is relatively small. When the blood sugar reaches a certain concentration, its activity can reach the highest. It is an allosteric enzyme, and its activity is inhibited by the autoreaction product 6-glucose phosphate. The direct regulatory factor of glucokinase in the liver is the blood glucose concentration. Because the glucokinase Km is relatively large, after meals and when the blood glucose concentration is very high, excessive glucose is transported to the liver, and the glucokinase in the liver is activated; Glucokinase is also an allosteric enzyme. Its activity is inhibited by fructose 6-phosphate rather than glucose 6-phosphate, which can ensure the smooth synthesis of glycogen.

（2） Allosteric regulation of 6-phosphate fructose kinase 1

6-phosphate fructose kinase 1 is the most important regulation point in the glycolysis pathway. It is an allosteric enzyme, composed of four subunits, and has many activators and inhibitors. High concentration ATP and citric acid are allosteric inhibitors of this enzyme. ADP, AMP, Fructose 2,6 bisphosphate (F-2,6-BP) are allosteric activators of this enzyme. Fructose 2,6-diphosphate Fructose 1,6 diphosphate The structure is similar, but F-2, 6-BP is not the product of 6-phosphofructokinase-1, but the strongest activator and the most important regulator of 6-phosphofructokinase-1.

The formation of F-2, 6-BP is catalyzed by 6-phosphofructose kinase 2 (PFK2) with fructose-6-phosphate as the substrate (Figure 6-5). 6- Phosphofructokinase 2 is a bifunctional enzyme, including 6-phosphofructose kinase 2 and 2,6-diphosphofructase 2 activities, which are simultaneously present in a 55x103（ Polypeptide chain Medium. 6-phosphofructokinase-2 Allosteric activator Is substrate F-6-P When sugar supply is sufficient, F-6-P activates the activity of 6-phosphofructose kinase 2 in the bifunctional enzyme, inhibits the activity of 2,6-diphosphofructase 2, and produces a large amount of F-2,6-BP. On the contrary, in the case of insufficient glucose supply, glucagon stimulates the production of cAMP, activates A kinase, and phosphorylates the bifunctional enzyme. After phosphorylation, the activity of 6-phosphofructokinase-2 in the bifunctional enzyme is inhibited while the activity of 2,6-diphosphofructokinase-2 is activated, reducing the production of F-2 and 6-BP. It can be seen that under the condition of high glucose concentration, the increase of fructose 2,6-diphosphate concentration can activate fructose-6-phosphate kinase 1 and promote the glycolysis process. F-2,6-BP plays an important role in the regulation of glucose metabolism.

（3） Pyruvate kinase

Books on sugar metabolism

Pyruvate kinase is the second regulation point in the glycolysis process. Fructose 1,6-diphosphate is the allosteric activator of the enzyme, while ATP is the allosteric inhibitor of the enzyme. ATP can reduce the affinity of the enzyme to the substrate phosphoenolpyruvate; Acetyl CoA Free long-chain fatty acids and free long-chain fatty acids are also inhibitors of the enzyme. They are important substances for ATP production.

Aerobic oxidation

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Aerobic oxidation refers to the process in which glucose is further oxidized to acetyl coenzyme A under aerobic conditions after generating pyruvate, and then thoroughly oxidized to water, carbon dioxide and energy through the tricarboxylic acid cycle. This is the main way of sugar oxidation and the main way for the body to obtain energy.

Reaction process

1、 Glucose oxidation to pyruvate;

This stage is similar to the glycolysis process, which is carried out in the cytoplasm. Pyruvate produces lactic acid under the condition of hypoxia. Pyruvate enters mitochondria to produce acetyl under aerobic conditions Coenzyme A , and then enter the tricarboxylic acid cycle.

2、 Oxidative decarboxylation of pyruvate to produce acetyl coenzyme A

Under aerobic conditions, pyruvate enters mitochondria from cytoplasm. stay Pyruvate Dehydrogenase The oxidative decarboxylation reaction is carried out under the catalysis of the complex (pyruvate dehydrogenasecomplex). The Δ G'0 of the reaction is - 39.5kJ/mol, and the reaction is irreversible (Figure 6-6). Pyruvate dehydrogenase complex It is composed of three enzymes Multienzyme complex , which includes pyruvate dehydrogenase, dihydrolipoic acid acetyl Transferases and Dihydrolipoic Dehydrogenase 。 Acetyltransferase is the core, surrounded by pyruvate dehydrogenase and dihydrolipoic dehydrogenase. Coenzymes involved include TPP, lipoic acid, FAD, NAD+, and coenzyme A. The closely linked chain reaction process is carried out in the multi enzyme complex, and the reaction is completed quickly with high catalytic efficiency, which enables the decarboxylation and dehydrogenation of pyruvate to generate acetyl coenzyme A and NADH+H+.

3、 Tricarboxylic acid cycle

Acetyl coenzyme A generated from oxidative decarboxylation of pyruvate should be thoroughly oxidized. This oxidation process is the tricarboxylic acid cycle (TCA cycle). The tricarboxylic acid cycle was discovered by Krebs in 1937. So it is also called Krebs cycle 。 Because the first intermediate product in the cycle is citric acid, it is also called citric acid cycle. Acetyl coenzyme A condenses with oxaloacetic acid to produce citric acid containing three carboxyl groups, and then undergoes a series of reactions to become oxaloacetic acid again to complete a cycle, in which the hydrogen removed by oxidation reaction Mitochondrial intima Superior meridian respiratory chain Transfer generated water, Oxidative phosphorylation ATP generation; The carbon dioxide generated by decarboxylation is transported to the respiratory system through blood and discharged, which is the main source of carbon dioxide in the body.

1. Tricarboxylic acid cycle reaction process:

⑴ Acetyl coenzyme A and oxaloacetic acid are condensed to produce citric acid

This reaction is generated by Citrate Synthase (Citrate synthase) catalysis is a key enzyme in the tricarboxylic acid cycle and an important regulation point. Since more free energy is released during the hydrolysis of high-energy thioester bond, ΔG'0=-32.2kJ/mol， This reaction is irreversible.

⑵ Citric acid generates isocitric acid through cis aconitic acid

This reaction is catalyzed by aconitase, citric acid is dehydrated, and water is added to produce isocitric acid.

⑶ β - oxidation and decarboxylation of isocitrate α - ketoglutaric acid

This reaction occurs in Isocitrate dehydrogenase Dehydrogenation and decarboxylation are carried out under the action, which is the first oxidative decarboxylation in the tricarboxylic acid cycle. Isocitrate dehydrogenase (isocitrate dehydrogenase) is cyclic with tricarboxylic acid Rate limiting enzyme , is the most important regulation point, the coenzyme is NAD+, and the NADH+H+generated by dehydrogenation is Mitochondrial intima Water is generated from the upper respiratory chain, and three molecules of ATP are generated by oxidative phosphorylation. Isocitric acid dehydrogenation Oxalosuccinic acid And then decarboxylate to form α - ketoglutaric acid. ΔG'0=-20.9kJ/mol。

⑷ Oxidation and decarboxylation of α - ketoglutaric acid Succinyl coenzyme A

This reaction generates succinyl coenzyme A through dehydrogenation and decarboxylation catalyzed by the α - ketoglutarate dehydrogenase complex, which is the second oxidative decarboxylation in the tricarboxylic acid cycle. α- Ketoglutarate dehydrogenase complex It is the key enzyme of the tricarboxylic acid cycle and the third regulation point. The α - ketoglutarate dehydrogenase complex is a multienzyme complex, and its composition and reaction mode are similar to Pyruvate dehydrogenase complex be similar. The three enzymes it contains are α- Ketoglutarate dehydrogenase (TPP is required); Lipoic acid amber Acyltransferase (lipoic acid and coenzyme A required); Dihydrolipoic acid dehydrogenase (requires FAD and NAD+). Dehydrogenation generates NADH+H+ Mitochondrial intima Water is generated from the upper respiratory chain, and three molecules of ATP are generated by oxidative phosphorylation.

Carbohydrate metabolism

Due to the internal energy rearrangement of molecules in the reaction, the product succinyl coenzyme A contains a high-energy thioester bond, and this reaction is irreversible. ΔG'0=-33.5kJ/mol。

(5) Succinyl coenzyme A is converted to succinic acid

This reaction is generated by Succinate thiokinase (Succinyl CoA synthetase ）Catalyzed, the high-energy thioester bond in succinyl coenzyme A releases energy, which can be transferred to ADP (or GDP) to form ATP (or GTP). There are two kinds of isoenzymes in cells, one forms ATP and the other forms GTP. This is because sulfosuccinate kinase consists of α, β Subunit The α subunit has phosphorylated histidine residues and CoA binding sites; The β subunit can bind both ATP and GTP. The formed GTP can Nucleoside kinase Under catalysis, high-energy phosphate groups are transferred to ADP to generate ATP. This is the only substrate level phosphorylation in the tricarboxylic acid cycle to generate 1 molecule ATP.

(6) Dehydrogenation of succinic acid to fumaric acid

This reaction is generated by Succinate dehydrogenase Catalyzed, the coenzyme is FAD. After dehydrogenation, it generates FADH2, which is transferred through the respiratory chain on the mitochondrial inner membrane to generate water, and oxidative phosphorylation generates 2 molecules of ATP.

(7) Conversion of fumaric acid to malic acid

This reaction is generated by Fumarase Catalysis, adding water to generate malic acid.

(8) Dehydrogenation of malic acid to oxaloacetic acid

This reaction is generated by Malate dehydrogenase Catalysis, coenzyme is NAD+, which generates NADH+H+after dehydrogenation, and generates water through the respiratory chain on the mitochondrial inner membrane, and generates 3 molecules of ATP through oxidative phosphorylation.

2. Characteristics of tricarboxylic acid cycle:

⑴ The tricarboxylic acid cycle is the complete oxidation process of acetyl coenzyme A. Oxalacetic acid has no quantitative change before and after reaction. Oxalacetic acid in the tricarboxylic acid cycle mainly comes from the direct carboxylation of pyruvate.

⑵ The tricarboxylic acid cycle is a process of energy generation. One molecule of acetyl CoA undergoes four dehydrogenations through TCA (three dehydrogenations to generate NADH+H+, one dehydrogenation to generate FADH2), two decarboxylations to generate CO2, one substrate horizontal phosphorylation, and a total of 12 molecules of ATP are generated.

⑶ Citrate synthase, isocitrate dehydrogenase and α - ketoglutarate dehydrogenase complex in the tricarboxylic acid cycle are the key enzymes of the reaction and the regulating points of the reaction.

3. Physiological significance of tricarboxylic acid cycle

(1) The tricarboxylic acid cycle is the final metabolic pathway for the metabolism of sugar, fat and protein. Sugar, fat and protein are metabolized in the body to finally produce acetyl coenzyme A, and then enter the tricarboxylic acid cycle thoroughly Oxidative decomposition Water, CO2 and energy generation.

⑵ The tricarboxylic acid cycle is the hub of the metabolism of sugar, fat and protein.

Oxidation significance

The main function of aerobic oxidation of sugar is to provide energy. Most tissue cells in the body pass through Aerobic oxidation of sugar Get energy. In vivo, l molecule glucose is completely oxidized to 38 (or 36) molecule ATP. During the complete oxidation of glucose to CO2 and H2O, ΔG'0=-2840kJ/mol， 38 molecules of ATP were generated, 38 × 30.5 kJ/mol=1159 kJ/mol, and the efficiency of energy generation was about 40%.

In the aerobic oxidation of sugar oxidative phosphorylation 34 (or 32) molecules of ATP are obtained, and 6 molecules of ATP are generated through substrate level phosphorylation. The complete oxidation of l glucose in liver, kidney, heart and other tissues can generate 38 molecules of ATP, while only 36 molecules of ATP can be generated in skeletal muscle and brain tissues. The reason for this difference is that the reaction from glucose to pyruvate is carried out in the cytoplasm, and the coenzyme NADH+H+of glyceraldehyde 3-phosphate dehydrogenase must be oxidized and phosphorylated in mitochondria, so NADH+H+must pass through Shuttle system When entering mitochondria, the number of ATP obtained is different due to different shuttle systems. Starting from the oxidation of the glucose residue of glycogen Glycosyl Oxidation can form 39 (or 37) molecular ATP.

Oxidation regulation

In the aerobic oxidation of sugar, the regulation of pyruvate formation from glucose is the same as that in glycolysis. Here we mainly discuss the regulation of pyruvate dehydrogenase complex and tricarboxylic acid cycle.

Regulation of Monopyruvate Dehydrogenase Complex

Pyruvate dehydrogenase complex can be divided into allosteric regulation and covalent regulation. Allosteric regulation Its inhibitors include ATP, acetyl coenzyme A, NADH, fatty acids, etc. Activators are ADP, CoA, NAD+, Ca2+, etc. When [ATP]/[ADP], [NADH]/[NAD+] and [acetyl CoA]/[CoA] are very high, it indicates that energy is sufficient and pyruvate dehydrogenase complex is inhibited by post allosteric activity.

Pyruvate dehydrogenase complex also exists Covalent modification Mechanism: The serine residue in pyruvate dehydrogenase, one of its components, can be phosphorylated by specific phosphokinase to inactivate pyruvate dehydrogenase; Corresponding phosphatase It can dephosphorylate phosphorylated pyruvate dehydrogenase and restore its activity. This specific Phosphokinase It is also activated by allosteric ATP: when ATP concentration is high, specific phosphokinase is allosteric activated, so that pyruvate dehydrogenase is Phosphorylation Inhibit its activity.

Regulation of the Tricarboxylic Acid Cycle

The three regulation points of the tricarboxylic acid cycle are: citrate synthase, isocitrate dehydrogenase, and α - ketoglutarate dehydrogenase complex. The most important regulation point is isocitrate dehydrogenase, followed by α - ketoglutarate dehydrogenase complex; The most important regulatory factor is the concentration of ATP and NADH. When [ATP]/[ADP], [NADH]/[NAD+] are very high, it indicates that the energy is sufficient and the three rate limiting enzyme activities are inhibited; On the contrary, the activities of these three rate limiting enzymes are activated. In addition, the deficiency of the substrate acetyl CoA and oxaloacetate and the excessive production of citric acid and ATP can inhibit citrate synthase.

Mutual adjustment

Carbohydrate metabolism

Pastuer effect refers to that the aerobic oxidation of sugar inhibits the anaerobic fermentation of sugar under aerobic conditions. This effect was discovered by Pastuer when he studied yeast glucose fermentation: under anaerobic conditions, Anaerobic glycolysis The speed and quantity of ATP produced is far greater than that of aerobic oxidation, which is the main way to generate ATP. However, in the presence of oxygen, the saccharolysis of yeast is inhibited. This phenomenon also occurs in muscles: when the oxygen supply of muscle tissue is sufficient, aerobic oxidation is inhibited Anaerobic glycolysis Produce a large amount of energy for muscle tissue activities. In case of hypoxia, anaerobic glycolysis is dominant.

In some normal tissues and tumor cells with vigorous metabolism, even under aerobic conditions, anaerobic glycolysis is still the main way to produce ATP. This phenomenon is called Cratree effect or anti Pasteur effect. In the tissue cells with Cratree effect, its glycolytic enzyme system（ Hexokinase 、6 Phosphofructokinase 1 、 Pyruvate kinase ）The activity is strong, but the activity of the enzyme system that produces ATP in the mitochondria is low, and the oxidative phosphorylation is weakened. The energy is mainly produced by the anaerobic glycolysis enzyme system.

Pentose phosphate pathway

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Pentose phosphate pathway is another important pathway of glucose oxidative decomposition. Its function is not to produce ATP, but to produce special substances with important physiological functions required by cells, such as NADPH and 5-phosphoribose. This pathway exists in the liver, adipose tissue, thyroid adrenal cortex , gonads, red blood cells and other tissues. Metabolism related enzymes exist in the cytoplasm.

Reaction process

Pentose phosphate pathway is a complex metabolic pathway: 6 molecules of glucose can transform 1 molecule of glucose into 6 molecules of CO2 through pentose phosphate pathway. The process of pentose phosphate pathway

The reaction can be divided into two stages: the first stage is the oxidation reaction to produce NADPH and 5-phosphoribose; The second stage is the non oxidation reaction, which is the transfer process of a series of groups.

Stage I: oxidation reaction

Glucose 6-phosphate is catalyzed by glucose 6-phosphate dehydrogenase (G-6-PD) and gluconate 6-phosphate dehydrogenase. NADP+is their coenzyme, and G-6-P dehydrogenates and decarboxylates at the first carbon atom to convert to 5-phosphate Ribulose At the same time, 2 molecules of NADPH+H+and 1 molecule of CO2 are generated. Ribose 5-phosphate becomes ribose 5-phosphate under the action of isomerase.

In this stage, NADPH+H+and 5-phosphate ribose are two important metabolites.

Stage II: Non oxidation reaction -- transfer of a series of groups

In this stage, pentose phosphate continues to metabolize and regenerates into G-6-P through a series of reactions. Ribulose 5-phosphate is converted into 5-phosphate by isomerization Ribose Or 5-phosphoric acid Xylulose , three forms of pentose phosphate Transketolase Catalytic transfer ketone alcohol group (- CO-CH20H) and Transaldolase Catalyze the transfer of aldehyde alcohol group (- CHOH-CO-CH20H), carry out group transfer, generate three carbon, seven carbon, four carbon and six carbon monosaccharide phosphate in the middle, and finally convert into fructose 6-phosphate and glyceraldehyde 3-phosphate, and further metabolize into G-6-P 。

Physiological significance

Pentose phosphate pathway is not the main way to supply energy, but its main physiological function is to provide some raw materials for biosynthesis.

（1） Provide NADPH+H+

1. NADPH+H+, as a hydrogen donor, participates in the biosynthetic reaction. Such as fatty acids Steroid hormone etc. biosynthesis NADPH+H+is required at all times, so pentose phosphate pathway is more active in tissues with strong lipid synthesis, such as liver, breast, adrenal cortex, adipose tissue and so on.

2. NADPH+H+is adding single oxygen Enzyme system It is one of the coenzymes involved in the hydroxylation reaction in vivo, such as the biotransformation of some drugs and poisons in the liver.

3. NADPH+H+Yes Glutathione reductase The coenzyme NADPH changes oxidized glutathione into GSH Reduced glutathione The normal content of GSH plays an important role. GSH can remove H2O2 from red blood cells and maintain the integrity of red blood cells: the accumulation of H2O2 in red blood cells will accelerate the oxidation of hemoglobin Methemoglobin To reduce the lifespan of red blood cells; The peroxidation of H2O2 on lipids will lead to the destruction of erythrocyte membrane and hemolysis.

In patients with hereditary G-6-PD deficiency, pentose phosphate pathway can not be carried out normally, resulting in the reduction of NADPH+H+, the low content of GSH, and the easily damaged red blood cells leading to hemolytic jaundice. They are often induced by eating broad beans, so they are called broad bean disease.

（2） Ribose 5-phosphate is nucleotide Provide raw materials for nucleic acid synthesis.

（3） Three carbon sugar, four carbon sugar, five carbon sugar, seven carbon sugar and six carbon sugar are converted to each other through pentose phosphate pathway.

Synthetic decomposition

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Glycogen is the storage form of sugar in the body, mainly in the form of liver glycogen and muscle glycogen. The synthesis and decomposition of liver glycogen is mainly to maintain a relatively constant blood sugar concentration; Muscle glycogen is the main source of muscle glycolysis. Glycogen is a branched polysaccharide (Fig. 6-11) formed by many glucose through α - 1,4-glycosidic bond (straight chain) and α - 1,6-glycosidic bond (branch), which exists in the cytoplasm.

Glycogen synthesis is the process of synthesizing glycogen from glucose. conversely, Glycogen decomposition Glycogenosis refers to the process of liver glycogen decomposition into glucose. Glycogen synthesis and decomposition reaction Are all non glycogen derived Reducibility Starting from the end, it is catalyzed by two different groups of enzymes.

Glycogen synthesis

Glycogen synthesis First, the glucose is used as the raw material to synthesize uridine diphosphate glucose (UDP Glc). Under the effect of the rate limiting enzyme glycogen synthase, UDP Glc is transferred to the glycogen protein in the liver and muscle to extend the sugar chain to synthesize glycogen. Secondly, the sugar chain Branching enzyme Under the action of, it branched to synthesize multiple glycogen. The reaction can be divided into two stages:

Stage I: sugar chain extension

Free glucose cannot directly synthesize glycogen. It must first be phosphorylated to G-6-P and then converted to G-1-P. The latter reacts with UTP to form UDP Glc and pyrophosphate (PPi). UDP Glc is the substrate of glycogen synthesis and the donor of glucose residues, called active glucose. UDP Glc transfers glucose residues to glycogenin On the non reducing end residue of the straight chain molecule of glycogen, it is connected and extended with α - 1,4-glycoside bond sugar chain 。

Stage 2: Sugar chain branching

Glycogen synthase can only extend the sugar chain and cannot form branches. When the straight chain part is continuously extended to more than 11 glucose residues, the branching enzyme can transfer a section of sugar chain (containing at least 6 glucose residues) to the adjacent sugar chain, connect it with α - 1,6-glycosidic bond, and form a new branch (Figure 6-13). The branch continues to extend the sugar chain with α - 1,4-glycosidic bond.

Carbohydrate metabolism

Glycogen protein is a protein with a molecular weight of 37 kDa, which is both a primer for sugar chain extension and an enzyme activity, and plays an important role in the initiation of glycogen synthesis (Fig. 6-15). ① A glucose residue provided by UDP Glc and glycogenin The tyrosine residues on the glycogen protein Glycosyltransferase (glossyltransfer). ② Glycogen protein and glycogen combined with a glucose residue Synthase Together, the three forms a solid complex on which subsequent reactions are carried out. ③ UDP Glc provides glucose residues under the catalysis of glycosyltransferase, and glycogen synthase catalyzes the synthesis, extending with α - 1,4-glycosidic bond to form short chains with more than 7 glucose residues. ④ along with sugar chain And glycogen synthase finally and glycogenin Separation. ⑤ Glycogen synthesis is completed under the combined action of glycogen synthase and branching enzyme, and the glycogen protein remains in the glycogen molecule.

Glycogen synthase is the rate limiting enzyme of glycogen synthesis and the regulating point of glycogen synthesis. Each addition of a glucose residue to a glycogen protein consumes 2 molecules of ATP (glucose phosphorylation and UDP Glc generation).

Glycogen decomposition

Under the catalysis of the rate limiting enzyme glycogen phosphorylase, glycogen starts from the non reducing end of the branch and decomposes glucose residues linked by α - 1,4-glycosidic bonds one by one to form G-1-P. G-1-P changes into G-6-P Later, the liver and kidney contain glucose-6-phosphatase, which hydrolyzes G-6-P into free glucose and releases it into the blood to maintain a relatively constant blood sugar concentration. Because muscle tissue does not contain glucose-6-phosphatase, muscle glycogen cannot be directly converted into blood sugar after decomposition. The generated G-6-P is completely decomposed by aerobic oxidation under aerobic conditions, and glycolysis generates lactic acid under anaerobic conditions. The latter is transported to the liver through blood circulation Gluconeogenesis To synthesize glucose or glycogen.

When the branch of glycogen molecule is acted by glycogen phosphorylase to only 4 glucose residues from the branch point, glycogen phosphorylase can no longer play a role. At this time, the debranching enzyme plays a role. The debranching enzyme has two enzyme activities, namely, trans oligosaccharide enzyme and α - 1,6-glucosidase. The trans oligosaccharide enzyme transfers the three glucose residues remaining on the branch to the terminal sugar group of the other branch, and carries out α - 1,4-glycosidic bond connection; The last residual glucose residue is hydrolyzed by α - 1,6-glucosidase to generate free glucose; After the branches are removed, glycogen phosphorylase continues to catalyze the decomposition of glucose residues to form G-1-P.

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The synthesis and decomposition of glycogen in muscle mainly provide ATP for muscle; In the liver, glycogen synthesis and glycogen decomposition are mainly to maintain a relatively constant blood sugar concentration. Their effects are affected by adrenaline, glucagon, insulin and other hormones: adrenaline mainly acts on muscles; Glucagon and insulin mainly regulate the balance of glycogen synthesis and decomposition in the liver. Glycogen synthase and glycogen phosphorylase are glycogen synthesis and glycogen decomposition Rate limiting enzyme , glycogen Phosphorylation The activities of enzymes and glycogen synthase will not be activated or inhibited at the same time. They can be Allosteric regulation And covalent modification.

（1） Regulation of glycogen phosphorylase activity

Glycogen phosphorylase exists in two forms, a and b. In glycogen Phosphorylase kinase In the presence of ATP, the serine residue of glycogen phosphorylase b is phosphorylated to transform inactive glycogen phosphorylase b into active glycogen phosphorylase a. Glycogen phosphorylase a can pass phosphorus Protein phosphatase The serine residue is dephosphorylated and becomes an inactive glycogen phosphorylase b.

During strenuous muscle exercise, the activity of glycogen phosphorylase is regulated by adrenaline. Adrenaline increases the concentration of cAMP through signal transduction system, activates A-kinase to phosphorylate inactive glycogen phosphorylase kinase b into active glycogen phosphorylase kinase a, and glycogen phosphorylase kinase a further converts inactive glycogen phosphorylase b into active glycogen phosphorylase a, promoting Glycogen decomposition , generating energy.

When muscles exercise violently, muscle glycogen decomposition increases, which is also involved in the regulation mechanism of two individual structures. One is Ca2+ Allosteric regulation : Ca2+is Muscle movement It combines and allosterically constructs glycogen phosphorylase kinase b to make it active, and promotes the conversion of inactive glycogen phosphorylase b into active glycogen phosphorylase a. The other is allosteric regulation of AMP and ATP: AMP accumulates in muscles undergoing intense exercise, and allosteric activation of glycogen phosphorylase; When ATP is sufficient, ATP binds to allosteric sites to inactivate glycogen phosphorylase.

In the liver, the activity of glycogen phosphorylase is mainly regulated by glucagon. When the concentration of blood sugar decreases to a certain extent, cAMP is formed through glucagon, phosphorylase kinase b becomes phosphorylase kinase a by activating A kinase, and inactive phosphorylase b is transformed into active phosphorylase a, promoting the decomposition of liver glycogen into glucose and releasing it into the blood, Achieve the goal of raising blood sugar. Glycogen phosphorylase activity also exists in the liver Allosteric regulation Mechanism. When the blood glucose concentration returns to normal, glucose enters the liver cells and interacts with glycogen Phosphorylation The allosteric site of enzyme a binds to expose the phosphorylated serine residue on glycogen phosphorylase a to glycogen phosphorylase a phosphatase, and glycogen phosphorylase a dephosphorylates into inactive glycogen phosphorylase b, where glucose is an allosteric agent.

（2） Regulation of glycogen synthase activity

Glycogen synthase can also be divided into two forms: a and b. Glycogen synthase a is active. Glycogen synthase a is phosphorylated into inactive glycogen synthase b. Under the action of phosphoprotein phosphatase, the inactive glycogen enzyme b is dephosphorylated into the active glycogen synthase a. The activities of glycogen phosphorylase and glycogen synthase are mutually regulated by phosphorylation and dephosphorylation. One enzyme is activated and the other enzyme is inhibited. The two enzymes will not be activated or inhibited at the same time.

Glycogen phosphorylase kinase a, glycogen phosphorylase a and glycogen synthase b, whose dephosphorylation is catalyzed by phosphoprotein phosphatase. Phosphoprotein phosphatase can combine with inhibitor of phosphoprotein phosphatase and lose its activity to ensure glycogen Phosphorylation Enzyme kinase a, glycogen phosphorylase a and glycogen synthase b maintain phosphorylation. Only phosphorylated phosphoprotein phosphatase inhibitor can combine with phosphoprotein phosphatase and make phosphoprotein phosphatase inactive. Therefore, cAMP activates A kinase, which not only promotes the phosphorylation of glycogen phosphorylase kinase b into glycogen phosphorylase kinase a, phosphorylase b into phosphorylase a, but also inhibits the dephosphorylation of phosphoprotein phosphatase to glycogen phosphorylase kinase a, glycogen phosphorylase a and glycogen synthase b through the phosphorylation of phosphoprotein phosphatase inhibitor, and ultimately promotes Glycogen decomposition , inhibit glycogen synthesis.

The phosphorylation and dephosphorylation of the enzyme in can change the enzyme activity accordingly, forming a group of continuous and cascade enzymatic reaction processes. All reactions at all levels can not only be regulated, but also have amplification effect. This regulatory mechanism is conducive to the body's response to different physiological conditions.

Storage disease

Glycogen storage disease is a kind of hereditary disease, which is characterized by abnormal types and quantities of glycogen deposition in tissues, resulting in different types of glycogen storage disease. Each type of glycogen storage disease is characterized by a specific enzyme defect or loss in glycogen metabolism, which causes glycogen storage. Since liver and skeletal muscle are important parts of glycogen metabolism, Therefore, it is the main involved part of glycogen storage disease, liver and muscle.

Heterogenesis

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Gluconeogenesis refers to the process of transforming non sugar substances such as raw sugar amino acids, lactic acid, pyruvic acid and glycerol into glucose or glycogen. The main organ of gluconeogenesis is the liver.

Reaction process

The process of gluconeogenesis is basically the reverse process of glycolysis. Because the glycolysis process Hexose Exciting

The three reactions catalyzed by enzyme, 6-phosphate fructose kinase 1 and pyruvate kinase release a lot of energy, which constitutes an energy barrier that is difficult to reverse. Therefore, these three reactions are irreversible. These three reactions can be respectively catalyzed by corresponding and special enzymes to reverse the reaction (Figure 6-19) Gluconeogenesis Reaction process.

（1） Conversion of pyruvate to phosphoenolpyruvate

The reaction of pyruvate to phosphoenolpyruvate includes Pyruvate carboxylase And phosphoenolpyruvate carboxyl kinase to form a so-called“ Pyruvate carboxylation branch ”Let the reaction proceed. This reaction is in the process of glycolysis Pyruvate kinase The reverse process of catalyzed phosphoenolpyruvate to pyruvate.

1. Carboxylation of pyruvate to generate oxaloacetic acid

This reaction is catalyzed by pyruvate carboxylase, the coenzyme is Biotin ATP and Mg2+(Mn2+) participate in the carboxylation reaction, and CO2 carboxylates pyruvate to oxaloacetic acid through biotin. This enzyme exists in mitochondria, so pyruvate must enter mitochondria to be carboxylated into oxaloacetate, which is also one of the important sources of oxaloacetate in the body.

2. Oxalacetic acid Decarboxylation Produce phosphoenolpyruvate (PEP)

This reaction is catalyzed by phosphoenolpyruvate carboxyl kinase, and GTP provides energy to release CO2.

Phosphoenolpyruvate carboxyl kinase exists in human mitochondria and cytosol. Phosphoenolpyruvate carboxyl in mitochondria kinase It can directly catalyze the decarboxylation of oxaloacetic acid to produce PEP, which is transported from mitochondria to cytoplasm and generates fructose 1,6-diphosphate through the reverse process of glycolysis. The phosphoenolpyruvate carboxyl kinase in the cytoplasm first transports oxaloacetate from mitochondria to the cytoplasm: because oxaloacetate cannot enter and exit freely Mitochondrial intima Therefore, oxaloacetic acid should be reduced to malic acid or Transamination Generation of aspartic acid; Malic acid and aspartic acid can freely enter and exit the inner membrane of mitochondria, and can reach the cytoplasm from mitochondria; In cytoplasm, malic acid can be dehydrogenated and oxidized, and aspartic acid can be converted into oxaloacetic acid through transamination, completing the process of transporting oxaloacetic acid from mitochondria to cytoplasm. Then, oxaloacetic acid transported into the cytoplasm can be decarboxylated to PEP under the catalysis of phosphoenolpyruvate carboxyl kinase.

（2） Conversion of fructose 1,6-diphosphate to fructose 6-phosphate

The reaction was catalyzed by fructose-1,6-diphosphate enzyme 1. This reaction is the reverse process of fructose 1,6-diphosphate production from fructose 6-phosphate catalyzed by fructose-1,6-diphosphate enzyme 1 during glycolysis.

（3） Conversion of glucose 6-phosphate to glucose

This reaction is catalyzed by glucose-6-phosphatase. This reaction is in the process of glycolysis Hexokinase Urge

The reverse process of converting glucose to glucose 6-phosphate.

Physiological significance

1. The most important physiological significance of gluconeogenesis is to maintain a relatively constant blood sugar concentration under fasting or starvation conditions

2. Lactic acid reuse:

Lactic acid is mostly produced by glycolysis in muscle and red blood cells. It is transported to the liver or kidney through blood, and forms glucose after gluconeogenesis. The latter can be transported back to various tissues through blood and continue to oxidize to provide energy. This process is called Lactic acid circulation Or Cori cycle. The amount of lactic acid produced in a quiet state is very small, and this approach is of little significance. But under some physiological or pathological conditions, such as intense exercise, muscle glycogen Zymolysis A large amount of lactic acid is produced, most of which can be transported to the liver through blood Gluconeogenesis Synthesize liver glycogen or glucose to supplement blood sugar, which can be used by muscles. Lactic acid circulation Avoidable loss Lactic acid and prevent acidosis caused by lactic acid accumulation.

3. Gluconeogenesis promotes kidney excretion of H+and alleviates acidosis

When acidosis occurs, H+can activate phosphoenolpyruvate carboxyl kinase in renal tubular epithelial cells and promote gluconeogenesis. Due to the tricarboxylic acid cycle Intermediate metabolism Physical progress Gluconeogenesis , causing the content of α - ketoglutaric acid to decrease, promoting glutamate The α - ketoglutarate generated by deamination of glutamine and glutamine supplements the tricarboxylic acid cycle, and the ammonia generated is secreted into the renal tubules, which combines with the H+in the original urine to form NH4+, which plays a buffer role in excess of H+, and can alleviate acidosis.

Heterogenesis regulation

The reaction catalyzed by four key enzymes in the gluconeogenesis pathway is the main regulation point of gluconeogenesis. Gluconeogenesis and glycolysis are the same but opposite Metabolic pathway Therefore, they must be mutually regulated, and the activation or inhibition of key enzymes in the two metabolic pathways should cooperate with each other: when sugar supply is sufficient, the activity of enzymes related to glycolysis increases, and the activity of enzymes related to gluconeogenesis decreases; When the sugar supply is insufficient, the activities of enzymes related to glycolysis are reduced, and the activities of enzymes related to gluconeogenesis are increased. In vivo, by changing the rate of enzyme synthesis, covalent modification Allosteric regulation To regulate the activities of key enzymes in these two pathways to achieve the best physiological effect.

1. Induce and inhibit the synthesis of key enzymes

When the blood glucose concentration increases, on the one hand, it can lead to an increase in insulin secretion, which becomes an inducement factor to increase the synthesis of key enzymes in glycolysis; On the other hand, it can inhibit the key enzyme of gluconeogenesis induced by glucocorticoid and glucagon.

2. Covalent modification and regulation of key enzymes

When the blood glucose concentration is reduced, glucagon and a small amount of adrenaline can be produced, and the purpose of inhibiting glycolysis and increasing gluconeogenesis can be achieved through cAMP. The increase of cAMP concentration can make A kinase yes acetone Phosphorylated acid kinase Pyruvate kinase The activity decreased and the glycolysis process was inhibited. Glucagon and adrenaline on 6- Phosphofructokinase 2 Yes Covalent modification Function: produce the corresponding amount of fructose 2,6-diphosphate according to the sugar supply, and then affect the activity of fructose-6-phosphate kinase 1 to regulate glycolysis.

3. Allosteric regulation of key enzymes

⑴ The role of acetyl CoA as allosteric agent: activate gluconeogenic pyruvate carboxylase, inhibit the activity of pyruvate dehydrogenase complex in the aerobic oxidation of sugar, and promote gluconeogenesis. When the cell energy is sufficient, the tricarboxylic acid cycle is inhibited and acetyl CoA accumulates, thereby inhibiting the activity of pyruvate dehydrogenase complex and slowing down the production of acetyl CoA from pyruvate; At the same time, pyruvate carboxylase is activated and increased Gluconeogenesis In the process, excess pyruvate is converted into glucose.

⑵ The role of AMP and ATP as allosterics: AMP is the gluconeogenic fructose-1,6-diphosphate enzyme 1 Allosteric inhibitor It is an allosteric activator of 6-phosphate fructose kinase 1 in glycolysis. ATP、 Citric acid is an allosteric inhibitor of 6-phosphate fructose kinase 1. These two enzymes coordinate with each other to regulate gluconeogenesis and glycolysis. When the ATP/ADP ratio in hepatocytes increases, gluconeogenesis is strengthened and glycolysis is inhibited; on the contrary, when the ATP/ADP ratio decreases, glycolysis is accelerated and gluconeogenesis is inhibited.

⑶ The role of fructose 2,6-diphosphate as allosteric agent: fructose 2,6-diphosphate plays an important role in the interaction between glycolysis and gluconeogenesis. Fructose 2, 6-diphosphate is the strongest 6-phosphate fructose kinase 1 Allosteric activator It is also an allosteric inhibitor of fructose-1,6-diphosphate enzyme 1. When the sugar supply is sufficient, the increased concentration of fructose 2,6-diphosphate activates fructose-6-phosphate kinase 1, inhibits fructose-1,6-diphosphate enzyme 1, and promotes glycolysis. In the absence of sugar supply, the concentration of fructose 2,6 diphosphate decreases, which reduces the activation of fructose 6-phosphate kinase 1 and the inhibition of fructose 1,6 diphosphate enzyme 1, Gluconeogenesis increase^[2] 。

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