Gluconeogenesis

The process by which organisms convert a variety of non sugar substances into glucose

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synonym Gluconeogenesis (gluconeogenesis) generally refers to gluconeogenesis

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The process by which an organism converts a variety of non sugar substances into glucose or glycogen. In mammals, the liver is the main organ of gluconeogenesis. Under normal circumstances, the gluconeogenesis capacity of the kidney is only 1/10 of that of the liver. The gluconeogenesis capacity of the kidney can be greatly enhanced when long-term hunger occurs. The main precursors of gluconeogenesis are lactic acid, pyruvic acid, amino acid and glycerol.^[1]

Chinese name: Gluconeogenesis
Foreign name: Gluconeogenesis

Type: sugar
Properties: Physiology

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brief introduction

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Gluconeogenesis (Gluconeogenesis refers to sugar, neogenesis is the Greek νε ογ? ννησ η, neoj é nnissi - regeneration): also known as gluconeogenesis. It consists of simple non sugar precursors (lactic acid, glycerol, raw sugar amino acid To sugar (glucose or Glycogen ）Process. Gluconeogenesis Glycolysis Simple reversal of. Although by pyruvic acid The initial gluconeogenesis utilizes the seven step approximation in glycolysis Equilibrium reaction The reverse reaction of Enzymatic reaction And bypass the three irreversible reactions in the fermentation process. Gluconeogenesis ensures that the blood sugar level of the body is at a normal level.

Gluconeogenesis, also known as gluconeogenesis, is a process of transforming simple non sugar precursors (lactic acid, glycerol, raw sugar amino acids, etc.) into sugar (glucose or glycogen). Gluconeogenesis is not a simple reversal of glycolysis. Although gluconeogenesis starting from pyruvate utilizes the reverse reaction of the seven steps of approximate equilibrium reaction in glycolysis, it is also necessary to bypass the three irreversible reactions in glycolysis by using the enzymatic reaction that did not occur in the other four steps of glycolysis. Gluconeogenesis ensures that the blood sugar level of the body is at a normal level. The main organ of gluconeogenesis is liver. Under normal circumstances, the renal gluconeogenesis is only 1/10 of that of the liver, but the renal gluconeogenesis can be greatly enhanced under long-term starvation^[2] 。

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When the liver or kidney pyruvic acid When gluconeogenesis is carried out as raw material, the seven steps in gluconeogenesis are Glycolysis They have the same enzyme catalysis. But there are three steps in glycolysis: Irreversible reaction 。 In gluconeogenesis, these three steps must be bypassed at the cost of more energy consumption.

These three reactions are strongly exothermic, and they are:

1. Glucose channel Hexokinase Catalytic production of glucose 6-phosphate Δ G=-33.5 kJ/mol;

2. Fructose phosphate Phosphofructokinase Catalytic formation Fructose 1,6 diphosphate ΔG= -22.2 kJ/mol；

3、 Phosphoenolpyruvate through Pyruvate kinase Generate pyruvic acid Δ G=-16.7 kJ/mol.

These three steps will be bypassed in this way:

1. Glucose-6-phosphatase catalyzes glucose 6-phosphate to produce glucose;

2. Fructose 1,6-diphosphatase catalyzes fructose 1,6-diphosphate to produce fructose 6-phosphate;

3. This process consists of two reactions. The first reaction consists of Pyruvate carboxylase Catalysis, coenzyme is biotin, and the reaction consumes 1 molecule ATP. The second reaction is composed of Phosphoenolpyruvate carboxyl kinase Catalysis, reaction consumes 1 molecule GTP.

Because pyruvate carboxylase only exists in mitochondrion Therefore, pyruvate in the cytosol must enter the mitochondria for carboxylation Oxaloacetic acid 。 Phosphoenolpyruvate carboxyl kinase^{[5 ]} It exists in both mitochondria and cytosol, so oxaloacetic acid can be directly transformed into phosphoenolpyruvate in mitochondria and then into cytosol, and can also be transformed into phosphoenolpyruvate in cytosol. However, oxaloacetic acid cannot pass through mitochondria directly, and it needs to be transported into the cytosol in two ways: Malate dehydrogenase Function, reducing it to malic acid, and then passing through mitochondrial membrane After entering the cytoplasm, malate dehydrogenase in the cytoplasm will dehydrogenate and oxidize malate to oxaloacetic acid and enter the gluconeogenesis pathway. The other way is to generate aspartic acid through the action of glutamic oxaloacetate transaminase, and then escape from the mitochondria. The aspartic acid entering the cytosol will be recovered to generate oxaloacetic acid through the catalysis of glutamic oxaloacetate transaminase in the cytosol. Some experiments show that pyruvic acid Or can be converted into pyruvate Raw sugar amino acid When used as raw material for isomerization of sugar, malic acid is passed through mitochondrion Methods: gluconeogenesis; When lactic acid undergoes gluconeogenesis, it is often converted into aspartic acid after the formation of oxaloacetic acid in mitochondria and enters the cytoplasm.

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1. Anything that can produce oxaloacetic acid can be changed into glucose. For example, the intermediate of the tricarboxylic acid cycle, citric acid Isocitrate 、 α - ketoglutaric acid 、 Succinic acid 、 Fumaric acid And malic acid can be transformed into oxaloacetate and enter the gluconeogenesis pathway.

2. Most amino acids are Raw sugar amino acid Such as alanine glutamate , aspartic acid serine 、 Cysteine 、 glycine 、 Arginine 、 histidine 、 threonine 、 proline 、 Glutamine amide 、 Asparagine 、 methionine , valine, etc., which can be converted into pyruvate α - ketoglutaric acid , oxaloacetic acid and other tricarboxylic acid cycle intermediates participate in the gluconeogenesis pathway.

3. Cori circulation: a large amount of lactic acid produced during strenuous exercise will quickly diffuse to the blood and flow to the liver with the blood flow, first oxidized to pyruvate, and then Gluconeogenesis It can be converted into glucose to supplement blood sugar, and can also regenerate muscle Glycogen Be stored. This lactic acid - glucose Cyclic process Is called the Cori cycle or Lactic acid circulation 。^[1]

4. The gluconeogenesis pathway of ruminants is very active, and the bacteria in the cow stomach break down cellulose into acetic acid propionic acid 、 butyrate Equal odd fatty acids can be converted into succinyl CoA to participate in gluconeogenesis to synthesize glucose.

process

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Gluconeogenesis

The main precursors of gluconeogenesis are lactic acid pyruvic acid 、 amino acid And glycerin, etc. In the digestive tract of ruminants, a large amount of cellulose can be converted into propionic acid by bacteria, and the latter can also be converted into sugar in the body.

The process is divided into two stages:

① Conversion of various gluconeogenic precursors (except glycerol) into Phosphoenolpyruvate ；

② Phosphoenolpyruvate is converted into glucose 6-phosphate, and then various monosaccharides or polysaccharides are generated.

from pyruvic acid The process of starting to synthesize sugar Glycolysis The reverse reaction of is similar, but due to Hexokinase 、 Phosphofructokinase and Pyruvate kinase It is difficult to reverse the three reactions catalyzed. stay Gluconeogenesis The reverse processes of the two reactions catalyzed by hexokinase and phosphofructose kinase are respectively- phosphatase And fructose 1,6-diphosphatase. The reverse process of the reaction catalyzed by pyruvate kinase Pyruvate carboxylase Catalytic pyruvate formation Oxaloacetic acid , and then Phosphoenolpyruvate The carboxyl kinase catalyzes the formation of phosphoenolpyruvate. Gluconeogenesis regulates body fat and Proteolysis Strengthened, muscle glycolysis is strengthened during strenuous exercise, which can provide more precursors to accelerate gluconeogenesis in the liver.

Hepatocyte ATP or Acetyl CoA (CoA) can strengthen the carboxylation of pyruvate to form sugar when the supply is sufficient.

adrenaline 、 Glucagon 、 Adrenocortical hormone Can increase gluconeogenesis in hepatocytes; Insulin inhibits it.

Physiological significance During fasting or starvation, normal blood glucose concentration is mainly maintained by gluconeogenesis to meet the need of brain tissue for continuous consumption of glucose, and also make full use of excessive non sugar substances in the body, such as lactic acid and pentose amino acid Etc.

Energy consumption

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From two molecules pyruvic acid At the beginning, the final synthesis of one molecule of glucose requires 6 molecules of ATP/GTP. comparison Glycolysis The process can produce 2ATP net, and gluconeogenesis is an energy consuming process.

These six molecules of ATP/GTP are consumed in the three-step reaction, and the process needs to be repeated to generate one molecule of six carbon compound, so the total energy consumption is 3 × 2=6:

1. Pyruvate in Pyruvate carboxylase It consumes a molecule of ATP and generates Oxaloacetic acid 。

2. Oxalacetic acid in Phosphoenolpyruvate With the help of carboxylated kinase, it becomes phosphoenolpyruvate. The reaction consumes 1 molecule of GTP.

3、3 Phosphoglycerate stay Phosphoglycerate kinase With the help of, consume one molecule of ATP to generate 1,3 Diphosphoglycerate 。 Note that this reaction is reversible.

effect

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I Gluconeogenesis Its main physiological significance is to ensure that the blood sugar concentration is relatively constant in the case of hunger.

The normal concentration of blood glucose is 3.89-11mmol/L. Even if fasting for several weeks, the blood glucose concentration can still be maintained at about 3.40mmol/L, which is of great significance to ensure the function of some tissues that mainly rely on glucose for energy supply. Normal people who are in a quiet state after a night of fasting (8-10 hours) use glucose in their bodies every day, about 125g in their brains, about 50g in their muscles (at rest), and about 50g in their blood cells, Only these organizations consume Sugar content 225g, about 150g of available sugar is stored in the body, and the muscle with the largest sugar storage capacity Glycogen It is only for its own oxidation energy supply. If only the storage amount of liver glycogen is used to maintain the blood glucose concentration for at most 12 hours, it can be seen that gluconeogenesis is important

II Gluconeogenesis Closely related to the action of lactic acid

During intense exercise, muscles Glycolysis A large amount of lactic acid is generated, and the latter can be transported to the liver through the blood to synthesize liver glycogen and glucose, so that the muscle glycogen that cannot directly produce glucose can be indirectly converted into blood sugar, which is conducive to recovering the energy in lactic acid molecules, renewing muscle glycogen, and preventing Lactic acidosis Occurrence of.

3、 Assistance amino acid metabolize

The experiment confirmed that after eating protein Glycogen Content increase; Fasting, late stage diabetes Or excessive cortisol Proteolysis The plasma amino acid increases and the heterogenesis of sugar increases, so the amino acid sugar formation may be Amino acid metabolism The main approach.

4、 Promoting the secretion of ammonia in renal tubules

After long-term fasting, renal gluconeogenesis can be significantly increased. This change may be caused by metabolic acidosis caused by hunger. The decrease of body fluid pH can promote the formation of gluconeogenesis in renal tubules phosphoenolpyruvate carboxylase The synthesis of α - ketoglutarate in the kidney increases the saccharification Oxaloacetic acid After accelerated sugar formation, it can be promoted by the reduction of α - ketoglutaric acid glutamine Deamination glutamate As well as the deamination of glutamic acid, renal tubular cells convert NH three Secreted into the lumen + Combined to reduce primary urine H + The concentration of is conducive to hydrogen removal and sodium retention, and plays an important role in preventing acidosis.

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The rate limiting enzymes of gluconeogenesis mainly include the following four enzymes: Pyruvate carboxylase Phosphoenolpyruvate carboxyl kinase^[4] Fructose diphosphatase and glucose phosphatase.

1、 Regulation of gluconeogenesis by hormones

Hormonal regulation Gluconeogenesis It is very important to maintain the steady state of the body. The essence of hormone regulation on gluconeogenesis is to regulate gluconeogenesis and gluconeogenesis Glycolysis These two approaches Regulatory enzyme As well as controlling the fatty acids supplied to the liver, the acquisition of more fatty acids makes the liver oxidize more fatty acids, which also promotes glucose synthesis, Glucagon Promote fat Organizational decomposition Fat increases plasma fatty acid, thus promoting gluconeogenesis; Insulin has the opposite effect. Both glucagon and insulin can regulate gluconeogenesis by affecting the phosphorylation of liver enzymes, and glucagon is activated Adenylate cyclase To produce cAMP, which activates cAMP dependent protein kinase, which phosphorylates Pyruvate kinase And make it suppress this Zymolysis Pathetic Regulatory enzyme Inhibition stimulates gluconeogenesis because it prevents Phosphoenolpyruvate To pyruvate. Glucagon reduces the concentration of fructose 2,6-diphosphate in the liver and promotes the conversion of fructose 1,6-diphosphate to fructose 6-phosphate, because fructose 2,6-diphosphate is fructose diphosphate phosphatase The other inhibitor of is 6 Phosphofructokinase Glucagon can promote the phosphorylation of bifunctional enzyme (6-phosphofructose kinase 2/fructose 2,6-diphosphatase) through cAMP. After phosphorylation, this enzyme inactivates the kinase site but activates the phosphatase site, so 2, 6- Fructose diphosphate Generation is reduced and hydrolysis Fructose 6-phosphate increased. The result of the decrease of fructose 2,6-diphosphate caused by glucagon is 6 Phosphofructokinase 1 The activity decreases, the activity of fructose diphosphatase increases, and the conversion of fructose diphosphate to fructose 6-phosphate increases, which is beneficial to gluconeogenesis, while insulin has the opposite effect.

In addition to the above Glucagon And insulin on the short-term regulation of gluconeogenesis and glycolysis, they also induce or inhibit the regulating enzymes of gluconeogenesis and glycolysis, respectively, and the high glucagon/insulin ratio induces a large number of phosphoenolpyruvate carboxylkinase^[4] , fructose 6-phosphatase and other gluconeogenic enzymes Glucokinase and Pyruvate kinase Synthesis of.

2、 Regulation of metabolites on gluconeogenesis

1. The concentration of gluconeogenic raw materials Gluconeogenesis Regulation of: glycerol, lactic acid and amino acid When the concentration increased, the heterogenesis of sugar increased. For example, in the case of hunger, Fat mobilization Increase, tissue protein decomposition is strengthened, and plasma glycerol and amino acid are increased; During intense exercise, Blood lactic acid The rapid increase of the content can promote gluconeogenesis.

2、 Acetyl CoA Effect of concentration on gluconeogenesis: acetyl coenzyme A determines pyruvic acid The direction of metabolism, Fatty acid oxidation Decomposition produces a large amount of Acetyl CoA Can be suppressed Pyruvate Dehydrogenase It accumulates a large amount of pyruvic acid, provides raw materials for gluconeogenesis, and can also activate Pyruvate carboxylase , accelerate the formation of pyruvate Oxaloacetic acid , make Gluconeogenesis enhance.

In addition, the condensation of acetyl CoA with oxaloacetic acid generates citric acid from mitochondrion Enter through Cytosol Medium, can suppress Phosphofructokinase It can increase the activity of fructose hexaphosphatase and promote gluconeogenesis.

The reverse process of glycolysis

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The specific reaction process from pyruvate to glucose is called gluconeogenesis, which is basically the reverse process of glycolysis. Most reactions in the glycolysis pathway are reversible, but the hexokinase (or Glucokinase ）, phosphofructose kinase and Pyruvate kinase The reactions catalyzed by these three key enzymes are exothermic Irreversible reaction , also called energy barrier. In gluconeogenesis, they are catalyzed by other enzymes to bypass these three energy barriers, and ATP is required to supply energy to ensure the progress of the synthetic pathway^[3] 。

Relevant research achievements

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Replication and stimulation of gluconeogenesis by novel coronavirus in human hepatocytes

By detecting the number of copies of new coronavirus RNA in hepatocytes infected with COVID-19, scientists showed that COVID-19 can replicate in hepatocytes without causing direct damage to hepatocytes. Next, it is a key research step. Scientists have proved that the glucose production of hepatocytes infected with COVID-19 increased about twice 48 hours after infection.

Further research found that the mRNA expression of genes related to gluconeogenesis or glycogen decomposition in infected hepatocytes did not increase, or even decreased; However, 48 hours after infection, the activity of phosphoenolpyruvate carboxyl kinase (PEPCK), the rate limiting enzyme of gluconeogenesis, increased by two to four times. This means that hyperglycemia caused by COVID-19 infection in non diabetic patients is caused by direct infection of liver cells, increasing the activity of phosphoenolpyruvate carboxykinase in the gluconeogenesis pathway, and increasing the amount of glucose produced through the gluconeogenesis pathway.

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