Gluconeogenesis, reactions, substrate, regulation - The virtual notebook (2023)

As we all know, our body needs glucose as a source of energy. A supply of glucose is particularly necessary for the nervous system and red blood cells. When our blood sugar levels are below or above the required level, it can create an imbalance. Therefore, it is extremely important for our system to maintain glucose balance. Our body has several processes and ways to keep glucose levels under control.gluconogenesais one of those ways. The gluconeogenesis pathway is found in all animals, plants, fungi, and microorganisms. The reactions are essentially the same in all tissues and in all species.

The gluconeogenic pathway converts pyruvate to glucose. Non-carbohydrate glucose precursors are first converted to pyruvate or enter the pathway in later intermediates such as oxaloacetate and dihydroxyacetone phosphate.

Importance of gluconeogenesis

The gluconeogenesis pathway occurs when glucose levels in the body drop below required levels. Helps maintain blood sugar levels throughout the daysqueezemiFomé. Therefore, it is a very important process and its failure is often fatal.hypoglycemia(a condition in which blood sugar levels drop below specified limits) is very fetal and can cause coma and even death.

Glucose is also important to maintain intermediate levelskrebs cyclealthough fatty acids are the main source of acetyl-CoA in tissues. Gluconeogenesis also removes lactate from muscle and erythrocytes and glycerol from adipose tissue.

Glycolysis and gluconeogenesis

glycolize: It is the main route of glucose metabolism, converting glucose into pyruvate (under aerobic conditions) or lactate (under anaerobic conditions). After that, pyruvate can be fully oxidized to CO²eh₂Or by enzymes present in the mitochondria. Basically, glycolysis takes place in the cytosol of all cells and is also called “Embden-Meyerhof-Parnas-Wanderweg".

For more information, see:glycolysis pathway

gluconogenesaGlucose is the process by which new glucose molecules are formed from non-carbohydrate precursors. The main substrates are glucogenic amino acids, lactate, glycerol and propionate. The liver and kidney are the major gluconeogenic tissues, but the small intestine can also be a source of fasting glucose.

Glycolysis converts glucose to pyruvate, while gluconeogenesis converts pyruvate to glucose. However, gluconeogenesis is not the opposite of glycolysis. The irreversible intervenesglycolizethey areignoredby four enzymes that are the key enzymes in gluconeogenesis.

I have written a separate article on the similarities and differences between glycolysis and gluconeogenesis. if you want to read itPlease read this article:Glycolysis vs. gluconeogenesis

Where does gluconeogenesis occur?

Gluconeogenesis occurs primarily in the liver and, to a lesser extent, in the renal cortex. A small part of gluconeogenesis takes place in the brain, skeletal muscle, or cardiac muscle. The liver preferentially uses lactate, glycerol, and glucogenic amino acids, while the kidney preferentially uses lactate, glutamine, and glycerol. The pathway is partly mitochondrial and partly cytoplasmic.

gluconeogenesis pathway

Gluconeogenesis requires apower sourcefor biosynthesis andcarbon sourcefor the formation of the skeleton of the glucose molecule. Carbon skeletons are provided by lactate (from tissues), amino acids (from muscles), and glycerol (from triglycerides).krebs cycleIntermediates can also act as substrates for gluconeogenesis. under these,muscle proteinit is the most important precursor of blood sugar during fasting and starvation.

Irreversible steps of glycolysis.

Before moving on to gluconeogenesis, let me give you a brief overview of glycolysis. In total, glycolysis consists of ten steps. Three of them are irreversible. For the gluconeogenesis pathway, we have to bypass these irreversible steps. A large amount of energy is required to reverse these steps. The irreversible steps of glycolysis are as follows:

1. Glucose phosphorylation to glucose-6-phosphate (G6P): In this step, glucose is converted to G6P by the enzymes hexokinase (found in all tissues) and glucokinase (found in the liver and pancreas). This reaction is step 1 of glycolysis.
2. Phosphorylation of F6P to fructose-1,6-bisphosphate (F-1,6-bisP): Fructose-6-phosphate phosphorylated to fructose-1,6-bisphosphate by the enzyme phosphofructokinase. (Step 3)
3. Dephosphorylation of PEP (phosphoenolpyruvate) to pyruvate: This reaction occurs in two steps. First, PEP is converted to the enolpyruvate intermediate. It then spontaneously isomerizes to ketopyruvate, the stable form of pyruvate. (Step 9)

The previous three steps (1,3,9) are irreversible steps of the glycolytic pathway.

There are slight variations in the pathway of gluconeogenesis, depending on the substrate. The metabolic pathway uses lactate, amino acids, glycerol, and propionate as the main substrate. We will discuss these substrate-specific pathways later..

Gluconeogenase enzyme

Gluconeogenesis uses several enzymes of glycolysis. In addition to glycolytic enzymes, it uses four other enzymes and they are:

1. pyruvatecarboxylase
2. Phosphoenolpyruvate carboxykinase
3. Fructose-1-6-bisphosphatase
4. Glucose-6-phosphatase

Steps of gluconeogenesis (irreversible steps)

STEP 1: Carboxylation of pyruvate to oxaloacetate

First, pyruvate enters the mitochondria in the cytoplasm. So the mitochondrial enzymespyruvatecarboxylasecatalyzes the carboxylation reaction of pyruvate to oxaloacetate. This reaction requires biotin and ATP molecules to continue.

The oxaloacetate must now be transported from the mitochondria to the cytosol, since other gluconeogenesis reactions take place in the cytosol. To do this, oxaloacetate is first converted to malate by malate dehydrogenase, which crosses the membrane and reaches the cytoplasm. The malate is then converted back to oxaloacetate.

STEP 2: Conversion of oxaloacetate to phosphoenolpyruvate (PEP)

Oxaloacetate is converted to phosphoenolpyruvate by the enzymePhosphoenolpyruvate carboxykinase(PEPCK). This reaction removes a CO₂Molecule. GTP or ITP donates the phosphate group to the reaction.

Phosphoenolpyruvate undergoes further reactions catalyzed by glycolytic enzymes to form fructose-1,6-bisphosphate.

For more information, see:stages of glycolysis

STEP 3: Conversion of fructose-1,6-bis-phosphate to fructose-6-phosphate

Fructose-1,6-bisphosphate is then converted to fructose-6-phosphate by the enzymeFructose-1,6-bisphosphatase. Subsequently, fructose-6-phosphate is isomerized to glucose-6-phosphate by the freely reversible reaction catalyzed byHexosefosfatisomerasa.

This enzyme is found in liver, kidney, and skeletal muscle, but is likely absent in heart and smooth muscle.

STEP 4: Hydrolysis of Glucose-6-Phosphate to Glucose

Glucose-6-phosphate is hydrolyzed by the enzyme to release glucoseGlucose-6-phosphatase. This enzyme is active in the liver. It is also present to a lesser extent in kidneys and intestinal mucosa, but is absent in muscle and adipose tissue.

This last step is not completed in the cytoplasm. Instead, glucose-6-phosphate migrated in the light of theEndoplasmatisches Retikulumfor the reaction to occur.

Regulation of gluconeogenesis

Gluconeogenesis and glycolysis regulate each other, such that one pathway is relatively inactive when the other is active. When there is a need for energy, glycolysis predominates, and when there is an excess of energy, gluconeogenesis takes over. There are the following steps in the regulation of gluconeogenesis:

Activators and Inhibitors

pyruvatecarboxylase(catalyst of the first irreversible reaction of gluconeogenesis) is an allosteric enzyme.

It requires acetyl-CoA as an allosteric activator. A higher level of acetyl-CoA favors the activity of pyruvate carboxylase, which in turn favors the production of oxaloacetate.

Likewise, citrate is an activator, while fructose-2,6-bisphosphate and AMP are inhibitors ofFructose-1,6-bisphosphatase.

Both acetyl-CoA and citrate activate the enzymes of gluconeogenesis while inhibiting the enzyme of glycolysis, pyruvate kinase.

Hormonal regulation of gluconeogenesis

glucagonmiAdrenaline(responsible for lowering blood sugar levels) inhibits glycolysis and
stimulate gluconeogenesis in the liver, increasing cAMP concentration. This, in turn, activates cAMP-dependent protein kinase, resulting in phosphorylation and inactivation of pyruvate kinase.

Insulinimproves the synthesis of key enzymes in glycolysis. It also antagonizes the action of glucocorticoids and glucagon-stimulated cAMP, which induces the synthesis of the main enzymes involved in gluconeogenesis (PEPCK, fructose-1,6-bisphosphatase, and glucose-6-phosphatase).

atp

ATP also increases gluconeogenesis.

gluconeogenesis substrate

The main substrates of the gluconeogenic pathway are glucogenic amino acids, lactate, glycerol, and propionate. Gluconeogenesis can be obtained from the following substrate above.

1. Lactate

Gluconeogenesis from lactate is conceptually the opposite of anaerobic glycolysis, but proceeds along a slightly different pathway involving mitochondrial and cytosolic enzymes. In the liver cell, lactate dehydrogenase converts lactate to pyruvate. Pyruvate enters the pathway to form glucose.

2. Glycerin

Glycerol enters the gluconeogenesis pathway at the triose phosphate level. Glycerol is phosphorylated in the liver cytosol by the enzymeglycerinquinasa. It is then oxidized to dihydroxyacetone phosphate by a NAD+-dependent dehydrogenase.

3. Amino acids

Most amino acids can serve as substrates for the gluconeogenic pathway. After deamination, their carbon skeletons can be converted to glucose. When glucose levels drop below the required level, the glucogenic amino acids are transaminated onto the appropriate carbon skeletons. After that, these amino acids can enterTCA-Zyklusand form oxalacetate or pyruvate.

All amino acids exceptleucinemilysineit can provide carbon for the net synthesis of glucose through gluconeogenesis. Alanine and glutamine are the major amino acids present in muscle and serve as substrates for gluconeogenesis.

4. Propionyl-CoA (propionate)

Propionate is a good precursor for gluconeogenesis and generates oxaloacetate via the anaplerotic pathway. Propionyl-CoA can be formed fromodd chain fatty acidsand the carbon skeleton of some amino acids. It is converted to succinyl-CoA.

Noticefrom which it is impossible to synthesize glucosesame chain of fatty acids. This is because acetyl-CoA and other straight-chain fatty acid oxidation intermediates cannot be converted to oxaloacetate or other intermediates of gluconeogenesis.

External sources and links

Biochemistry Textbook for Medical Students, Seventh Edition, by DM Vasudevan; Chapter 9: Important Glucose Metabolic Pathways

In addition, BRS Biochemistry 6th Edition, Molecular Biology and Genetics by Michael A. Lieberman, PhD and Rick Ricer; Chapter #6: Carbohydrate Metabolism.

Also Lippincott's Illustrated Review Biochemistry, 6th Edition; Chapter 8: Introduction to metabolism and glycolysis Pages #187 to #199and Chapter 10: Gluconeogenesis.

Harper's Illustrated Biochemistry, 28th edition; Chapter 18: Pyruvate Glycolysis and Oxidation, pages #317 to #327.Also Chapter 10: Gluconeogenesis and Blood Sugar Control

Textbook of Biochemistry with Clinical Correlations 4th Edition by Thomas L Delvin Pages Nos. 274 and

Lehninger: Principles of Biochemistry, 7th Edition, Chapter 14 Glycolysis, Gluconeogenesis,
and via das pentose phosphate

https://en.wikipedia.org/wiki/Gluconeogénesis

https://www.ncbi.nlm.nih.gov/books/NBK544346/