GLUCONEOGENESIS: STAGES (REACTIONS) AND REGULATION - CHEMISTRY - 2024

The gluconeogenesis is a metabolic process that occurs in almost all living things, including plants, animals and various types of microorganisms. It consists of the synthesis or formation of glucose from compounds that contain carbon that are not carbohydrates, such as amino acids, glucogens, glycerol and lactate.

It is one of the pathways of carbohydrate metabolism that is anabolic. It synthesizes or forms glucose molecules present mainly in the liver and, to a lesser extent, in the cortex of the kidneys of humans and animals.

Metabolic pathway of glucogenesis. Names in blue indicate the substrates of the pathway, arrows in red the unique reactions of this pathway, broken arrows indicate reactions of glycolysis, which go against this pathway, bold arrows indicate the direction of the pathway. By BiobulletM, from Wikimedia Commons

This anabolic process occurs by following the reverse direction of the catabolic pathway of glucose, having different specific enzymes at the irreversible points of glycolysis.

Gluconeogenesis is important for increasing glucose levels in the blood and tissues in hypoglycemia. It also dampens the decrease in carbohydrate concentration in prolonged fasts or in other adverse situations.

characteristics

It is an anabolic process

Gluconeogenesis is one of the anabolic processes of carbohydrate metabolism. Through its mechanism, glucose is synthesized from precursors or substrates made up of small molecules.

Glucose can be generated from simple biomolecules of a protein nature, such as glucogenic amino acids and glycerol, the latter coming from the lipolysis of triglycerides in adipose tissue.

Lactate also functions as a substrate and, to a lesser extent, odd-chain fatty acids.

Provide glucose supplies

Gluconeogenesis is of great importance for living beings and especially for the human body. This is because it serves to supply in special cases the great demand for glucose that the brain requires (approximately 120 grams per day).

What parts of the body demand glucose? The nervous system, the kidney marrow, among other tissues and cells, such as red blood cells, which use glucose as the sole or main source of energy and carbon.

The stores of glucose such as glycogen stored in the liver and muscles are barely enough for one day. This without considering diets or intense exercises. For this reason, through gluconeogenesis, the body is supplied with glucose formed from other non-carbohydrate precursors or substrates.

Also, this route is involved in glucose homeostasis. The glucose formed in this way, in addition to being a source of energy, is the substrate for other anabolic reactions.

An example of this is the case of biomolecule biosynthesis. These include glycoconjugates, glycolipids, glycoproteins and amino sugars and other heteropolysaccharides.

Stages (reactions) of gluconeogenesis

By AngelHerraez, from Wikimedia Commons

Synthetic route

Gluconeogenesis takes place in the cytosol or cytoplasm of cells, mainly of the liver and to a lesser extent in the cytoplasm of cells of the renal cortex.

Its synthetic pathway constitutes a large part of the reactions of glycolysis (glucose catabolic pathway), but in the opposite direction.

However, it is important to note that the 3 reactions of glycolysis that are thermodynamically irreversible, will be catalyzed by specific enzymes in gluconeogenesis different from those involved in glycolysis, which makes it possible for the reactions to occur in the opposite direction.

They are specifically those glycolytic reactions catalyzed by the enzymes hexokinase or glucokinase, phosphofructokinase and pyruvate kinase.

Reviewing the crucial steps of gluconeogenesis catalyzed by specific enzymes, the conversion of pyruvate to phosphoenolpyruvate requires a series of reactions.

The first occurs in the mitochondrial matrix with the conversion of pyruvate to oxaloacetate, catalyzed by pyruvate carboxylase.

In turn, for oxaloacetate to participate, it must be converted to malate by mitochondrial malate dehydrogenase. This enzyme is transported through the mitochondria to the cytosol, where it is transformed back to oxaloacetate by malate dehydrogenase found in the cell cytoplasm.

Action of the enzyme phosphoenolpyruvate carboxykinase

Through the action of the enzyme phosphoenolpyruvate carboxykinase (PEPCK), oxaloacetate is converted to phosphoenolpyruvate. The respective reactions are summarized below:

All these events make the transformation of pyruvate to phosphoenolpyruvate possible without the intervention of pyruvate kinase, which is specific for the glycolytic pathway.

However, phosphoenolpyruvate is transformed into fructose-1,6-bisphosphate by the action of glycolytic enzymes that reversibly catalyze these reactions.

Action of the enzyme fructose-1,6-bisphosphatase

The next reaction that supplies the action of phosphofructokinase in the glycolytic pathway is the one that transforms fructose-1,6-bisphosphate into fructose-6-phosphate. The enzyme fructose-1,6-bisphosphatase catalyzes this reaction in the gluconeogenic pathway, which is hydrolytic and is summarized below:

This is one of the points of regulation of gluconeogenesis, since this enzyme requires Mg ²⁺ for its activity. Fructose-6-phosphate undergoes an isomerization reaction catalyzed by the phosphoglycoisomerase enzyme that transforms it into glucose-6-phosphate.

Action of the enzyme glucose-6-phosphatase

Finally, the third of these reactions is the conversion of glucose-6-phosphate into glucose.

This proceeds through the action of glucose-6-phosphatase that catalyzes a hydrolysis reaction and that replaces the irreversible action of hexokinase or glucokinase in the glycolytic pathway.

This glucose-6-phosphatase enzyme is bound to the endoplasmic reticulum of liver cells. It also needs the cofactor Mg ²⁺ to exert its catalytic function.

Its location guarantees the function of the liver as a glucose synthesizer to supply the needs of other organs.

Gluconeogenic precursors

When there is not enough oxygen in the body, as can happen in muscles and erythrocytes in the case of prolonged exercise, glucose fermentation occurs; that is, glucose is not completely oxidized under anaerobic conditions and therefore lactate is produced.

This same product can pass into the blood and from there reach the liver. There it will act as a gluconeogenic substrate, since upon entering the Cori cycle the lactate will be converted into pyruvate. This transformation is due to the action of the enzyme lactate dehydrogenase.

Lactate

Lactate is an important gluconeogenic substrate in the human body, and once glycogen stores are depleted, the conversion of lactate to glucose helps to replenish glycogen stores in muscles and liver.

Pyruvate

On the other hand, through reactions that make up the so-called glucose-alanine cycle, pyruvate transamination occurs.

This is found in extra-hepatic tissues, transforming pyruvate into alanine, which constitutes another of the important gluconeogenic substrates.

In extreme conditions of prolonged fasting or other metabolic disturbances, protein catabolism will be a source of glucogenic amino acids as a last resort. These will form intermediates of the Krebs cycle and generate oxaloacetate.

Glycerol and others

Glycerol is the only significant gluconeogenic substrate originating from lipid metabolism.

It is released during the hydrolysis of triacylglycerides, which are stored in adipose tissue. These are transformed by consecutive phosphorylation and dehydrogenation reactions to dihydroxyacetone phosphate, which follow the gluconeogenic pathway to form glucose.

On the other hand, few odd-chain fatty acids are gluconeogenic.

Regulation of gluconeogenesis

One of the first controls of gluconeogenesis is carried out by an intake of foods with low carbohydrate content, which promote normal levels of glucose in the blood.

In contrast, if carbohydrate intake is low, the gluconeogenesis pathway will be important to meet the body's glucose requirements.

There are other factors involved in the reciprocal regulation between glycolysis and gluconeogenesis: ATP levels. When they are high, glycolysis is inhibited, while gluconeogenesis is activated.

The opposite happens with AMP levels: if they are high, glycolysis is activated, but gluconeogenesis is inhibited.

There are certain checkpoints in specific enzyme-catalyzed reactions in gluconeogenesis. Which? The concentration of enzymatic substrates and cofactors such as Mg ²⁺, and the existence of activators such as phosphofructokinase.

Phosphofructokinase is activated by AMP and the influence of the pancreatic hormones insulin, glucagon, and even some glucocorticoids.

References

1. Mathews, Holde and Ahern. (2002). Biochemistry (3rd ed.). Madrid: PEARSON
2. Wikibooks. (2018). Principles of Biochemistry / Gluconeogenesis and Glycogenesis. Taken from: en.wikibooks.org
3. Shashikant Ray. (December 2017). Gluconeogenesis Regulation, Measurements, and Disorders. Taken from: researchgate.net
4. Gluconeogenesis.. Taken from: imed.stanford.edu
5. Lecture 3-Glycolysis and Gluconeogenesis.. Taken from: chem.uwec.edu
6. Gluconeogenesis.. Taken from: chemistry.creighton.edu