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Gluconeogenesis Pathway Enzymes, Steps, Regulation

What is Gluconeogenesis? The synthesis of glucose from non-carbohydrate compounds is known as gluconeogenesis pathway. The major substrates/precursors for gluconeogenesis are lactate, pyruvate, glucogenic amino acids, propionate and glycerol.

Gluconeogenesis Definition

It is the gluconeogenesis pathway process of producing glucose molecules from non-carbohydrate precursors. These include lactate, glucogenic amino acids, fat-derived glycerol, and propionyl CoA produced from odd-chain fatty acids.

Gluconeogenesis Location

Gluconeogenesis pathway is mostly a cytosolic process, although some precursors are generated in the mitochondria. Gluconeogenesis occurs mostly in the liver (approximately 1 kg glucose is generated daily) and to a lesser extent in the kidney matrix.

Gluconeogenesis Importance

Glucose plays a significant position in the metabolism, and the body’s continual supply of glucose is vital for a number of processes. Brain and central nervous system, red blood cells, testes, and kidney medulla all get their energy from glucose. The human brain needs about 120 g of glucose every day, out of the 160 g that the whole body needs.

Under anaerobic conditions, glucose is the only fuel that can supply energy to the skeletal muscles. Even if you don’t eat for more than a day, your body needs gluconeogenesis to make glucose and keep the intermediates of the citric acid cycle going. This is important for people and other animals to stay alive.

Certain metabolites produced in the tissues, such as lactate, glycerol, and propionate, accumulate in the blood. They are effectively eliminated from the blood by gluconeogenesis pathway.

Gluconeogenesis Enzymes

Pyruvate carboxylase

Phosphoenol pyruvate carboxy kinase

Fructose-1-6-bisphosphatase

Glucose-6-phosphatase

Gluconeogenesis involves multiple glycolysis enzymes, however it is not a glycolysis reversal. The irreversible steps in glycolysis are circumvented by four enzymes which are designated as the key enzymes of gluconeogenesis.

Gluconeogenesis Steps

Gluconeogenesis closely resembles the reversed route of glycolysis, however it is not an exact reversal. Three of the ten glycolysis processes are essentially irreversible. Seven chemical processes are shared by glycolysis and gluconeogenesis. Enzymes catalyse the three irreversible steps of glycolysis, namely hexokinase, phosphofructokinase, and pyruvate kinase. These three stages bypassed by alternate enzymes specific to gluconeogenesis are discussed

gluconeogenesis pathway

Figure 1: Gluconeogenesis Steps. Figure 1 shows the gluconeogenesis pathway. [The enzymes catalysing irreversible glycolysis steps are shown in red. The key enzymes involved in gluconeogenesis are highlighted in green. The gluconeogenic substrates are shown in blue. (1) Alanine, glycine, serine, cysteine, threonine, and tryptophan; (2) Aspartate and asparagine; (3) Arginine, glutamate, glutamine, histidine, proline; (4) Isoleucine, methionine, valine; and (5) Phenylalanine, tyrosine].

Step 1

The conversion of pyruvate to phosphoenolpyruvate occurs in two steps. Pyruvate carboxylase is a mitochondrial enzyme that requires biotin to convert pyruvate to oxaloacetate in the presence of ATP and CO2. This enzyme controls gluconeogenesis and requires acetyl CoA to function.

gluconeogenesis pathway Conversion of pyruvate to phosphoenolpyruvate

Figure 2: Gluconeogenesis Pathway Conversion of Pyruvate to Phosphoenolpyruvate

The mitochondrial matrix is where oxaloacetate is made. It must be transported to the cytosol in order to be used in gluconeogenesis, which is where the rest of the pathway takes place. Oxaloacetate cannot diffuse out of the mitochondria due to membrane impermeability. It is converted to malate before entering the cytosol. Regeneration of oxaloacetate in the cytosol. Malate dehydrogenase, an enzyme found in both the mitochondria and cytoplasm, catalyses the reversible conversion of oxaloacetate and malate.

Phosphoenolpyruvate carboxykinase transforms oxaloacetate to phosphoenolpyruvate in the cytosol. This reaction utilises GTP or ITP (not ATP) and releases CO2 (fixed by carboxylase). 2 ATP equivalents are consumed during the conversion of pyruvate to phosphoenol pyruvate. In contrast, only one ATP is released for this process during glycolysis.

Step 2

Fructose 1,6-bisphosphate to fructose 6-phosphate conversion: Phosphoenolpyruvate undergoes glycolysis reversal until fructose 1,6-bisphosphate is produced. Fructose 1,6-bisphosphatase is an enzyme that converts fructose 1,6-bisphosphate to fructose 6-phosphate. Mg2+ ions are required for this enzyme. Smooth muscle and heart muscle lack Fructose 1,6-bisphosphatase. This enzyme is also involved in gluconeogenesis regulation.

Step 3

Glucose 6-phosphate to glucose conversion: Glucose 6-phosphatase catalyses the conversion of glucose 6-phosphate to glucose. The presence or absence of this enzyme in a tissue determines whether or not the tissue can contribute glucose to the blood. It is mostly found in the liver and kidney, but not in muscle, brain, or adipose tissue.

Gluconeogenesis Summary

The overall summary of gluconeogenesis pathway for the conversion of pyruvate to glucose is shown below

2 Pyruvate + 4ATP + 2GTP + 2NADH + 2H+ + 6H2O → Glucose + 2NAD+ + 4ADP + 2GDP + 6Pi + 6H+

Gluconeogenesis Reactions

i) From Amino Acids

Amino acid gluconeogenesis: All glucogenic amino acids (with the exception of leucine and lysine) contribute their carbon skeletons to the synthesis of glucose via the citric acid cycle, where they are converted to pyruvate or citrate.

ii) From the Glycerol

Glycerol is liberated mostly in the adipose tissue by the hydrolysis of fats (triacylglycerols). The enzyme glycerokinase (found in liver and kidney, absent in adipose tissue) activates glycerol to glycerol 3-phosphate. The latter is converted to dihydroxyacetone phosphate by glycerol 3-phosphate dehydrogenase. Dihydroxyacetone phosphate is an intermediate in glycolysis which can be conveniently used for glucose production.

iii) From propionate

Three-carbon propionyl CoA is produced by the oxidation of odd-chain fatty acids and the degradation of certain amino acids (methionine, isoleucine). Propionyl CoA carboxylase transforms it to methyl malonyl CoA in the presence of ATP and biotin, which is then transformed to succinyl CoA in the presence of B12 coenzyme. Through the citric acid cycle, succinyl CoA produced from propionyl CoA enters gluconeogenesis.

iv)From the lactate

From lactate or the Cori cycle, glucose is converted to pyruvate and then lactate in muscle. The lactate is then released into the circulation and transported to the liver, where it is reconverted to pyruvate and used for gluconeogenesis.

Gluconeogenesis Regulation

Gluconeogenesis pathway is mostly controlled by the hormone glucagon and the availability of substrates.

Influence of glucagon: Glucagon is a hormone that is made by D-cells in the islets of the pancreas. Glucagon speeds up the process of making glucose in two ways.

Active form of pyruvate kinase is converted to inactive form through the mediation of cyclic AMP, brought about by glucagon. Decreased pyruvate kinase results in the reduced conversion of phosphoenol pyruvate to pyruvate and the former is diverted for the synthesis of glucose.

Glucagon reduces the concentration of fructose 2,6-bisphosphate. This compound allosterically inhibits phosphofructokinase and activates fructose 1,6-bisphosphatase, both favour increased gluconeogenesis.

Availability of substrates : Among the various substrates, glucogenic amino acids have stimulating influence on gluconeogenesis. This is particularly important in a condition like diabetes mellitus (decreased insulin level) where amino acids are mobilized from muscle protein for the purpose of gluconeogenesis.

FAQ

FAQs on Gluconeogenesis Pathway

The liver and, to a lesser degree, the kidney are responsible for gluconeogenesis.

Yes, glucagon speeds up gluconeogenesis by helping the liver break down stored glycogen and by making it easier for compounds like amino acids and fatty acids to be turned into glucose.

Insulin slows down gluconeogenesis, which is part of how it is controlled. Insulin informs the liver and muscle cells to take glucose from the blood. This means that the body doesn’t have to make new glucose through gluconeogenesis as much.

Gluconeogenesis is considered a catabolic process. It is the breakdown of non-carbohydrate molecules, such as amino acids and fatty acids, into glucose, which is the primary source of energy for the body.

Gluconeogenesis often happens when the body needs to increase blood glucose levels, such as during fasting, endurance exercise, or in diabetics with high blood sugar.

Gluconeogenesis occurs in the cytosol, which is the fluid-like component of the cell that is present outside of the cell’s organelles.

Gluconeogenesis is the process by which the body makes glucose from non-carbohydrate molecules like lactate, pyruvate, amino acids, and glycerol.