Gluconeogenesis

The synthesis of glucose from noncarbohydrate compounds is known as gluconeogenesis.

The major substrates/precursors for gluconeogenesis are lactate, pyruvate, glucogenic amino acids, propionate and glycerol.

Gluconeogenesis is an important metabolic pathway that helps maintain blood glucose levels during fasting, starvation, or prolonged exercise. This process is essential for providing glucose to organs such as the brain and red blood cells, which depend heavily on glucose for energy.

Salient features of Gluconeogenesis:

• Gluconeogenesis is essentially the reverse of glycolysis, but the irreversible steps of glycolysis are bypassed by special enzymes.
• It is an energy-consuming pathway, requiring 4 ATP, 2 GTP, and 2 NADH for the formation of one molecule of glucose from pyruvate.
• The pathway is important for glucose supply to glucose-dependent tissues, especially the brain, red blood cells (RBCs), and muscles during fasting.
• Gluconeogenesis is a ubiquitous process, observed in all of living kingdom including plants, animals, fungi and bacteria. This process is also referred to as an endogenous glucose production (EGP)
• Gluconeogenesis and glycogenolysis are the two mechanism that help in maintaining blood glucose levels in the body.

Location of Gluconeogenesis:

Gluconeogenesis mainly occurs in the cytosols of liver cells and to a lesser extent in the kidneys.

Gluconeogenesis mostly takes place in liver (about 1 kg glucose synthesized everyday) and, to lesser extent, in kidney matrix (about one-tenth of liver capacity).

Reactions of Gluconeogenesis:

Gluconeogenesis closely resembles the reversed pathway of glycolysis, although it is not the complete reversal of glycolysis. Essentially, 3 reactions of glycolysis are irreversible. The other remaining reactions are common in both glycolysis and gluconeogenesis.

Here you can see the differences in these reactions in a comparative image:

Description of steps occurs in Gluconeogenesis:

Step 1: Formation of Phosphoenol Pyruvate (PEP) from Pyruvate

This is the first step in which the pyruvate which is formed in glycolysis entered inside mitochondria and converted into oxaloacetate, this reaction is catalysed by enzyme pyruvate carboxylase in the presence of biotin.

Then Oxaloacetate is converted into malate inside mitochondria by enzyme malate dehydrogenase.

Then this malate comes out from the mitochondria to the cell cytoplasm and is converted back into oxaloacetate by enzyme malate dehydrogenase.

This oxaloacetate converts into Phosphoenolpyruvate by the enzyme Phosphoenolpyruvate carboxykinase. From this phosphoenolpyruvate the gluconeogenesis begins in reverse direction of glycolysis to form glucose molecule. This synthesis of glucose from pyruvate is called gluconeogenesis.

Step 2: Formation of 2-Phosphoglycerate

Phosphoenolpyruvate (PEP) is converted into 2-phosphoglycerate. The reaction is catalyzed by the enzyme enolase.

Step 3: Formation of 3-Phosphoglycerate

2-Phosphoglycerate is converted into 3-phosphoglycerate. The reaction is catalyzed by the enzyme phosphoglycerate mutase.

Step 4: Formation of 1,3-Bisphosphoglycerate

3-Phosphoglycerate is converted into 1,3-bisphosphoglycerate. The reaction is catalyzed by the enzyme phosphoglycerate kinase.

Step 5: Formation of Glyceraldehyde-3-phosphate

1,3-Bisphosphoglycerate is converted into glyceraldehyde-3-phosphate (G3P). The reaction is catalyzed by the enzyme glyceraldehyde-3-phosphate dehydrogenase.

Step 6: Formation of Dihydroxyacetone Phosphate (DHAP)

Glyceraldehyde-3-phosphate is converted into dihydroxyacetone phosphate (DHAP). The reaction is catalyzed by the enzyme triose phosphate isomerase.

Step 7: Formation of Fructose-1,6-bisphosphate

Glyceraldehyde-3-phosphate combines with dihydroxyacetone phosphate to form fructose-1,6-bisphosphate. The reaction is catalyzed by the enzyme aldolase.

Step 8: Formation of Fructose-6-phosphate

The phosphate of both the phosphoglycerate molecules is relocated from the third to the second carbon to produce two molecules of 2-phosphoglycerate by the enzyme phosphoglyceromutase.

Step 9: Formation of Glucose-6-phosphate

Fructose-6-phosphate is converted into glucose-6-phosphate. The reaction is catalyzed by the enzyme phosphoglucose isomerase.

Step 10: Formation of Glucose

Glucose-6-phosphate is converted into glucose. The reaction is catalyzed by the enzyme glucose-6-phosphatase.

Energetics of Gluconeogenesis:

Gluconeogenesis is an energy-consuming process because energy is required to convert pyruvate into glucose.

Total energy consumed = 4 ATP + 2 GTP + 2 NADH