Gluconeogenesis

 Gluconeogenesis

Definition

Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates.

I. From fats. It is certain that the glycerol, portion of fat, which makes up about 10% of the fat molecule, is converted into glucose in the body but the conversion of fatty acid portion of fat molecules to glucose is a matter of dispute especially in animal body as contrast to plants. It can be concluded that the synthesis of carbohydrates from fats takes place indirectly.

 II. From proteins. Formation of glucose and glycogen may take place from proteins. These amino acids like glycine and alanine are called glucogenic or antiketogenic amino acids. About 80% of the food proteins can form glucose.

Steps

Gluconeogenesis is a pathway consisting of a series of eleven enzyme-catalyzed reactions. The pathway will begin in either the liver or kidney, in the mitochondria or cytoplasm of those cells, this being dependent on the substrate being used. Many of the reactions are the reverse of steps found in Glycolysis.

1. Gluconeogenesis begins in the mitochondria with the formation of oxaloacetate by the carboxylation of pyruvate. This reaction also requires one molecule of ATP, and is catalyzed by pyruvate carboxylase. This enzyme is stimulated by high levels of acetyl-CoA (produced in β-oxidation in the liver) and inhibited by high levels of ADP and glucose.
2. Oxaloacetate is reduced to malate using NADH, a step required for its transportation out of the mitochondria.
3. Malate is oxidized to oxaloacetate using NAD⁺ in the cytosol, where the remaining steps of Gluconeogenesis take place.
4. Oxaloacetate is decarboxylated and then phosphorylated to form phosphoenolpyruvate using the enzyme PEPCK. A molecule of GTP is hydrolyzed to GDP during this reaction.
5. The next steps in the reaction are the same as reversed Glycolysis. However, fructose 1,6-bisphosphatase converts fructose 1,6-bisphosphate  to fructose 6-phosphate, using one water molecule and releasing one phosphate (in Glycolysis, phosphofructokinase 1 converts F6P and ATP to F1,6BP and ADP). This is also the rate-limiting step of Gluconeogenesis.
6. 1. Glucose-6-phosphate is formed from fructose 6-phosphate by  phosphoglucoisomerase (the reverse of step 2 in Glycolysis). Glucose-6-phosphate can be used in other metabolic pathways or dephosphorylated to free glucose. Whereas free glucose can easily diffuse in and out of the cell, the phosphorylated form (glucose-6-phosphate) is locked in the cell, a mechanism by which intracellular glucose levels are controlled by cells.
   2. The final Gluconeogenesis, the formation of glucose, occurs in the lumen of the endoplasmic reticulum, where glucose-6-phosphate is hydrolyzed by glucose-6-phosphatase to produce glucose and release an inorganic phosphate. Like two steps prior, this step is not a simple reversal of Glycolysis, in which hexokinase catalyzes the conversion of glucose and ATP into G6P and ADP. Glucose is shuttled into the cytoplasm by glucose transporters located in the endoplasmic reticulum's membrane.

   Importance of Gluconeogenesis

   As glucose is the basis of energy metabolism its constant supply is essential to maintain energy flow in the body. Its importance is as given below-

   1.     Brain & CNS, testes, RBC and renal medulla depend on constant supply of glucose for their functions. In fact brain uses 120 gm glucose out of 160 gm daily needed by whole body.

   2.     Under anaerobic conditions, glucose is the only source of energy for skeletal muscles.

   3.     In fasting, even for a day, Gluconeogenesis becomes important to supply the required basal energy to the body.

   4.     Gluconeogenesis effectively removes certain metabolites from blood circulation like glycerol, lactates, propionates etc.