Gluconeogenesis- Pathway and its significance

Gluconeogenesis pathway

• A non-sugar precursor is converted into glucose during glucose synthesis.
• The process of glucose synthesis relies primarily on the liver, which produces glucose from noncarbohydrate molecules.
• Obtaining glucose for polysaccharide synthesis is not a problem for a cell that is growing on hexose such as glucose.
• The cell must synthesize glucose when it expands on other carbon compounds. Glucose synthesis is the process involved in this.
• A glycolytic intermediate, phosphoenolpyruvate, is used as the starting point for glucose biosynthesis and proceeds through the glycolytic pathway backward to form glucose.
• A simple reversal of glycolysis, however, does not create glucose by itself as it involves several enzymes not involved in glycolysis.
• Glycerol (as an intermediate in the DHAP cycle), amino acids (which form the pyruvate or TCA cycle), and lactate are the major precursors for gluconeogenesis.
• The synthesis of one mole of glucose from two moles of lactate requires approximately six moles of ATP.

The location where gluconeogenesis takes place

This enzyme is not found in skeletal muscle; it is found in the liver, kidneys, and intestines. Pyruvate carboxylase catalyzes the first reaction within mitochondria, but the remaining reactions occur outside the mitochondria.

Step involved in gluconeogenesis

• As pyruvate is converted to oxaloacetate in the mitochondrion, it is called pyruvate carboxylase.
• Acetate is converted into malate or aspartate in the cell's cytosol, where it is reconstituted to acetate.
• Oxaloacetate is converted to phosphoenolpyruvate-by-phosphoenolpyruvate carboxykinase.
• Reversing glycolysis steps produces fructose 1,6-bisphosphate from phosphoenolpyruvate.
• As fructose 1,6-bisphosphate is oxidized to fructose-6-phosphate and glucose-6-phosphate, fructose 1,6-bisphosphatase converts it to glucose-6-phosphate.
• The enzyme glucose-6-phosphatase is responsible for turning glucose-6-phosphate into free glucose and releasing it into the blood.

Reactions

1. Phosphoenolpyruvate is produced by pyruvate conversion
Phosphoenolpyruvate is formed in the liver from pyruvate.

• By using pyruvate (made from lactate), alanine, and other amino acids, the mitochondrial enzyme pyruvate carboxylase first converts lactate, alanine, and other amino acids into oxaloacetate.
• The mitochondrial inner membrane cannot be directly crossed by oxaloacetate. Consequently, it can cross the mitochondrial membrane and be rearranged into oxaloacetate in the cytosol when converted to malate or aspartate.
• The decarboxylation of phosphoenolpyruvate is catalyzed by the carboxykinase of phosphoenolpyruvate. GTP is required for this reaction.
• A reversal in the glycolytic processes leads to fructose 1,6-bisphosphate from phosphoenolpyruvate.

2. Transformation of fructose 1,6-bisphosphate into fructose-6-phosphate

• By catalyzing the fructose-1,6-bisphosphateto fructose-6-phosphate reaction, fructose-1,6-bisphosphatase releases inorganic phosphate.
• It is the same isomerase that converts glucose-6-phosphate to fructose-6-phosphate.

3. The process of converting glucose-6-phosphate into glucose

• By releasing inorganic phosphate from glucose-6-phosphate, free glucose is released into the bloodstream. Glucose 6-phosphatase is responsible for this reaction.

Accordingly, one glucose molecule has the following net requirements:

• Four ATP and 2 GTP
• Six H2O
• Two pyruvates
• Two NADH

Significance

• When the body does not have access to sufficient carbohydrates from the diet or glycogen stores, glucose is produced in the liver.
• A process called glycogenolysis converts glycogen into glucose in skeletal muscle and adipose tissue. When glycogen stores are depleted during heavy exercise, diabetic conditions, or fasting, glucose is produced through gluconeogenesis.
• For the nervous system as well as erythrocytes, it is essential to have a steady supply of glucose as a source of energy.
• A mechanism of glucose synthesis is used to remove from the blood products of organ metabolism. Such products include lactate, which is produced by muscles, erythrocytes, and adipose tissue, and glycerol, which is produced continuously by fat cells.

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