Gluconeogenesis, a glucose synthesizing pathway

(Last Updated On: July 20, 2021)

Gluconeogenesis is a biosynthetic pathway involved in glucose production from non-carbohydrate precursors. Glucose is necessary for all tissues as it is the main source of energy production. Some tissues such as the brain, RBCs, and exercising muscles require glucose more preferentially than any other source and, therefore, they are dependent on a constant supply of blood glucose. There are three sources of blood glucose; diet, gluconeogenesis, and glycogen breakdown.

Gluconeogenesis pathway
Schematic representation of gluconeogenesis and glycolysis: Top to bottom represents glycolysis while bottom to represents gluconeogenesis

When the dietary source of glucose is not available and liver glycogen is also exhausted, blood glucose levels will then be maintained by the gluconeogenesis. During the process, glucose is synthesized from different intermediates of the glycolytic pathway and the citric acid cycle such as pyruvate, lactate, oxaloacetate, citrate, succinate, and carbon skeleton of most of the amino acids.

Amino acids are of two types; ketogenic and glucogenic. Amino acids that can give pyruvate and thus undergo gluconeogenesis are called glucogenic amino acids and the rest of others are called ketogenic amino acids. Though lactate and pyruvate can directly undergo gluconeogenesis, the carbon skeleton of amino acids is first converted to oxaloacetate and then enter into the gluconeogenesis.

Gluconeogenesis is an energy-requiring anabolic pathway where two molecules of pyruvate are converted into a glucose molecule at the expense of 6 molecules of ATP. The gluconeogenic pathway is found in all plants, animals, and microorganisms and the main site of gluconeogenesis in mammals is the liver and the minor site is the kidney. This pathway occurs in the cytoplasm of the cell (cellular site).

Though most of the enzymes catalyzing different reactions are similar to that of the glycolytic pathway and this pathway looks like as if it is a reverse process of glycolysis. But three reactions are different as they are catalyzed by a different set of enzymes. As you know glycolysis is a catabolic pathway and releases energy in the form of ATP (net 2 molecules of ATP are produced per one glucose molecule breakdown) while gluconeogenesis is an anabolic pathway requiring energy in the form of ATP (net 6 molecules of ATP are consumed per one molecule of glucose formation).

Therefore, some steps of glycolysis that are exergonic and unidirectional in nature are modified to occur in a reverse direction for the gluconeogenesis. This only is possible by utilizing a different set of enzymes. These steps are called bypass steps.

First bypass: conversion of pyruvate to phosphoenolpyruvate.

This is a two-step process of which the first step occurs in a mitochondrial matrix. Pyruvate is first transported into the mitochondrial matrix where it is converted into the oxaloacetate catalyzed by biotin-dependent enzyme pyruvate carboxylase. Pyruvate carboxylase requires biotin as a cofactor and ATP is cleaved to drive this reaction on which carbon dioxide in the form of bicarbonate ion is condensed to pyruvate to form oxaloacetate.

However, oxaloacetate formed must be transported out of the matrix. In some species, phosphoenolpyruvate (PEP) carboxykinase is located in the cytosol and in some species it is located in the mitochondria. This enzyme is the one which catalyzes the conversion of oxaloacetate to phosphoenolpyruvate and again one molecule of ATP is used to phosphorylate oxaloacetate.

Malate-Aspartate Suttle system
Malate-Aspartate Suttle system

In human beings, PEP carboxykinase is equally distributed in both location and thus either oxaloacetate or PEP formed inside the matrix of mitochondria must be transported out into the cytosol. The transport of oxaloacetate requires a shuttle system. It is converted either into malate catalyzed by malate dehydrogenase or into aspartate catalyzed by aspartate aminotransferase in the matrix before being transported out of the matrix into the cytosol through their respective transporter. In the cytosol, malate or aspartate is converted back into the oxaloacetate catalyzed by cytosolic isoenzymes and then oxaloacetate is converted into the phosphoenolpyruvate catalyzed by PEP carboxykinase.

Second bypass: conversion of fructose-1, 6-bisphosphate to fructose-6-phosphate

This step is catalyzed by fructose-1, 6-bisphosphatase (FBPase). This step is just hydrolysis which releases energy to drive the reaction in a forward direction.

Third bypass: conversion of glucose-6-phosphate into glucose

In this step, glucose-6-phosphatase catalyzes the hydrolytic cleavage of the phosphate group of glucose-6-phosphate to form glucose residue. This is a hydrolysis reaction and energy released by the hydrolytic cleavage of the phosphate group drives the reaction in a forward direction (towards the formation of glucose).

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