Gluconeogenesis

Entering the pathway

Many 3- and 4-anaerobic respiration in skeletal muscle is easily converted to pyruvate in the liver cells; this happens as part of the Cori cycle. However, the first designated substrate in the gluconeogenic pathway is pyruvate.

α-ketoglutarate to oxaloacetate.

glycerol, which is a part of all triacylglycerols, can be used in gluconeogenesis. In organisms in which glycerol is derived from glucose (e.g., humans and other mammals), glycerol is sometimes not considered a true gluconeogenic substrate, as it cannot be used to generate new glucose.

Pathway

• Gluconeogenesis is a pathway consisting of eleven enzyme-catalyzed reactions.
• Gluconeogenesis begins with the formation of oxaloacetate through carboxylation of pyruvate at the expense of one molecule of acetyl-CoA, i.e., when fatty acid oxidation is high in the liver.
• Oxaloacetate is then decarboxylated and simultaneously phosphorylated by NAD⁺ where said reactions can occur.
• 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. The purpose of this reaction is to overcome the large negative ΔG.
• Glucose-6-phosphate is formed from fructose-6-phosphate by phosphoglucoisomerase. Glucose-6-phosphate is used in other pathways. Free glucose is not generated automatically because glucose, unlike glucose-6-phosphate, tends to freely diffuse out of the cell. The reaction of actual glucose formation is carried out in the lumen of the endoplasmic reticulum. Here, glucose-6-phosphate is hydrolyzed by glucose-6-phosphatase, the last enzyme in gluconeogenesis, to produce glucose. Glucose is then shuttled into the cytosol by glucose transporters located in the membrane of the endoplasmic reticulum.

Regulation

Gluconeogenesis cannot be considered to be simply a reverse process of glycolysis and gluconeogenesis follow reciprocal regulation, that is, cellular conditions, which inhibit glycolysis, may in turn activate gluconeogenesis.

Glucose-6-phosphate regulates the enzyme glucose-6-phosphatase in the lumen of ER by inducing its activity. In contrast, its accumulation will feed-back inhibit hexokinase in glycolysis. Once again, it follows the principle of reciprocal regulation.

The majority of the mitochondrion into the cytosol, the cytosolic enzyme is believed to be the isozyme important for gluconeogeneis. The rate of gluconeogenesis is ultimately controlled by the action of a key enzyme, fructose-1,6-bisphosphatase, which is also regulated through signal tranduction by cAMP and its phosphorylation.

Most factors that regulate the activity of the gluconeogenesis pathway do so by inhibiting the activity or expression of key enzymes. However, both glycolysis.

References