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Entering the pathway
Many 3- and 4-carbon substrates can enter the gluconeogenesis pathway. Lactate from 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.
Oxaloacetate (an intermediate in the citric acid cycle) can also be used for gluconeogenesis. Many amino acids, upon amino group removal, yield intermediates of the citric acid cycle and can therefore be used for net synthesis of oxaloacetate (and thereafter glucose) .
Even-chain fatty acids are oxidized into the two-carbon acetyl CoA, which is further oxidized to CO2 in the citric acid cycle. Acetyl CoA cannot be used for gluconeogenesis in animals because it cannot be converted in oxaloacetate (or other gluconeogenic subtrates). However, plants and some microorganisms can convert acetylCoA into oxaloacetate through the glyoxylate cycle. The last round of beta-oxidation of odd-chain fatty acids yields propionyl CoA, a precursor for the citric acid cycle intermediate succinyl CoA. These fatty acids may therefore be used for gluconeogenesis.
- Gluconeogenesis begins with the formation of oxaloacetate through carboxylation of pyruvate at the expense of one molecule of ATP, but is inhibited in the presence of high levels of ADP. This reaction is catalyzed by pyruvate carboxylase.
- Oxaloacetate is then decarboxylated and simultaneously phosphorylated by phosphoenolpyruvate carboxykinase to produce phosphoenolpyruvate. One molecule of GTP is hydrolyzed to GDP in the course of this reaction. Both reactions take place in mitochondria. Oxaloacetate has to be transformed into malate in order to be transported out of the mitochondria.
- Typically, the last step of gluconeogenesis is the formation of glucose-6-phosphate from fructose-6-phosphate by phosphoglucose isomerase. 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, a regulated membrane-bound enzyme, to produce glucose. Glucose is then shuttled into cytosol by glucose transporters located in the membrane of the endoplasmic reticulum.
Gluconeogenesis cannot be considered to be a reverse process of glycolysis, as the three irreversible steps in glycolysis are bypassed in gluconeogenesis. This is done to ensure that glycolysis and gluconeogenesis do not operate at the same time in the cell, making it a futile cycle.
The majority of the enzymes responsible for gluconeogenesis are found in the cytoplasm; the exception is pyruvate carboxylase, which is located both in the mitochondria and in cytoplasm. The rate of gluconeogenesis is ultimately controlled by the action of a key enzyme fructose-1,6-bisphosphatase.
Most factors that regulate the activity of the gluconeogenesis pathway do so by inhibiting the activity of key enzymes. However, both acetyl CoA and citrate activate gluconeogenesis enzymes (pyruvate carboxylase and fructose-1,6-bisphosphatase, respectively).