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Gluconeogenesis is the generation of glucose from non-sugar carbon substrates like pyruvate, lactate, glycerol, and glucogenic amino acids (primarily alanine and glutamine).
The vast majority of gluconeogenesis takes place in the liver and, to a smaller extent, in the cortex of kidney. This process occurs during periods of fasting, starvation, or intense exercise and is highly endergonic.
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. The gluconeogenic pathway can also generate glucose from amino acids, such as alanine, aspartate, glutamate, or others. Following removal of the amino group (by transamination or deamination) from the amino acid, the remaining carbon skeleton can enter gluconeogenesis directly (as pyruvate or oxaloacetate), or indirectly, e.g., via the citric acid cycle, converting α-ketoglutarate to oxaloacetate.
Most fatty acids cannot be converted into glucose unless the glyoxylate cycle is used, the exception being odd-chain fatty acids, which can yield propionyl CoA, a precursor for succinyl CoA. Fatty acids are regularly broken down into the two-carbon acetyl CoA, which becomes degraded in the citric acid cycle. In contrast, glycerol, which is a part of all triacylglycerols, can be used in gluconeogenesis. In organisms in which glycerol is derived from glucose (eg, humans and other mammals), glycerol is sometimes not considered a true gluconeogenic substrate, as it cannot be used to generate new glucose.
Gluconeogenesis cannot be considered to be simply 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 are not operating at the same time in the cell, making it a futile cycle. Therefore, 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 enzymes responsible for gluconeogenesis are found in the cytoplasm; the exceptions are mitochondrial pyruvate carboxylase and mitochondrial phosphoenolpyruvate carboxykinase which are located in the mitochondria. 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 acetyl CoA and citrate activate gluconeogenesis enzymes (pyruvate carboxylase and fructose-1,6-bisphosphatase, respectively). Notably, acetyl-CoA and citrate also play inhibitory roles in pyruvate kinase activity in glycolysis.