Gluconeogenesis is the synthesis of glucose from noncarbohydrate precursors, a metabolic pathway very important because the brain and erythrocytes are highly dependent on glucose.

The major site of gluconeogenesis is the liver (very little gluconeogenesis takes place in the cortex of the kidney, in the brain, skeletal muscle, or heart muscle, but only liver and kidney help to maintain the glucose level in the blood.

Noncarbohydrate precursors of glucose enter the pathway cheifly at pyruvate, oxaloacetate, and dihydroxyacetone-P. The major noncarbohydrate precursors are lactate, amino acids, glycerol (but animals cannot convert fatty acids into glucose), and intermediates of the Citric Acid Cycle (as oxaloacetate).

Gluconeogenesis is not a reversal of glycolysis. Several different reactions are required because the thermodynamic equilibrium of glycolysis lies far on the side of pyruvate formation. Most of the decrease in free energy in glycolysis takes place in the three essentially irreversible steps catalyzed by hexokinase, phosphofructokinase, and pyruvate kinase. In gluconeogenesis, these virtually irreversible reactions of glycolysis are bypassed by the following new steps:

Phosphoelonpyruvate is formed from pyruvate by way of oxaloacetate

Pyruvate carboxylase catalyzes the ATP-driven carboxylation of pyruvate to oxaloacetate. This step occurs in the mitochondria.

PEP carboxykinase decarboxylates oxaloacetate to PEP using GTP as a phosphorylating agent. This step can occur in the mitochondria and the PEP formed is then transported to the cytosol. Alternatively, the oxaloacetate can be converted to PEP by a cytosolic PEP carboxykinase. There is, however, no transport system for oxaloacetate. It must first be converted either to aspartate or to malate. The malate dehydrogenase route results in the transport of reducing equivalents from the mitochondrion to the cytosol, since it utilizes mitochondrial NADH and produce cytosolic NADH.

Hydrolitic reaction bypass PFK and Hexokinase

At these points, instead of generating ATP by reversing the glycolytic reactions, FBP and G6P are hydrolyzed, releasing Pi in exergonic proccesses catalyzed by fructose-1,6-biphosphatase and glucose-6-phosphatase respectively.