Question

In gluconeogenesis, what are it's thermodynamics and enzymatic regulations?

Answer 1

The synthesis of glucose from noncarbohydrate precursors is called gluconeogenesis. This metabolic pathway is very important because glucose is the primary energy source for the brain. Erythrocytes do not have mitochondria and derive all of their energy by glycolysis converting glucose into two molecules of lactate. The daily requirement for glucose for a typical adult is around 160 grams. In the blood, approximately 20 grams of glucose is carried at any one time. In the liver approximately 190 grams of glucose is stored in the form of glycogen. This is a little more than a day’s supply of glucose. For fasting periods longer than one day, or during periods of intense exercise, glucose must be synthesized from noncarbohydrate precursors in order to maintain the blood glucose levels. The noncarbohydrate precursors are pyruvate, lactate, oxaloacetate, amino acids and glycerol. The noncarbohydrate precursors enter the gluconeogenic pathway in the forms of pyruvate, oxaloacetate and dihydroxyacetone phosphate. There are two major sites for gluconeogenesis, the liver and the kidneys. The liver accounts for 90% of gluconeogenesis in the body, the kidney’s produce the other 10%. Very little gluconeogenesis occurs in the other tissues of the body. The liver and kidneys maintain the glucose level in the blood so that the brain, muscle and red blood cells have sufficient glucose to meet their metabolic demands. The net reaction of glycolysis and the standard change in free energy is shown below:

Glucose + 2ADP + 2Pi + 2NAD⁺ 2Pyruvate + 2ATP + 2NADH +2H2O + 2H⁺ ∆G^o = -85 kJ/mol

Gluconeogenesis is not merely the reversal of glycolysis because that would be highly endergonic.

2Pyruvate + 2ATP + 2NADH +2H2O + 2H⁺ Glucose + 2ADP + 2Pi + 2NAD⁺ ∆G^o = +85 kJ/mol

Glycolysis has three irreversible steps catalyzed by hexokinase, phosphofructokinase and pyruvate kinase. In gluconeogenesis these irreversible steps have to be bypassed. In order to make gluconeogenesis spontaneous (exergonic) six NTPs are consumed.

2Pyruvates + 4ATP + 2GTP + 2NADH + 4H₂O Glucose + 4ADP + 2GDP + 6Pi + 2NAD⁺ + 2H⁺

∆G^o = −37 kJ/mol

The reactions of Gluconeogenesis:

Pyruvate Carboxylase uses the energy of ATP to carboxylate pyruvate to from oxaloacetate. The enzyme requires biotin, a cofactor that is covalently attached to a lysine residue. Biotin serves as a carrier of activated carbon dioxide, just as acyl-CoA carries activated acyl groups

Pyruvate carboxylase is allosterically activated by acyl-CoA. In order to activate bicarbonate, an acylCoA must be bound to an allosteric binding site of the enzyme. The second half of the enzyme catalyzed reaction, the nucleophilic attack of the pyruvate enolate on N-carboxybiotin, is not affected by this allosteric regulator. The activation by acyl-CoA provides important physiological regulation. If the concentration of ATP is low (remember that ATP is a substrate for this enzyme) and/or the concentration of acyl-CoA’s is low, then pyruvate is directed into the citric acid cycle, to promote the synthesis of ATP. If the concentrations of ATP and acyl-CoAs are high, then pyruvate is converted in oxaloacetate and consumed in gluconeogenesis. High concentrations of ATP and acyl-CoA’s are signals that the cells energy level is high and metabolites are converted into glucose. It the energy status of the cell is low, then the concentrations of ATP and acyl-CoAs are low and pyruvate is directed towards the TCA cycle.