Gluconeogenesis

Introduction Glucose remains the nearly universal and building block in modern organisms, from microbes to humans. In mammals, some tissues depend almost completely on glucose for their metabolic energy. The human brain alone requires 120 g of glucose each day, more than half of which is stored as glycogen in muscle and liver.

However, the supply of glucose from these stores is not always sufficient . For these times, organisms need a method of synthesizing glucose from non carbohydrate precursors. This is accomplished by a pathway called gluconeogenesis , which converts pyruvate and related three and four carbon compounds to glucose.

Gluconeogenesis occurs in all plants, animals, fungi and microorganisms. The import precursors of glucose in animals are three-carbon compounds, which are lactate, pyruvate, glycerol and certain amino acids. In mammals, gluconeogenesis takes place inside liver and in minute quantities inside the renal cortex.

Is gluconeogenesis the reverse of glycolysis? Both these pathways are not identical, running in opposite reactions, although they share some common steps; 7 out of 10 enzymatic reactions of gluconeogenesis are the reverse of glycolytic reactions. However, three reactions of glycolysis are irreversible: Conversion of glucose to glucose-6-phosphate by hexokinase. Phosphorylation of frusctose-6-phosphate to fructose-1,6-bisphosphate by Phosphofructokinase-I. Conversion of phosphoenolpyruvate to pyruvate by pyruvate kinase.

In gluconeogenesis, three irreversible steps are carried out by a separate set of enzymes. Thus, both glycolysis and gluconeogenesis are irreversible processes in cells. In animals, both pathways occur largely in the cytosol, necessitating their reciprocal and coordinated regulation.

Conversion of Pyruvate to Phosphoenolpyruvate This reaction cannot occur by the simple reversal of the pyruvate kinase reaction of glycolysis . Pyruvate is first transported from the cytosol into the mitochondria or is generated from alanine within mitochondria by transamination. Then, pyruvate carboxylase, a mitochondrial enzyme converts the pyruvate to oxaloacetate. Pyruvate+ HCO3- + ATP  oxaloacetate + ADP+ Pi

Conversion of Fructose-1,6-bisphosphate to Fructose-6-phosphate The second glycolytic reaction that cannot participate in gluconeogenesis is the phosphorylation of fructose-6-phosphate by PFK-I . Because this reaction is highly exergonic and therefore irreversible in intact cells, the generation of fructose-6-phosphate from fructose-1,6-bisphosphate is catalyzed by a different enzyme, Mg2+ dependent fructose-1,6-bisphosphatase Fructose-1,6-bisphosphate + H2O  fructose-6-phosphate + Pi

Conversion of glucose-6-phosphate to glucose. This is the final reaction of gluconeogenesis, the dephosphorylation of glucose6-phosphate to yield glucose . Reversal of the hexokinase reaction would require phosphoryl group transfer from glucose-6-phosphate, to ADP, forming ATP, an energetically unfavourable reaction. Thus, the reaction is catalyzed by glucose-6-phosphatase ; carries out simple hydrolysis. Glucose-6-phosphate+ H2O glucose + Pi

Gluconeogenesis is Energetically expensive, but essential. The net reaction for gluconeogenesis is 2 pyruvate+ 4ATP+ 2GTP+ 2NADH+ 2H+ +4H2O  glucose +4ADP + 2GDP + 6Pi + 2NAD+ Thus , it is an energetically expensive process . Much of the high energy cost is necessary to ensure the irreversibility of glycolysis. Hence , it is essential.

Glycolysis and Gluconeogenesis are regulated reciprocally If both the processes were allowed to proceed simultaneously, the result would be the consumption of ATP and the production of heat . Hence, they are regulated reciprocally.

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