The brain alone requires about 120 g of glucose each day—more than half of all the glucose stored as glycogen in muscle and liver. However, the supply of glucose from these stores is not always sufficient; between meals and during longer fasts, or after vigorous exercise, glycogen is depleted. For these times, organisms need a method for synthesizing glucose from noncarbohydrate precursors. This is accomplished by a pathway called gluconeogenesis (“new formation of sugar”), which converts pyruvate and related three- and four-carbon compounds to glucose.
Gluconeogenesis occurs in all animals, plants, fungi, and microorganisms. The reactions are essentially the same in all tissues and all species. The important precursors of glucose in animals are three-carbon compounds such as lactate, pyruvate, and glycerol, as well as certain amino acids. In mammals, gluconeogenesis takes place mainly in the liver, and to a lesser extent in renal cortex and in the epithelial cells that line the inside of the small intestine.
The glucose produced passes into the blood to supply other tissues. After vigorous exercise, lactate produced by anaerobic glycolysis in skeletal muscle returns to the liver and is converted to glucose, which moves back to muscle and is converted to glycogen—a circuit called the Cori cycle. In plant seedlings, stored fats and proteins are converted, via paths that include gluconeogenesis, to the disaccharide sucrose for transport throughout the developing plant. Glucose and its derivatives are precursors for the synthesis of plant cell walls, nucleotides and coenzymes, and a variety of other essential metabolites.
PROCESS OF GLUCONEOGENESIS
1ST The first of the bypass reactions in gluconeogenesis is the conversion of pyruvate to phosphoenolpyruvate (PEP).
Pyruvate is first transported from the cytosol into mitochondria or is generated from alanine within mitochondria by transamination, in which the α-amino group is transferred from alanine (leaving pyruvate) to an α-keto carboxylic acid. Then pyruvate carboxylase, a mitochondrial enzyme that requires the coenzyme biotin, converts the pyruvate to oxaloacetate.
The formation of phosphoenolpyruvate (PEP) from pyruvate, the reverse of the pyruvate kinase reaction, is endergonic and therefore requires free energy input. This is accomplished by first converting the pyruvate to oxaloacetate. Oxaloacetate is a “high-energy” intermediate whose exergonic decarboxylation provides the free energy necessary for PEP synthesis. The process requires the participation of two enzymes.
- Pyruvate carboxylase catalyzes the ATP-driven formation of oxaloacetate from pyruvate and.
- PEP carboxykinase (PEPCK) converts oxaloacetate to PEP
Gluconeogenesis Requires Metabolite Transport between Mitochondria and Cytosol The generation of oxaloacetate from pyruvate or citric acid cycle intermediates occurs only in the mitochondrion, whereas the enzymes that convert PEP to glucose are cytosolic. The cellular location of PEPCK varies with the species. In mouse and rat liver it is located almost exclusively in the cytosol, in pigeon and rabbit liver it is mitochondrial, and in guinea pig and humans it is more or less equally distributed between both compartments. In order for gluconeogenesis to occur, either oxaloacetate must leave the mitochondrion for conversion to PEP or the PEP formed there must enter the cytosol. PEP is transported across the mitochondrial membrane by specific membrane transport proteins
2ND The second glycolytic reaction that cannot participate in gluconeogenesis is the phosphorylation of fructose 6-phosphate by PFK-1. 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, Mg 2+ -dependent fructose 1,6-bisphosphatase (FBPase-1), which promotes the essentially irreversible hydrolysis of the C-1 phosphate (not phosphoryl group transfer to ADP): FBPase-1 is so named to distinguish it from another, similar enzyme (FBPase-2) with a regulatory role
3RD The third bypass is the final reaction of gluconeogenesis, the dephosphorylation of glucose 6-phosphate to yield glucose. Reversal of the hexokinase reaction would require phosphoryl group transfer from glucose 6-phosphate to ADP, forming ATP, an energetically unfavorable reaction. The reaction catalyzed by glucose 6-phosphatase does not require synthesis of ATP; it is a simple hydrolysis of a phosphate ester.
- Gluconeogenesis is a ubiquitous multistep process in which glucose is produced from lactate, pyruvate, or oxaloacetate, or any compound (including citric acid cycle intermediates) that can be converted to one of these intermediates. Seven of the steps in gluconeogenesis are catalyzed by the same enzymes used in glycolysis; these are the reversible reactions.
- In mammals, gluconeogenesis in the liver, kidney, and small intestine provides glucose for use by the brain, muscles, and erythrocytes.
- Pyruvate carboxylase is stimulated by acetyl-CoA, increasing the rate of gluconeogenesis when the cell has adequate supplies of other substrates (fatty acids) for energy production.
- Animals cannot convert acetyl-CoA derived from fatty acids into glucose; plants and microorganisms can.
- Glycolysis and gluconeogenesis are reciprocally regulated to prevent wasteful operation of both pathways at the same time.
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:- Article Written By Zahra Madraswala