Why gluconeogenesis is important

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Care 27, — Palmieri, D. Analyses of resected human brain metastases of breast cancer reveal the association between up-regulation of hexokinase 2 and poor prognosis. Parry, R. Otherwise it is hidden from view. Forgot Username? About MyAccess If your institution subscribes to this resource, and you don't have a MyAccess Profile, please contact your library's reference desk for information on how to gain access to this resource from off-campus.

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Clinical Sports Medicine Collection. Davis AT Collection. Davis PT Collection. Murtagh Collection. About Search. Enable Autosuggest. You have successfully created a MyAccess Profile for alertsuccessName. Home Books Harper's Illustrated Biochemistry, 30e. Previous Chapter. Next Chapter. Bender D. Bender, David A. Note: Malate-aspartate shuttle is the most active shuttle for the transport of NADH-reducing equivalents from the cytosol into the mitochondria.

It is found in mitochondria of liver, kidney, and heart. The reaction enables the transport into the cytosol of mitochondrial reducing equivalents in the form of NADH. This transfer is needed for gluconeogenesis to proceed , as in the cytosolic the NADH, oxidized in the reaction catalyzed by glyceraldehydes 3-phosphate dehydrogenase EC 1. Finally, the oxaloacetate is converted to phosphoenolpyruvate in the reaction catalyzed by PEP carboxykinase.

Lactate is one of the major gluconeogenic precursors. It is produced for example by:. When lactate is the gluconeogenic precursor, PEP synthesis occurs through a different pathway than that previously seen. The production of cytosolic NADH makes unnecessary the export of reducing equivalents from the mitochondria.

Pyruvate enters the mitochondrial matrix to be converted to oxaloacetate in the reaction catalyzed by pyruvate carboxylase. In the mitochondria, oxaloacetate is converted to phosphoenolpyruvate in the reaction catalyzed by mitochondrial pyruvate carboxylase.

Phosphoenolpyruvate exits the mitochondria through an anion transporter located in the inner mitochondrial membrane, and, once in the cytosol, continues in the gluconeogenesis pathway. Note: The synthesis of glucose from lactate may be considered as the part of the Cori cycle that takes place in the liver.

The second step of gluconeogenesis that bypasses an irreversible step of the glycolytic pathway, namely the reaction catalyzed by PFK-1, is the dephosphorylation of fructose 1,6-bisphosphate to fructose 6-phosphate.

The third step of gluconeogenesis that bypasses an irreversible step of the glycolytic pathway, namely the reaction catalyzed by hexokinase or glucokinase, is the dephosphorylation of glucose 6-phosphate to glucose. This reaction is catalyzed by the catalytic subunit of glucose 6-phosphatase , a protein complex located in the membrane of the endoplasmic reticulum of hepatocytes, enterocytes and cells of the proximal tubule of the kidney. Glucose 6-phosphatase complex is composed of a glucose 6-phosphatase catalytic subunit and a glucose 6-phosphate transporter called glucose 6-phosphate translocase or T1.

Glucose 6-phosphatase catalytic subunit has the active site on the luminal side of the organelle. This means that the enzyme catalyzes the release of glucose not in the cytosol but in the lumen of the endoplasmic reticulum.

Glucose 6-phosphate, both resulting from gluconeogenesis, produced in the reaction catalyzed by glucose 6-phosphate isomerase or phosphoglucose isomerase EC 5. Its transport is mediated by glucosephosphate translocase. And, like the reaction catalyzed by fructose 1,6-bisphosphatase, this reaction leads to the hydrolysis of a phosphate ester. It should also be underlined that, due to orientation of the active site , the cell separates this enzymatic activity from the cytosol, thus avoiding that glycolysis, that occurs in the cytosol, is aborted by enzyme action on glucose 6-phosphate.

Similar considerations can be made for the reaction catalyzed by FBPase Glucose and P i group seem to be transported into the cytosol via different transporters, referred to as T2 and T3, the last one an anion transporter. Finally, glucose leaves the hepatocyte via the membrane transporter GLUT2, enters the bloodstream and is transported to tissues that require it. Conversely, under physiological conditions, as previously said, glucose produced by the kidney is mainly used by the medulla of the kidney itself.

Like glycolysis, much of the energy consumed is used in the irreversible steps of the process. Furthermore, two molecules of NADH are required for the reduction of two molecules of 1,3-bisphosphoglycerate in the reaction catalyzed by glyceraldehyde 3-phosphate dehydrogenase. The oxidation of NADH causes the lack of production of 5 molecules of ATP that are synthesized when the electrons of the reduced coenzyme are used in oxidative phosphorylation.

Also these energetic considerations show that gluconeogenesis is not simply glycolysis in reverse, in which case it would require the consumption of two molecules of ATP, as shown by the overall glycolytic equation.

If glycolysis and gluconeogenesis were active simultaneously at a high rate in the same cell, the only products would be ATP consumption and heat production, in particular at the irreversible steps of the two pathways, and nothing more. Two reactions that run simultaneously in opposite directions result in a futile cycle or substrate cycle. These apparently uneconomical cycles allow to regulate opposite metabolic pathways.

In fact, a substrate cycle involves different enzymes, at least two, whose activity can be regulated separately. A such regulation would not be possible if a single enzyme would operate in both directions.

The modulation of the activity of involved enzymes occurs through:. Allosteric mechanisms are very rapid and instantly reversible, taking place in milliseconds. The others, triggered by signals from outside the cell, such as hormones, like insulin, glucagon, or epinephrine, take place on a time scale of seconds or minutes, and, for changes in enzyme concentration, hours. This allows a coordinated regulation of the two pathways , ensuring that when pyruvate enters gluconeogenesis, the flux of glucose through the glycolytic pathway slows down, and vice versa.

The regulation of gluconeogenesis and glycolysis involves the enzymes unique to each pathway , and not the common ones. While the major control points of glycolysis are the reactions catalyzed by PFK-1 and pyruvate kinase, the major control points of gluconeogenesis are the reactions catalyzed by fructose 1,6-bisphosphatase and pyruvate carboxylase. The other two enzymes unique to gluconeogenesis, glucosephosphatase and PEP carboxykinase, are regulated at transcriptional level.

The metabolic fate of pyruvate depends on the availability of acetyl-CoA, that is, by the availability of fatty acids in the mitochondrion. Acetyl-CoA is a positive allosteric effector of pyruvate carboxylase, and a negative allosteric effector of pyruvate kinase.

Moreover, it inhibits pyruvate dehydrogenase complex both through feedback inhibition and phosphorylation through the activation of a specific kinase. This means that when the energy charge of the cell is high, the formation of acetyl-CoA from pyruvate slows down, while the conversion of pyruvate to glucose is stimulated. Therefore acetyl-CoA is a molecule that signals that additional glucose oxidation for energy is not required and that glucogenic precursors can be used for the synthesis and storage of glucose.

Conversely, when acetyl-CoA levels decrease, the activity of pyruvate kinase and of the pyruvate dehydrogenase complex increases, and therefore also the flow of metabolites through the citric acid cycle. This supplies energy to the cell. Summarizing, when the energy charge of the cell is high pyruvate carboxylase is active, and that the first control point of gluconeogenesis determines what will be the fate of pyruvate in the mitochondria.

The second major control point in gluconeogenesis is the reaction catalyzed by fructose 1,6-bisphosphatase. The enzyme is allosterically inhibited by AMP. This means that, as previously seen, FBPase-1 is active when the energy charge of the cell is sufficiently high to support de novo synthesis of glucose. The liver plays a key role in maintaining blood glucose homeostasis: this requires regulatory mechanisms that coordinate glucose consumption and production. Two hormones are mainly involved: glucagon and insulin.

This molecule is structurally related to fructose 1,6-bisphosphate, but is not an intermediate in glycolysis or gluconeogenesis. In the subsequent year, the same researchers showed that it is also a potent inhibitor of FBPase Fructose 2,6-bisphosphate, by binding to the allosteric site on PFK-1, reduces the affinity of the enzyme for ATP and citrate, allosteric inhibitors, and at the same time increases the affinity of the enzyme for fructose 6-phosphate, its substrate.

PFK-1, in the absence of fructose 2,6-bisphosphate, and in the presence of physiological concentrations of ATP, fructose 6-phosphate, and of allosteric effectors AMP, ATP and citrate, is practically inactive.

Conversely, the presence of fructose 2,6-bisphosphate activates PFK-1, thus stimulating glycolysis in the hepatocytes. At the same time fructose 2,6-bisphosphate slows down gluconeogenesis by inhibiting fructose 1,6-bisphosphatase, even in the absence of AMP. Fructose-2,6-bisphosphate concentration is regulated by the relative rates of synthesis and degradation. It is synthesized from fructose 6-phosphate in the reaction catalyzed by phosphofructokinase-2 or PFK-2 EC 2.