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Basically the small pump is all you need to pump on the go. Functional biochemistry in health and disease. Most fatty acids are non-essential, meaning the body can produce them as needed, generally from other fatty acids and always by expending energy to do so. While hexokinase allows to trap glucose inside the cell, phosphofructokinase 1 prevents glucose to be used for glycogen synthesis or the production of other sugars , but is instead metabolized in the glycolytic pathway. Glucose leaves the liver, enters into the bloodstream and is delivered to the muscle, as well as to other tissues and cells that require it, such as red blood cells and neurons, thus closing the cycle. Pure ethanol provides 7 calories per gram.

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Ceva Animal Health Inc. Deep Valley Farm Inc. Exel International Exhibitor Labs Inc. Figuerola Laboratories Filters Inc. Finish Line Horse Products Inc. Four Paws Products Ltd. International Jacks Manufacturing Inc. Metropolitan Vacuum Cleaner Co. Miller Little Giant Miracle Corp. Pastures Cookies Muck Boot Co. Moreover, in vertebrates, there are at least three isozymes of pyruvate kinase, of which the M type predominates in muscle and brain, while the L type in liver.

These isozymes have many properties in common, whereas differ in the response to hormones such as glucagon, epinephrine and insulin. And, of the The remaining energy, While the reaction catalyzed by phosphoglycerate kinase, in the seventh step of the glycolytic pathway, pays off the ATP debt of the preparatory phase, the reaction catalyzed by pyruvate kinase allows a net gain of two ATP. Such pathways allow, therefore, maintenance of the redox balance of the cell.

Pyruvate is a versatile metabolite that can enter several metabolic pathways, both anabolic and catabolic, depending on the type of cell, the energy state of the cell and the availability of oxygen. With the exception of some variations encountered in bacteria, exploited, for example, in food industry for the production of various foods such as many cheeses, there are essentially three pathways in which pyruvate may enter:.

This allows glycolysis to proceed in both anaerobic and aerobic conditions. It is therefore possible to state that the catabolic fate of the carbon skeleton of glucose is influenced by the cell type, the energetic state of the cell, and the availability of oxygen. In animals, with few exceptions, and in many microorganisms when oxygen availability is insufficient to meet the energy requirements of the cell, or if the cell is without mitochondria, the pyruvate produced by glycolysis is reduced to lactate in the cytosol, in a reaction catalyzed by lactate dehydrogenase EC 1.

The conversion of glucose to lactate is called lactic acid fermentation. The overall equation of the process is:. In other words, in the conversion of glucose, C 6 H 12 O 6 , to lactate, C 3 H 6 O 3 , the ratio of hydrogen to carbon atoms of the reactants and products does not change.

From an energy point of view, it should however be emphasized that fermentation extracts only a small amount of the chemical energy of glucose. In humans, much of the lactate produced enters the Cori cycle for glucose production via gluconeogenesis. We can also state that lactate production shifts part of the metabolic load from the extrahepatic tissues, such as skeletal muscle during intense bouts of exercise, like a meter, when the rate of glycolysis can almost instantly increase 2,fold, to the liver.

Therefore, portion of the lactate released by skeletal muscle engaged in intense exercise is used by the heart muscle for fuel. Lactate produced by microorganisms during lactic acid fermentation is responsible for both the scent and taste of sauerkraut, namely, fermented cabbage, as well as for the taste of soured milk. The first step involves the non-oxidative decarboxylation of pyruvate to form acetaldehyde, an essentially irreversible reaction.

The reaction is catalyzed by pyruvate decarboxylase EC 4. The enzyme is absent in vertebrates and in other organisms that perform lactic acid fermentation. In the second step, acetaldehyde is reduced to ethanol in a reaction catalyzed by alcohol dehydrogenase EC 1. At neutral pH, the equilibrium of the reaction lies strongly toward ethyl alcohol formation.

The conversion of glucose to ethanol and CO 2 is called alcoholic fermentation. The overall reaction is:. And, as for lactic fermentation, even in alcoholic fermentation no net oxidation-reduction occurs. Alcoholic fermentation is the basis of the production of beer and wine. In cells with mitochondria and under aerobic conditions, the most common situation in multicellular and many unicellular organisms, the oxidation of NADH and pyruvate catabolism follow distinct pathways.

In the mitochondrial matrix, pyruvate is first converted to acetyl-CoA in a reaction catalyzed by the pyruvate dehydrogenase complex. In the reaction, a oxidative decarboxylation , pyruvate loses a carbon atom as CO 2 , and the remaining two carbon unit is bound to Coenzyme A to form acetyl-coenzyme A or acetyl-CoA.

Pyruvate dehydrogenase therefore represents a bridge between glycolysis, which occurs in the cytosol, and the citric acid cycle, which occurs in the mitochondrial matrix. In turn, electrons derived from oxidations that occur during glycolysis are transported into mitochondria via the reduction of cytosolic intermediates.

Here the electrons flow to oxygen to form H 2 O, a transfer that supplies the energy needed for the synthesis of ATP through the process of oxidative phosphorylation. Of course, also the electrons carried by NADH formed by pyruvate dehydrogenase and citric acid cycle and by FADH 2 formed by citric acid cycle meet a similar fate.

Under anabolic conditions, the carbon skeleton of pyruvate may have fates other than complete oxidation to CO 2 or conversion to lactate. In fact, after its conversion to acetyl-CoA, it may be used, for example, for the synthesis of fatty acids , or of the amino acid alanine see Fig. In the glycolytic pathway the glucose molecule is degraded to two molecules of pyruvate. In the first phase, the preparatory phase, two ATP are consumed per molecule of glucose in the reactions catalyzed by hexokinase and PFK In the second phase, the payoff phase, 4 ATP are produced through substrate-level phosphorylation in the reactions catalyzed by phosphoglycerate kinase and pyruvate kinase.

So there is a net gain of two ATP per molecule of glucose used. In addition, in the reaction catalyzed by glyceraldehyde 3-phosphate dehydrogenase, two molecules of NADH are produced for each glucose molecule. Here are the two reactions.

Cancelling the common terms on both sides of the equation, we obtain the overall equation shown above. Under anaerobic conditions , regardless of what is the metabolic fate of pyruvate, conversion to lactate, ethanol or other molecules, there is no additional production of ATP downstream of glycolysis. Under aerobic conditions , in cells with mitochondria, the amount of chemical energy that can be extracted from glucose and stored within ATP is much greater than under anaerobic conditions.

If we consider the two NADH produced during glycolysis, the flow of their 4 reducing equivalents along the mitochondrial electron transport chain allows the production of ATP per electron pair through oxidative phosphorylation.

Therefore, 6 to 8 ATP are produced when one molecule of glucose is converted into two molecules of pyruvate, 2 from glycolysis and from oxidative phosphorylation.

Considering both estimates, the production of ATP is about 15 times greater than under anaerobic condition. Other carbohydrates besides glucose, both simple and complex, can be catabolized via glycolysis, after enzymatic conversion to one of the glycolytic intermediates. Among the most important are:. Dietary starch and disaccharides must be hydrolyzed in the intestine to the respective monosaccharides before being absorbed. Once in the venous circulation, monosaccharides reach the liver through the portal vein; this organ is the main site where they are metabolized.

Regarding the phosphorolytic breakdown of starch and endogenous glycogen refer to the corresponding articles. Under physiological conditions, the liver removes much of the ingested fructose from the bloodstream before it can reach extrahepatic tissues.

The hepatic pathway for the conversion of the monosaccharide to intermediates of glycolysis consists of several steps. In the first step fructose is phosphorylated to fructose 1-phosphate at the expense of one ATP.

This reaction is catalyzed by fructokinase EC 2. As for glucose, fructose phosphorylation traps the molecule inside the cell. In the second step fructose 1-phosphate aldolase catalyzes the hydrolysis , an aldol cleavage, of fructose 1-phosphate to dihydroxyacetone phosphate and glyceraldehyde.

Dihydroxyacetone phosphate is an intermediate of the glycolytic pathway and, after conversion to glyceraldehyde 3-phosphate, may flow through the pathway. Conversely, glyceraldehyde is not an intermediate of the glycolysis, and is phosphorylated to glyceraldehyde 3-phosphate at the expense of one ATP. The reaction is catalyzed by triose kinase EC 2. In hepatocytes, therefore, a molecule of fructose is converted to two molecules of glyceraldehyde 3-phosphate , at the expense of two ATP, as for glucose.

In extrahepatic sites , such as skeletal muscle, kidney or adipose tissue, fructokinase is not present, and fructose enters the glycolytic pathway as fructose 6-phosphate. In fact, as previously seen , hexokinase can catalyzes the phosphorylation of fructose at C However, the affinity of the enzyme for fructose is about 20 times lower than for glucose, so in the hepatocyte, where glucose is much more abundant than fructose , or in the skeletal muscle under anaerobic conditions, that is, when glucose is the preferred fuel, little amounts of fructose 6-phosphate are formed.

Conversely, in adipose tissue , fructose is more abundant than glucose, so that its phosphorylation by hexokinase is not competitively inhibited to a significant extent by glucose. In this tissue, therefore, fructose 6-phosphate synthesis is the entry point into glycolysis for the monosaccharide. Conversely, when fructose is phosphorylated at C-6, it enters the glycolytic pathway upstream of PFK Fructose is the entry point into glycolysis for sorbitol , a sugar present in many fruits and vegetables, and used as a sweetener and stabilizer, too.

In the liver, sorbitol dehydrogenase EC 1. Galactose , for the most part derived from intestinal digestion of the lactose , once in the liver is converted, via the Leloir pathway , to glucose 1-phosphate.

For a more in-depth discussion of the Leloir pathway , see the article on galactose. The metabolic fate of glucose 1-phosphate depends on the energy status of the cell. Under conditions promoting glucose storage, glucose 1-phosphate can be channeled to glycogen synthesis. Conversely, under conditions that favor the use of glucose as fuel, glucose 1-phosphate is isomerized to glucose 6-phosphate in the reversible reaction catalyzed by phosphoglucomutase EC 5.

Mannose is present in various dietary polysaccharides, glycolipids and glycoproteins. In the intestine, it is released from these molecules, absorbed, and, once reached the liver, is phosphorylated at C-6 to form mannose 6-phosphate, in the reaction catalyzed by hexokinase. Mannose 6-phosphate is then isomerized to fructose 6-phosphate in the reaction catalyzed by mannose 6-phosphate isomerase EC 5. The flow of carbon through the glycolytic pathway is regulated in response to metabolic conditions, both inside and outside the cell, essentially to meet two needs: And in the liver, to avoid wasting energy, glycolysis and gluconeogenesis are reciprocally regulated so that when one pathway is active, the other slows down.

As explained in the article on gluconeogenesis , during evolution this was achieved by selecting different enzymes to catalyze the essentially irreversible reactions of the two pathways, whose activity are regulated separately.

Indeed, if these reactions proceeded simultaneously at high speed, they would create a futile cycle or substrate cycle. A such fine regulation could not be achieved if a single enzyme operates in both directions.

The control of the glycolytic pathway involves essentially the reactions catalyzed by hexokinase , PFK-1 , and pyruvate kinase , whose activity is regulated through:. Glucokinase differs from the other hexokinase isozymes in kinetic and regulatory properties. Isoenzymes or isozymes are different proteins that catalyze the same reaction, and that generally differ in kinetic and regulatory properties, subcellular distribution, or in the cofactors used.

They may be present in the same species, in the same tissue or even in the same cell. Hexokinase I and II have a K m for glucose of 0. Therefore these isoenzymes work very efficiently at normal blood glucose levels, mM. Conversely, glucokinase has a high K m for glucose, approximately 10 mM ; this means that the enzyme works efficiently only when blood glucose concentration is high, for example after a meal rich in carbohydrates with a high glycemic index.

Hexokinases I-III are allosterically inhibited by glucose 6-phosphate , the product of their reaction. This ensures that glucose 6-phosphate does not accumulate in the cytosol when glucose is not needed for energy, for glycogen synthesis , for the pentose phosphate pathway , or as a source of precursors for biosynthetic pathways, leaving, at the same time, the monosaccharide in the blood, available for other organs and tissues.

For example, when PFK-1 is inhibited, fructose 6-phosphate accumulates and then, due to phosphoglucose isomerase reaction, glucose 6-phosphate accumulates. In skeletal muscle , the activity of hexokinase I and II is coordinated with that of GLUT4 , a low K m glucose transporter 5mM , whose translocation to the plasma membrane is induced by both insulin and physical activity.

The combined action of GLUT4 on plasma membrane and hexokinase in the cytosol maintains a balance between glucose uptake and its phosphorylation. Glucokinase differs in three respects from hexokinases I-III, and is particularly suitable for the role that the liver plays in glycemic control. The binding between glucokinase and GKRP is much tighter in the presence of fructose 6-phosphate , whereas it is weakened by glucose and fructose 1-phosphate.

In the absence of glucose, glucokinase is in its super-opened conformation that has low activity. The rise in cytosolic glucose concentration causes a concentration dependent transition of glucokinase to its close conformation, namely, its active conformation that is not accessible for glucokinase regulatory protein. Hence, glucokinase is active and no longer inhibited. Hence, fructose relieves the inhibition of glucokinase by glucokinase regulatory protein.

Example After a meal rich in carbohydrates , blood glucose levels rise, glucose enters the hepatocyte through GLUT2, and then moves inside the nucleus through the nuclear pores. In the nucleus glucose determines the transition of glucokinase to its close conformation, active and not accessible to GKRP, allowing glucokinase to diffuse in the cytosol where it phosphorylates glucose.

Conversely, when glucose concentration declines, such as during fasting when blood glucose levels may drop below 4 mM, glucose concentration in hepatocytes is low, and fructose 6-phosphate binds to GKRP allowing it to bind tighter to glucokinase. This results in a strong inhibition of the enzyme.

This mechanism ensures that the liver, at low blood glucose levels, does not compete with other organs, primarily the brain, for glucose. In the cell, fructose 6-phosphate is in equilibrium with glucose 6-phosphate, due to phosphoglucose isomerase reaction. Through its association with GKRP, fructose 6-phosphate allows the cell to decrease glucokinase activity, so preventing the accumulation of intermediates.

To sum up, when blood glucose levels are normal, glucose is phosphorylated mainly by hexokinases I-III, whereas when blood glucose levels are high glucose can be phosphorylated by glucokinase as well. Phosphofructokinase 1 is the key control point of carbon flow through the glycolytic pathway. The enzyme, in addition to substrate binding sites, has several binding sites for allosteric effectors. It should be noted that ATP, an end product of glycolysis, is also a substrate of phosphofructokinase 1.

Indeed, the enzyme has two binding sites for the nucleotide: What do allosteric effectors signal? The equilibrium constant, K eq , of the reaction is:. Therefore, considering that the total adenylate pool is constant over the short term, even a small reduction in ATP concentration leads, due to adenylate kinase activity, to a much larger relative increase in AMP concentration.

Therefore, the activity of phosphofructokinase 1 depends on the cellular energy status:. There are two reasons. A further control point of carbon flow through glycolysis and gluconeogenesis is the substrate cycle between phosphoenolpyruvate and pyruvate, catalyzed by pyruvate kinase for glycolysis, and by the combined action of pyruvate carboxylase and phosphoenolpyruvate carboxykinase EC 4.

All isozymes of pyruvate kinase are allosterically inhibited by high concentrations of ATP , long-chain fatty acids , and acetyl-CoA , all signs that the cell is in an optimal energy status. Alanine , too, that can be synthesized from pyruvate through a transamination reaction, is an allosteric inhibitor of pyruvate kinase; its accumulation signals that building blocks for biosynthetic pathways are abundant. Conversely, pyruvate kinase is allosterically activated by fructose 1,6-bisphosphate , the product of the first committed step of glycolysis.

Therefore, F-1,6-BP allows pyruvate kinase to keep pace with the flow of intermediates. It should be underlined that, at physiological concentration of PEP, ATP and alanine, the enzyme would be completely inhibited without the stimulating effect of F-1,6-BP. The hepatic isoenzyme , but not the muscle isoenzyme, is also subject to regulation through phosphorylation by:. Phosphorylation of the enzyme decreases its activity, by increasing the K m for phosphoenolpyruvate, and slows down glycolysis.

For example, when the blood glucose levels are low, glucagon-induced phosphorylation decreases pyruvate kinase activity. The phosphorylated enzyme is also less readily stimulated by fructose 1,6-bisphosphate but more readily inhibited by alanine and ATP. Conversely, the dephosphorylated form of pyruvate kinase is more sensitive to fructose 1,6-bisphosphate, and less sensitive to ATP and alanine.

In this way, when blood glucose levels are low, the use of glucose for energy in the liver slows down, and the sugar is available for other tissues and organs, such as the brain. However, it should be noted that pyruvate kinase does not undergo glucagon-induced phosphorylation in the presence of fructose 1,6-bisphosphate. The dephosphorylated enzyme is more readily stimulated by its allosteric activators F-1,6-BP, and less readily inhibited by allosteric inhibitors alanine and ATP.

The role of the regulatory protein of glucokinase in the glucose sensory mechanism of the hepatocyte. Xylulose 5-phosphate mediates glucose-induced lipogenesis by xylulose 5-phosphate-activated protein phosphatase in rat liver. Glucose-induced dissociation of glucokinase from its regulatory protein in the nucleus of hepatocytes prior to nuclear export.

Bisphosphoglycerate mutase controls serine pathway flux via 3-phosphoglycerate. Biochem Soc Trans ;31 6: Inhibition of fructose-1,6-bisphosphatase by fructose-2,6-bisphosphate.

Control of liver 6-phosphofructokinase by fructose 2,6-bisphosphate and other effectors. Gluconeogenesis is a metabolic pathway that leads to the synthesis of glucose from pyruvate and other non-carbohydrate precursors, even in non-photosynthetic organisms. It occurs in all microorganisms, fungi, plants and animals, and the reactions are essentially the same, leading to the synthesis of one glucose molecule from two pyruvate molecules. Glycogenolysis is quite distinct from gluconeogenesis: The following discussion will focus on gluconeogenesis that occurs in higher animals, and in particular in the liver of mammals.

During fasting, as in between meals or overnight, the blood glucose levels are maintained within the normal range due to hepatic glycogenolysis, and to the release of fatty acids from adipose tissue and ketone bodies by the liver.

Fatty acids and ketone bodies are preferably used by skeletal muscle, thus sparing glucose for cells and tissues that depend on it, primarily red blood cells and neurons.

However, after about 18 hours of fasting or during intense and prolonged exercise, glycogen stores are depleted and may become insufficient.

At that point, if no carbohydrates are ingested, gluconeogenesis becomes important. In higher animals, gluconeogenesis occurs in the liver, kidney cortex and epithelial cells of the small intestine, that is, the enterocytes.

The key role of the liver is due to its size; in fact, on a wet weight basis, the kidney cortex produces more glucose than the liver.

In the kidney cortex, gluconeogenesis occurs in the cells of the proximal tubule, the part of the nephron immediately following the glomerulus. Much of the glucose produced in the kidney is used by the renal medulla, while the role of the kidney in maintaining blood glucose levels becomes more important during prolonged fasting and liver failure. It should, however, be emphasized that the kidney has no significant glycogen stores, unlike the liver, and contributes to maintaining blood glucose homeostasis only through gluconeogenesis and not through glycogenolysis.

Part of the gluconeogenesis pathway also occurs in the skeletal muscle, cardiac muscle, and brain, although at very low rate. In adults, muscle is about 18 the weight of the liver; therefore, its de novo synthesis of glucose might have quantitative importance.

However, the release of glucose into the circulation does not occur because these tissues, unlike liver, kidney cortex, and enterocytes, lack glucose 6-phosphatase EC 3.

Therefore, the production of glucose 6-phosphate, including that from glycogenolysis , does not contribute to the maintenance of blood glucose levels, and only helps to restore glycogen stores, in the brain small and limited mostly to astrocytes. For these tissues, in particular for skeletal muscle due to its large mass, the contribution to blood glucose homeostasis results only from the small amount of glucose released in the reaction catalyzed by enzyme debranching EC 3. With regard to the cellular localization , most of the reactions occur in the cytosol, some in the mitochondria, and the final step within the endoplasmic reticulum cisternae.

The irreversibility of the glycolytic pathway is due to three strongly exergonic reactions, that cannot be used in gluconeogenesis, and listed below. In gluconeogenesis, these three steps are bypassed by enzymes that catalyze irreversible steps in the direction of glucose synthesis: Below, such reactions are analyzed. The first step of gluconeogenesis that bypasses an irreversible step of glycolysis, namely the reaction catalyzed by pyruvate kinase , is the conversion of pyruvate to phosphoenolpyruvate.

Phosphoenolpyruvate is synthesized through two reactions catalyzed, in order, by the enzymes:. Pyruvate carboxylase catalyzes the carboxylation of pyruvate to oxaloacetate, with the consumption of one ATP. The enzyme requires the presence of magnesium or manganese ions. The enzyme, discovered in by Merton Utter, is a mitochondrial protein composed of four identical subunits, each with catalytic activity.

An allosteric binding site for acetyl-CoA is also present in each subunit. It should be noted that the reaction catalyzed by pyruvate carboxylase, leading to the production of oxaloacetate, also provides intermediates for the citric acid cycle or Krebs cycle. Phosphoenolpyruvate carboxykinase is present, approximately in the same amount, in mitochondria and cytosol of hepatocytes. The isoenzymes are encoded by separate nuclear genes.

PEP carboxykinase requires the presence of both magnesium and manganese ions. The reaction is reversible under normal cellular conditions. During this reaction, a CO 2 molecule, the same molecule that is added to pyruvate in the reaction catalyzed by pyruvate carboxylase, is removed. Carboxylation-decarboxylation sequence is used to activate pyruvate, since decarboxylation of oxaloacetate facilitates, makes thermodynamically feasible, the formation of phosphoenolpyruvate.

More generally, carboxylation-decarboxylation sequence promotes reactions that would otherwise be strongly endergonic, and also occurs in the citric acid cycle, in the pentose phosphate pathway , also called the hexose monophosphate pathway, and in the synthesis of fatty acids. The levels of PEP carboxykinase before birth are very low, while its activity increases several fold a few hours after delivery.

This is the reason why gluconeogenesis is activated after birth. The sum of the reactions catalyzed by pyruvate carboxylase and phosphoenolpyruvate carboxykinase is:. This is due to the fast consumption of phosphoenolpyruvate in other reactions, that maintains its concentration at very low levels.

Therefore, under cellular conditions, the synthesis of PEP from pyruvate is irreversible. It is noteworthy that the metabolic pathway for the formation of phosphoenolpyruvate from pyruvate depends on the precursor: The bypass reactions described below predominate when alanine or pyruvate is the glucogenic precursor.

These proteins , associating, form a hetero-oligomer that facilitates pyruvate transport. Pyruvate can also be produced from alanine in the mitochondrial matrix by transamination, in the reaction catalyzed by alanine aminotransferase EC 2. Since the enzymes involved in the later steps of gluconeogenesis, except glucosephosphatase , are cytosolic, the oxaloacetate produced in the mitochondrial matrix is transported into the cytosol.

The transfer to the cytosol occurs as a result of its reduction to malate, that, on the contrary, can cross the inner mitochondrial membrane. The reaction is catalyzed by mitochondrial malate dehydrogenase EC 1. Once in the cytosol, the malate is re-oxidized to oxaloacetate in the reaction catalyzed by cytosolic malate dehydrogenase. 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. 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.

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.

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. Six high-energy phosphate bonds are consumed: 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.

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 both through end-product 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 pyruvate dehydrogenase 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: Two hormones are mainly involved: 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. Iodophores eg, povidone-iodine are water-soluble combinations of iodine with detergents, wetting agents that are solubilizers, and other carriers.

They slowly release iodine as an antimicrobial agent and are widely used as skin disinfectants, particularly before surgery. Medical iodophobia has reached pandemic proportions. It is highly contagious and has wreaked havoc on the practice of medicine and on the U.

According to current W. Along with magnesium and selenium, iodine is one of the most deficient minerals in our bodies. Iodine is essential for the synthesis of thyroid hormone, but selenium-dependent enzymes iodothyronine deiodinases are also required for the conversion of thyroxine T4 to the biologically active thyroid hormone, triiodothyronine T3. Selenium is the primary mineral responsible for T4 to T3 thyroid hormones conversion in the liver.

Selenium is absolutely essential in the age of mercury toxicity for it is the perfect antidote for mercury exposure. It is literally raining mercury all over the world but especially in the northern hemisphere. And of course with the dentists poisoning a world of patients with mercury dental amalgam and the doctors with their mercury laden vaccines, selenium is more important than most of us can imagine.

One must remember that mercury strips the body of selenium for the selenium stores get used up quickly because of its great affinity for mercury. Iodine is the agent which arouses kindles and keeps going the flame of life. Symptoms of iodine deficiency include m uscle cramps, cold hands and feet, proneness to weight gain, poor memory, constipation, depression and headaches, edema, myalgia, weakness, dry skin, and brittle nails.

Sources include most sea foods, ocean fish, but not fresh fish, shellfish, especially oysters , unrefined sea salt, kelp and other sea weeds, fish broth, butter, pineapple, artichokes, asparagus, dark green vegetables and eggs. Certain vegetables, such as cabbage and spinach, can block iodine absorption when eaten raw or unfermented and are called goitrogens.

But eating fish won't give you iodine in mg amounts. Therefore, the body has the metabolic mechanism for using inorganic iodine beneficially, effectively and safely. Iodine is as safe as magnesium chloride with a track record of years of use in medicine. Published data confirms its safety even when used in pulmonary patients in amounts four orders of magnitude greater than the US RDA [x]. When patients take between Optimal intake of iodine in amounts two orders of magnitude greater than iodine levels needed for goiter control may be required for iodization of hormone receptors [xii].

Iodine helps us utilize our proteins properly. In all likelihood an iodine deficient person will remain protein deficient. Iodine is the essential ingredient in thyroid hormone synthesis. So if deficient, protein synthesis will be disturbed. Thyroid hormones have two major physiological effects. The thyroid gland needs iodine to synthesize thyroxine T4 and triiodothyronine T3 , hormones that regulate metabolism and steer growth and development. Thyroid hormones are essential for life as they regulate key biochemical reactions, especially protein synthesis and enzymatic activities, in target organs such as are the developing brain, muscle, heart, pituitary and kidney [xiii] ; thus iodine is critically important to the developing fetus.

Iodine transport damage can be corrected, in part, by administration of reasonably high doses of ascorbic acid or more natural Vitamin C.

The thyroid hormones are synthesized in the follicular cells of the thyroid. Thyroid hormone regulates mitochondrial protein synthesis through the stimulation of synthesis of mitochondrial protein synthesis modulators, and that the tissue specific modulators stimulatory in liver and inhibitory in kidney can be produced by the hormone. Long-term use of these drugs is associated with depletion of thyroid and tissue iodine levels, as well as increased rates of cancer.

All thyroid patients should be on iodine therapy. Iodine is a powerful primary nutrient with broad medicinal effects and a hundred years ago it was used universally by most doctors. From to the s almost every single U. In fact, iodine was considered a panacea for all human ills. The Nobel laureate Dr. Albert Szent Györgi - , the physician who discovered vitamin C, writes: Nobody knew what it did, but it did something and did something good.

Iodine is a gatekeeper of mammary gland integrity. Though few know it swollen ovaries is a condition analogous to goiter, when the thyroid swells in response to iodine deficiency. Goiters often also result in a hormonal imbalance leading to hypothyroidism. In the case of Polycystic Ovary Syndrome PCOS the starvation of the ovaries causes them to become cystic, swollen and eventually unable to regulate the synthesis of their hormones leading to imbalances and infertility.

Russian studies when investigating Fibrocystic breast disease also discovered that the greater the iodine deficiency the greater the number of cysts in the ovaries. Since , the iodine concentration in the ovary has been known to be higher than in every other organ except the thyroid. Browstein has found in his research with high doses of iodine that cysts on the ovaries became smaller and began to disappear.

He also found that libido in women and men increased. In sufficient amounts iodine can not only adjust a dysfunctional thyroid, it can assist with a host of glandular imbalances as well as a wide assortment of internal as well as external bacteria, fungi, and virus's. Iodine has many non-endocrine biologic effects, including the role it plays in the physiology of the inflammatory response. Iodides increase the movement of granulocytes into areas of inflammation and improve the phagocytosis of bacteria by granulocytes and the ability of granulocytes to kill bacteria [xv].

Robert Rowen informs that iodine reduces the activity of lipoprotein a. When elevated, this protein can lead to excessive blood clotting and vascular disease. Doses up to six times the RDA have been used safely for months to combat the excessive mucous in chronic lung diseases. She recovered within three weeks. When he discovered his mistake, he switched to digitalis, and her symptoms came back. The occurrence of iodine deficiency in cardiovascular disease is frequent.

The thyroid hormone deficiency on cardiovascular function can be characterized with decreased myocardial contractility and increased peripheral vascular resistance as well as with the changes in lipid metabolism.

A study done with 42 patients with cardiovascular disease were divided into 5 subgroups on the ground of the presence of hypertension, congestive heart failure, cardiomyopathy, coronary dysfunction and arrhythmia. When urine concentrations were tested the most decreased urine iodine concentration was detected in the subgroups with arrhythmia and congestive heart failure. An elevated TSH level was found by 3 patients and elevation in lipid metabolism cholesterol, triglyceride associated with all subgroups without arrhythmia.

The researchers concluded that iodine supplementation might prevent the worsening effect of iodine deficiency on cardiovascular disease. Iodine made its leap into medical history when a Swiss physician, Dr Jean François Condet announced that iodine could reduce goiters enlarged thyroids.

At this moment, modern medical science was born because for the first time we have a specific disorder that is relieved by a specific treatment. It is most ironic to note that the very first step of allopathic medicine was into nutritional not chemical medicine with iodine being a common mineral from the sea. The required daily amount RDA of iodine is just enough to keep our thyroids from expanding, like the RDA of vitamin C today which is just enough to keep us free of scurvy, but not enough to prevent pre scurvy syndromes or Cardiovascular Disease.

She experienced a tremendous increase in energy, endurance, well being, and memory. At six months all her skin peeled off and was replaced by new, younger-looking skin. She was flabbergasted and amazed at her new appearance. Breast tissue has an affinity for iodine. Iodine deficiency causes fibrocystic breast disease with nodules, cyst enlargement, pain and scar tissue.

Abraham, Flechas and Brownstein tested more than 4, patients taking iodine in daily doses ranging from Most physicians and surgeons view iodine from a narrow perspective and this is one of the greatest tragedies of allopathic medicine. Most health officials are chemical terrorists in disguise as they ignore the toxic buildup going on in the general population and they have no intention of informing them what they can do about it.

Mercury is a perfect case in point. Mercury is toxic from whatever source it arrives into our bodies but doctors and dentists still insist on using it, which puts us solidly in the modern age of medical and dental barbarism. We like to think we are an advanced race of intelligent beings but lo and behold we find what are supposed to be the best and most intelligent of us poisoning young and old alike with mercury. It is beyond criminality what they are doing and what they are denying.

George Flechas relates that many of his diabetic patients need lowering of insulin dosage and diabetic drugs after repletion of iodine deficiency and others have observed the same thing. Something is dangling itself before our very eyes, a medical mystery that will enlighten us about our ignorance about how important minerals are for life.

Both general and medical scientists can explain why diabetics and others benefit so greatly from heavy iodine supplementation, but will allopathic medical officials listen? Iodine is utilized by every hormone receptor in the body. This, in part, would already start to explain why Dr. Flechas sees such dramatic results with his diabetic patients. Why would many people who take iodine report that they have a greater sense of well-being, increased energy, and a lifting of brain fog?

They feel warmer in cold environments, need somewhat less sleep, improved skin complexion, and have more regular bowel movements. The most obvious answer is that iodine is a trace mineral used to synthesize hormones and is a mineral that is very important to how hormones function at the hormone receptor sites. Thyroxin and Triiodo-thyronine stimulates and maintains normal heart rate, blood pressure and body temperature.

The oral temperature before getting out of bed in the morning should be

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