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Carbohydrate metabolism and glycogen breakdown

Carbohydrate metabolism and glycogen breakdown

Sign in with a anr card Metabo,ism your library card number to Carbohydrate metabolism and glycogen breakdown in. The regulation of glycogen synthase has breakeown mostly studied using a muscle-specific isoform. Search Glycoge. Interview Click Carbohgdrate see an interview with subject collection editor Tom Cech. The Argentine Luis Federico Leloir, who received the Nobel Prize in Chemistry, discovered galactose catabolism. Gluconeogenesis and the pentose phosphate pathway represent the two main anabolic pathways to produce new carbohydrate molecules. Glycogen is degraded and synthesized in the cytosol, notably in liver and muscle cells, but also in other cells, including tumor cells and cells in the retina.


10. Glycogen metabolism- Glycogenesis and Glycogenolysis Carbohydrates are organic molecules composed of carbon, Carbohjdrate, and oxygen atoms. The family of Carbohydrate metabolism and glycogen breakdown includes both simple and complex breakdosn. Body cleanse for better gut health and breakdiwn are examples of simple sugars, and starch, glycogen, and cellulose are all examples of complex sugars. The complex sugars are also called polysaccharides and are made of multiple monosaccharide molecules. Polysaccharides serve as energy storage e. During digestion, carbohydrates are broken down into simple, soluble sugars that can be transported across the intestinal wall into the circulatory system to be transported throughout the body.

Carbohydrate metabolism and glycogen breakdown -

Branching Enzyme Fig. Allosteric Fig. B Summary of Cascade Regulation replacing Figs. As Å diameter cytoplasmic granules containing up to , glucose units.

Highly branched, permits rapid degradation through simultaneous release of glucose units from the end of each branch. Liver and muscle are two major storage sites. Catalyzes the rate-limiting step in glycogen breakdown. Transfers the last 3 units to the 4-OH group at the end of another longer branch.

In cells with mitochondrial oxidative phosphorylation defects, galactose metabolism through glycolysis is too slow to generate enough ATP to meet metabolic demands, resulting in metabolic catastrophe and cell death. Mitochondrial biologists use galactose sensitivity to determine whether a genetic mutation or pharmacologic inhibitor is suppressing oxidative phosphorylation.

Galactose catabolism occurs through the Leloir pathway. The Argentine Luis Federico Leloir, who received the Nobel Prize in Chemistry, discovered galactose catabolism.

Galactokinase converts galactose into galactose 1-phosphate, which subsequently becomes glucose 1-phosphate, which can either be stored as glycogen or enter glycolysis by being converted into glucose 6-phosphate.

Fructose metabolism. Fructokinase converts fructose into fructose 1-phosphate, which subsequently is converted into glyceraldehyde and dihydroxyacetone phosphate by aldolase B that enters glycolysis. A key feature of fructose metabolism is that it bypasses the major regulatory step in glycolysis, the PFK1-catalyzed reaction.

Fructose is primarily metabolized by the liver and, to a lesser extent, by the small intestine and kidney. The first step is the phosphorylation of fructose to fructose 1-phosphate by fructokinase. Subsequently, fructose 1-phosphate is cleaved into glyceraldehyde and dihydroxyacetone phosphate by a specific fructose 1-phosphate aldolase B Fig.

Glyceraldehyde is then phosphorylated to glyceraldehyde 3-phosphate, a glycolytic intermediate, by triose kinase. The glycolytic intermediates generated can either proceed through glycolysis and its subsidiary biosynthetic reactions, including generation of fatty acids or storage as glycogen.

At first glance, it seems that fructose metabolism eventually mirrors glucose metabolism; however, fructose enters glycolysis after the important regulatory step of PFK1 in glycolysis. At the end of this review, we will discuss how high consumption of fructose through bypassing this regulatory step is linked to the alarming obesity epidemic.

The maintenance of glucose levels around 5. Blood glucose levels are maintained by gluconeogenesis and glycogenolysis. Any drop in these levels—hypoglycemia—can impair brain function, resulting in dizziness and unconsciousness. Too-high glucose levels in the blood—hyperglycemia—can also be detrimental because this condition is linked to diabetes.

The widely used antidiabetic drug, metformin, diminishes hyperglycemia by reducing hepatic gluconeogenesis. Thus, proper maintenance of glucose levels is critical to our health. At the cellular level, liver and kidney cells can generate glucose either by converting stored glycogen in the liver into glucose or synthesizing new glucose molecules gluconeogenesis to maintain blood glucose levels Fig.

It is important to note that many cells, including tumor cells, can use their stored glycogen to generate glucose to fuel glycolysis and its subsidiary pathways.

Cells can also initiate gluconeogenesis to generate glycolytic intermediates that can go into subsidiary pathways, if needed, to generate macromolecules, such as lipids. Glycolysis and gluconeogenesis share many enzymes; however, there are three irreversible reactions in glycolysis that have to be bypassed so that gluconeogenesis can ensue.

The first reaction is the generation of PEP from pyruvate requiring pyruvate carboxylase and PEP carboxykinase. The second reaction is the conversion of fructose 1,6-bisphosphate to fructose 6-phosphate by F-1,6-BPase.

The third reaction is the conversion of glucose 6-phosphate to glucose by glucose 6-phosphatase. Gluconeogenesis primarily occurs in the liver and, to a lesser degree, in the kidney, in which the newly synthesized glucose is exported into circulating blood to provide glucose to vital organs, such as the brain, as well as red blood cells that derive their ATP solely from glucose-dependent glycolysis.

Gluconeogenesis reactions occur both in the mitochondrial matrix and cytosol. In mammals, important sources that provide the carbons for gluconeogenesis are lactate, glycerol, and the amino acids alanine and glutamine. Lactate is generated by muscle and transported to the liver, in which it is converted into pyruvate to enter the gluconeogenesis.

This is referred to as the Cori cycle see Box 1. Carl — and Gerty Cori — began their scientific partnership during their years as medical school students in Prague in the early 20th century. After a stint serving in the Austrian Army during World War I, Carl finished medical school, as did Gerty, in , and they married soon after.

After their marriage, Carl spent a year at the University of Vienna and with Otto Loewi at the University of Graz. Gerty, who had been born Jewish, stayed in Vienna at the Children's Hospital and began her research there.

The fear of anti-Semitism convinced them that they needed to leave Europe. The United States was their goal, but they also applied to serve the Dutch government as doctors in Java.

A position as biochemist at the New York Institute for the Study of Malignant Diseases later the Roswell Park Cancer Institute came through for Carl in , but only a lesser position was available for Gerty in the Pathology Laboratory. The trajectory of their research began here with the demonstration of the Warburg effect, showing that tumors added lactate to the bloodstream.

Next was the groundbreaking work that resulted in the delineation of the Cori cycle of carbohydrates, with the Coris showing, experimentally, that lactic acid was the key element in the cycle of glycogen from the liver to muscle and back again. In , Carl was offered the Chairmanship of the Pharmacology Department at Washington University in St.

Again, Gerty was forced to take a backseat, as there was a proscription against two members of the same family holding faculty positions. So, she was taken on, essentially, as a postdoc with the title of research associate at one-tenth the salary as that of her husband.

Their exploration of glucose and glycogen metabolism continued here with the isolation of glucose 1-phosphate the Cori ester , establishment of the enzymatic pathways of glycogenolysis and glycolysis, and crystallization and regulation of phosphorylase.

Gerty died at a relatively young age from a bone marrow disorder, possibly a result of her early exposure to X rays while studying their effect on skin and organ metabolism. In , the United States Postal Service released a stamp honoring Gerty, but ironically the stamp had a small error in the structure of the Cori ester that the Coris had worked so hard to determine.

Their approach to research was to put forth extraordinary ideas and then design a precise research method and analytic means to test these ideas. Remarkably, among the students, postdocs, and research associates in their St. Louis laboratory were at least six future Nobelists: Christian de Duve , Arthur Kornberg , Luis F.

Leloir , Severo Ochoa , Earl W. Sutherland , and Edwin G. Krebs This discovery led to Edmond Fischer and Edwin G. Krebs showing that the phosphorylase b to phosphorylase a conversion involved phosphorylation, which turned out to be a broader method for regulating protein function.

As discussed in Chandel a , there are three irreversible steps in glycolysis. These steps have to be bypassed for gluconeogenesis to proceed. The first step is the generation of PEP from pyruvate Fig. Pyruvate in the mitochondrial matrix is converted into oxaloacetate by the enzyme pyruvate carboxylase.

This enzyme requires biotin as a cofactor and bicarbonate HCO 3 as a substrate. The reaction is thermodynamically unfavorable and coupled to the Gibbs free energy provided by converting ATP to ADP. Acetyl-CoA is a positive allosteric regulator of pyruvate carboxylase.

Therefore, if acetyl-CoA levels increase, then acetyl-CoA stimulates pyruvate carboxylase to generate oxaloacetate, and these two metabolites could make citrate to initiate TCA cycle.

However, if the liver cells' energy charge is not low, they can convert the oxaloacetate into PEP by PEPCK by coupling this reaction to the conversion of GTP to GDP Fig.

Human liver cells have two distinct PEPCK genes that encode cytosolic and mitochondrial matrix enzymes. Gluconeogenic amino acid alanine is converted into pyruvate and uses the cytosolic PEPCK, which converts cytosolic oxaloacetate to generate PEP Fig.

In this pathway, the pyruvate in the mitochondria is converted into mitochondrial oxaloacetate by pyruvate carboxylase. Mitochondria do not have a mechanism to transport oxaloacetate.

Thus, oxaloacetate must be converted into malate, which can be transported into the cytosol. This reaction is catalyzed by mitochondrial malate dehydrogenase 2. Once PEP is generated, it uses most of the glycolytic enzymes to eventually become glucose.

The NADH generated by malate dehydrogenase 1 is used by glyceraldehyde 3-phosphate dehydrogenase GAPDH to convert 1,3-bisphosphoglycerate into glyceraldehyde 3-phosphate.

Multiple substrates feed into gluconeogenesis. Alanine, lactate, glycerol, and glutamine can generate glucose. Glycerol enters gluconeogenesis through conversion into dihydroxyacetone phosphate DHAP , a reaction catalyzed by glycerol 3-phosphate dehydrogenase.

Alanine, lactate, and glutamine have to be converted into oxaloacetate, which enters gluconeogenesis through conversion into PEP by phosphoenolpyruvate carboxykinase. Lactate generated by muscle is also used as a gluconeogenic substrate through conversion into pyruvate.

Pyruvate becomes oxaloacetate by pyruvate carboxylase PC. Oxaloacetate is converted into PEP in the mitochondrial matrix by PEPCK2 and, subsequently, is transported into the cytosol to enter gluconeogenesis. The generation of lactate from pyruvate already generates NADH in the cytosol needed for GAPDH reaction, thus alleviating the necessity of malate shuttling out of the mitochondria to generate NADH.

Once PEP goes through reverse glycolysis, there are two steps of glycolysis that are not reversible: those catalyzed by PFK1 and hexokinase. The corresponding enzymes that catalyze the reverse reactions are fructose 1,6-bisphosphatase F-1, 6-BPase and glucose 6-phosphatase, respectively Fig.

Glycerol can also contribute to gluconeogenesis by the conversion of glycerol to glycerol 3-phosphate by glycerol kinase. Subsequently, glycerol 3-phosphate becomes the glycolytic intermediate dihydroxyacetone phosphate by mitochondrial glycerol 3-phosphate dehydrogenase.

Dihydroxyacetone phosphate is converted into glyceraldehyde 3-phosphate, which eventually becomes glucose. Gluconeogenesis is an endergonic process requires energy when glycerol, alanine, and lactate are substrates.

Glycerol, alanine, and lactate entry does not generate ATP. Moreover, the conversion of pyruvate to oxaloacetate uses ATP and gluconeogenesis, through reversal of glycolytic steps, also consumes ATP Fig.

However, glutamine gluconeogenesis is unique in that it represents an exergonic reaction. Glutamine through glutaminolysis see Chandel b becomes α-ketoglutarate, which goes through the TCA cycle to ultimately produce malate, which shuttles into the cytosol to enter gluconeogenesis.

Entry of glutamine into the TCA cycle generates GTP, NADH, and FADH 2 in the mitochondrial matrix that produces ATP to drive gluconeogenesis in the cytosol. It is important to realize that gluconeogenesis is a tightly regulated pathway that does not allow cells to simultaneously conduct glucose degradation by glycolysis and glucose synthesis by gluconeogenesis.

There is reciprocal control of these pathways to prevent a futile cycle Fig. A key regulatory step is how PFK1 and F-1,6-BPase are reciprocally regulated by AMP, citrate, and fructose 2,6-bisphosphate F-2,6-BP.

If the energy charge decreases in cells, then AMP levels increase, leading to PFK1 activation increasing glycolytic flux and inhibition of F-1,6-BPase decreasing gluconeogenic flux.

In contrast, if citrate levels build up in the cytosol because the TCA cycle is backed up, then glycolytic flux is reduced through citrate inhibition of PFK1. Simultaneously, gluconeogenic flux is increased through citrate activation of F-1,6-BPase. The third metabolite and most potent allosteric regulator of glycolysis and gluconeogenesis is F-2,6-BP, which is generated by phosphofructokinase-2 PFK2 and degraded by fructose 2,6-bisphosphatase F-2,6-BPase.

F-2,6-BP activates PFK1 and inhibits F-1,6-BPase. A single protein contains both PFK2 and F-2,6-BPase activities. The interconversion of PFK2 and F-2,6-BPase is achieved by cAMP-dependent protein kinase A PKA phosphorylation of PFK2 to produce F-2,6-BPase. Thus, stimuli that increase cAMP, such as the hormone glucagon, promote gluconeogenesis see Box 2.

The fed—fast cycle starts nightly after our evening meals fed state followed by nightly sleep fast state. Throughout this cycle, blood glucose levels have to be maintained.

The cycle has fluctuations in metabolic hormones insulin and glucagon, which help maintain blood glucose levels. After a meal, the increase in glucose levels quickly triggers secretion of insulin by the pancreas, which suppresses liver gluconeogenesis.

Insulin activates glycogen synthase and inactivates glycogen phosphorylase, resulting in liver glycogen synthesis. Insulin also stimulates glucose uptake in the muscle and adipose tissue for storage. Collectively, these actions of insulin lower blood glucose levels. Several hours after a meal, the blood glucose levels begin to decrease, leading to a decrease in insulin secretion and an increase in glucagon secretion from the pancreas.

Hexokinase has a higher affinity for glucose than glucokinase and therefore is able to convert glucose at a faster rate than glucokinase. This is important when levels of glucose are very low in the body, as it allows glucose to travel preferentially to those tissues that require it more.

In the next step of the first phase of glycolysis, the enzyme glucosephosphate isomerase converts glucosephosphate into fructosephosphate. Like glucose, fructose is also a six carbon-containing sugar. The enzyme phosphofructokinase-1 then adds one more phosphate to convert fructosephosphate into fructosebisphosphate, another six-carbon sugar, using another ATP molecule.

Aldolase then breaks down this fructosebisphosphate into two three-carbon molecules, glyceraldehydephosphate and dihydroxyacetone phosphate. The triosephosphate isomerase enzyme then converts dihydroxyacetone phosphate into a second glyceraldehydephosphate molecule. Therefore, by the end of this chemical- priming or energy-consuming phase, one glucose molecule is broken down into two glyceraldehydephosphate molecules.

The second phase of glycolysis, the energy-yielding phase , creates the energy that is the product of glycolysis. Glyceraldehydephosphate dehydrogenase converts each three-carbon glyceraldehydephosphate produced during the.

energy-consuming phase into 1,3-bisphosphoglycerate. NADH is a high-energy molecule, like ATP, but unlike ATP, it is not used as energy currency by the cell. Because there are two glyceraldehydephosphate molecules, two NADH molecules are synthesized during this step.

Each 1,3-bisphosphoglycerate is subsequently dephosphorylated i. Each phosphate released in this reaction can convert one molecule of ADP into one high- energy ATP molecule, resulting in a gain of two ATP molecules. The enzyme phosphoglycerate mutase then converts the 3-phosphoglycerate molecules into 2-phosphoglycerate.

The enolase enzyme then acts upon the 2-phosphoglycerate molecules to convert them into phosphoenolpyruvate molecules. The last step of glycolysis involves the dephosphorylation of the two phosphoenolpyruvate molecules by pyruvate kinase to create two pyruvate molecules and two ATP molecules.

In summary, one glucose molecule breaks down into two pyruvate molecules, and creates two net ATP molecules and two NADH molecules by glycolysis.

Therefore, glycolysis generates energy for the cell and creates pyruvate molecules that can be processed further through the aerobic Krebs cycle also called the citric acid cycle or tricarboxylic acid cycle ; converted into lactic acid or alcohol in yeast by fermentation; or used later for the synthesis of glucose through gluconeogenesis.

When oxygen is limited or absent, pyruvate enters an anaerobic pathway. In these reactions, pyruvate can be converted into lactic acid. In this reaction, lactic acid replaces oxygen as the final electron acceptor. Anaerobic respiration occurs in most cells of the body when oxygen is limited or mitochondria are absent or nonfunctional.

For example, because erythrocytes red blood cells lack mitochondria, they must produce their ATP from anaerobic respiration. This is an effective pathway of ATP production for short periods of time, ranging from seconds to a few minutes. The lactic acid produced diffuses into the plasma and is carried to the liver, where it is converted back into pyruvate or glucose via the Cori cycle.

Similarly, when a person exercises, muscles use ATP faster than oxygen can be delivered to them. They depend on glycolysis and lactic acid production for rapid ATP production. The NADH and FADH2 pass electrons on to the electron transport chain, which uses the transferred energy to produce ATP.

As the terminal step in the electron transport chain, oxygen is the terminal electron acceptor and creates water inside the mitochondria.

Figure 3. Click to view a larger image. The process of anaerobic respiration converts glucose into two lactate molecules in the absence of oxygen or within erythrocytes that lack mitochondria.

During aerobic respiration, glucose is oxidized into two pyruvate molecules. The pyruvate molecules generated during glycolysis are transported across the mitochondrial membrane into the inner mitochondrial matrix, where they are metabolized by enzymes in a pathway called the Krebs cycle Figure 4.

The Krebs cycle is also commonly called the citric acid cycle or the tricarboxylic acid TCA cycle. During the Krebs cycle, high-energy molecules, including ATP, NADH, and FADH2, are created.

NADH and FADH2 then pass electrons through the electron transport chain in the mitochondria to generate more ATP molecules. Figure 4. During the Krebs cycle, each pyruvate that is generated by glycolysis is converted into a two-carbon acetyl CoA molecule.

The acetyl CoA is systematically processed through the cycle and produces high- energy NADH, FADH2, and ATP molecules. The three-carbon pyruvate molecule generated during glycolysis moves from the cytoplasm into the mitochondrial matrix, where it is converted by the enzyme pyruvate dehydrogenase into a two-carbon acetyl coenzyme A acetyl CoA molecule.

This reaction is an oxidative decarboxylation reaction. Acetyl CoA enters the Krebs cycle by combining with a four-carbon molecule, oxaloacetate, to form the six-carbon molecule citrate, or citric acid, at the same time releasing the coenzyme A molecule.

The six-carbon citrate molecule is systematically converted to a five-carbon molecule and then a four-carbon molecule, ending with oxaloacetate, the beginning of the cycle. Along the way, each citrate molecule will produce one ATP, one FADH2, and three NADH.

The FADH2 and NADH will enter the oxidative phosphorylation system located in the inner mitochondrial membrane. In addition, the Krebs cycle supplies the starting materials to process and break down proteins and fats. To start the Krebs cycle, citrate synthase combines acetyl CoA and oxaloacetate to form a six-carbon citrate molecule; CoA is subsequently released and can combine with another pyruvate molecule to begin the cycle again.

The aconitase enzyme converts citrate into isocitrate. In two successive steps of oxidative decarboxylation, two molecules of CO2 and two NADH molecules are produced when isocitrate dehydrogenase converts isocitrate into the five-carbon α-ketoglutarate, which is then catalyzed and converted into the four-carbon succinyl CoA by α-ketoglutarate dehydrogenase.

The enzyme succinyl CoA dehydrogenase then converts succinyl CoA into succinate and forms the high-energy molecule GTP, which transfers its energy to ADP to produce ATP.

Succinate dehydrogenase then converts succinate into fumarate, forming a molecule of FADH2. Oxaloacetate is then ready to combine with the next acetyl CoA to start the Krebs cycle again see Figure 4. For each turn of the cycle, three NADH, one ATP through GTP , and one FADH2 are created.

Each carbon of pyruvate is converted into CO2, which is released as a byproduct of oxidative aerobic respiration. The electron transport chain ETC uses the NADH and FADH 2 produced by the Krebs cycle to generate ATP.

Electrons from NADH and FADH 2 are transferred through protein complexes embedded in the inner mitochondrial membrane by a series of enzymatic reactions.

In the presence of oxygen, energy is passed, stepwise, through the electron carriers to collect gradually the energy needed to attach a phosphate to ADP and produce ATP.

The role of molecular oxygen, O 2 , is as the terminal electron acceptor for the ETC. This means that once the electrons have passed through the entire ETC, they must be passed to another, separate molecule. This is the basis for your need to breathe in oxygen. Without oxygen, electron flow through the ETC ceases.

Figure 5.

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