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Term Paper on Glycogenolysis

Term Paper Contents:

  1. Term Paper on the Introduction to Glycogenolysis
  2. Term Paper on the Energy Yield
  3. Term Paper on the Metabolism of Fructose
  4. Term Paper on the Metabolism of Galactose
  5. Term Paper on the Regulation of Glycolysis
  6. Term Paper on the Transport of Oxaloacetate
  7. Term Paper on the Pyruvate Carboxylase Activation
  8. Term Paper on the Reciprocal Regulation of Glycolysis and Gluconeogenesis

Term Paper # 1 . Introduction to Glycogenolysis:

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The process of breakdown of glycogen to glucose or glucose- 6-phosphate in the tissues is referred to as glycogenolysis. It may be broken down to glucose as in liver and kidney; or glucose-6-PO4 as in the muscles. The process is enhanced by hypoglycemia, or under the influence of certain hyperglycemic hormones. Liver glycogen is metabolically more easily available as compared to muscle glycogen.

Active phosphorylase acts upon glycogen in the presence of inorganic phosphate (Pi) cleaving a-1, 4-glucosidic linkages from the outer ends of the straight chains. Another enzyme, a glucantransferase, splits trisaccharide residues from one side of the branched chains and transfers these to the other side exposing the branching points (1, 6 lindages).

Glucose- 1-PO4 is produced by the combined action of these two enzymes. The 1, 6-linkages are hydrolysed by a specific disbranching enzyme (α-1, 6-glucosidase) splitting free glucose molecules. Glucose-1-PO4 is converted into glucose-6-PO4 by the action of phosphoglucomutase. Liver and kidney tissues contain another enzyme glucose-6-phosphatase which can remove phosphate from glucose-6-phosphate.

Glucose, therefore, represents the final product of glycogenolysis in these tissues. However muscle tissues lack this enzyme, and hence, glucose-6-PO4 represents the final product of glycogenolysis in this tissue.

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A brief reference may be made here of phosphorylases involved in hepatic and muscular glycogenolysis. In the liver, phosphorylase exists in an inactive form, known as dephosphorylase which can be converted into active phosphorylase in the presence of ATP and an enzyme dephosphorylase kinase. This enzyme binds phosphate groups to serine in the dephosphorylase molecule. The action of dephosphorylase kinase is promoted by cyclic- AMP (3’5′-adenylic acid). Cyclic-AMP itself is produced from ATP by the action of an enzyme adenyl cyclase in the presence of Mg++ ions.

Muscle phosphorylase in the rabbit muscles has been shown to exist in two distinct forms, namely phosphorylase-a and phosphorylase-b. Phosphorylase-a (molecular weight 495,000) contains four molecules of pyridoxal phosphate, whereas phosphorylase-a, (molecular weight 242,000) contains only two molecules of pyridoxal phosphate. Phosphorylase is more active than phosphorylase-b, phosphorylase-b may be converted into phosphorylase-a in the presence of ATP and the enzyme phosphorylase-b-kinase.

Phosphorylase-a may also be hydrolytically changed into phosphorylase-b in the presence of phosphorylase rupturing enzyme.

Mechanism of Glycogenolysis in Liver and Muscles

Term Paper # 2. Energy Yield:

Early in glycolysis, two ATPs are required for the conversion of glucose to glucose 6-phosphate by hexokinase and for the conversion of fructose 6-phosphate to fructose 1, 6-bisphosphate by PFK. However, fructose 1, 6-bisphosphate then gives rise to two three-carbon units, each of which generates two ATPs in subsequent steps (catalyzed by phosphoglycerate kinase and pyruvate kinase) giving a net yield of two ATPs per original glucose molecule.

The overall reaction is:

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Glucose + 2 P + 2 ADP + 2 NAD+ → 2 pyruvate + 2 ATP + 2 NADH + 2 H+ + 2 H2O

Note that, under aerobic conditions, the two NADH molecules that are synthesized are re-oxidized via the electron transport chain generating ATP. Given the cytoplasmic location of these NADH molecules, each is re-oxidized via the glycerol 3-phosphate shuttle and produces approximately two ATPs during oxidative phosphorylation or via the malate-aspartate shuttle and produces approximately three ATPs during oxidative phosphorylation.

Term Paper # 3. Metabolism of Fructose:

Fructose is an abundant sugar in the human diet; sucrose (table sugar) is a disaccharide which when hydrolyzed yields fructose and glucose and fructose is also a major sugar in fruits and honey. There are two pathways for the metabolism of fructose; one occurs in muscle and adipose tissue, the other in liver.

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1. In muscle and adipose tissue, fructose can be phosphorylated by hexokinase (which is capable of phosphorylating both glucose and fructose) to form fructose 6-phosphate which then enters glycolysis.

2. In liver, the cells contain mainly glucokinase instead of hexokinase and this enzyme phosphorylates only glucose. Thus in liver, fructose is metabolized instead by the fructose 1- phosphate pathway.

Fructose 1-Phosphate Pathway

i. Fructose is converted to fructose 1-phosphate by fructokinase.

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ii. Fructose 1-phosphate is then split into glyceraldehyde and dihydroxyacetone phosphate by fructose 1-phosphate aldolase. The dihydroxyacetone feeds into glycolysis at the triose phosphate isomerase step.

iii. The glyceraldehyde is phosphorylated by triose kinase to glyceraldehyde 3-phosphate and so also enters glycolysis.

Term Paper # 4. Metabolism of Galactose:

The hydrolysis of the disaccharide lactose (in milk) yields galactose and glucose.

Thus galactose is also a major dietary sugar for humans. Galactose and glucose are epimers that differ in their configuration at C-4. Thus the entry of galactose into glycolysis requires an epimerization reaction.

This occurs via a four-step pathway called the galactose-glucose inter-conversion pathway:

1. Galactose is phosphorylated by galactokinase to give galactose 1-phosphate.

2. Galactose 1-phosphate uridylyl transferase catalyzes the transfer of a uridyl group from UDP-glucose to galactose 1-phosphate to form UDP-galactose and glucose 1- phosphate.

3. The UDP-galactose is converted back to UDP-glucose by UDP-galactose 4-epimerase. Thus, overall, UDP-glucose is not consumed in the reaction pathway.

4. Finally the glucose 1-phosphate is converted to glucose 6- phosphate by phosphoglucomutase. The glucose 6-phosphate then enters glycolysis.

Galactosemia is a genetic disease caused by an inability to convert galactose to glucose. Toxic substances accumulate such its galactitol, formed by the reduction of galactose, and lead to dire consequences for the individual. Children who have the disease fail to thrive, may vomit or have diarrhea after drinking milk, and often have an enlarged liver and jaundice.

Galactose-Glucose Interconversion Pathway

The formation of cataracts in the eyes, mental retardation and an early death from liver damage are also possible. Most cases of galactosemia are due to a deficiency of the galactose 1-phosphate uridylyl transferase enzyme and hence these individuals cannot metabolize galactose.

The disease is treated by prescribing a galactose-free diet which causes all the symptoms to regress except mental retardation which may be irreversible. Since such patients have normal levels of UDP-galactose 4-epimerase, they can still synthesize UDP-galactose from UDP-glucose and so can still synthesize, for example, oligosaccharides in glycoproteins that involve Gal residues.

Term Paper # 5. Regulation of Glycolysis:

1. Phosphofructokinase:

The most important control step of glycolysis is the irreversible reaction catalyzed by phosphofructokinase (PFK).

The enzyme is regulated in several ways:

i. ATP/AMP:

PFK is allosterically inhibited by ATP but this inhibition is reversed by AMP. This allows glycolysis to be responsive to the energy needs of the cell, speeding up when ATP is in short supply (and AMP is plentiful) so that more ATP can be made, and slowing down when sufficient ATP is already available.

ii. Citrate:

PFK is also inhibited by citrate, the first product of the citric acid cycle proper. A high level of citrate signals that there is a plentiful supply of citric acid cycle intermediates already and hence no additional breakdown of glucose via glycolysis is needed.

iii. Fructose 2, 6-Bisphosphate:

Fructose 2, 6-bisphosphate (F-2 6-BP) is synthesized from fructose 6-phosphate by an enzyme railed phosphofructokinase 2 (PFK2), a different enzyme from PFK. F-2, 6-BP is hydrolyzed back to fructose 6-phosphate by fructose bisphosphatase 2 (FBPase2). Amazingly, both PFK2 and FBPase2 are activities catalyzed by the same polypeptide; hence this is a bi-functional enzyme.

Fructose 6-phosphate stimulates the synthesis of F-2, 6-BP and inhibits its hydrolysis. F-2, 6-BP in turn strongly activates PFK and hence stimulates glycolysis. The overall effect is that when fructose 6-phosphate levels are high, PFK (and hence glycolysis) is stimulated. PFK2 and FBPase2 are also controlled by covalent modification.

Synthesis and Degradation of Fructose 2. 6- Bisphosphate

When blood glucose levels fall, the hormone glucagon is released into the bloodstream and triggers a cAMP cascade that leads to phosphorylation of the PFK2/FBPase2 polypeptide at a single serine residue. This activates FBPase2 and inhibits PFK2, lowering the level of F-2, 6-BP and hence decreasing the rate of glycolysis.

The reverse is true as glucose levels rise; the phosphate group is removed from the PFK2/FBPase2 polypeptide by a phosphatase, thus inhibiting FBPase2 and activating PFK2, raising the level of F-2, 6-BP and hence increasing the rate of glycolysis.

F-2, 6-BP is also important in preventing glycolysis (glucose degradation) and gluconeogenesis (glucose synthesis) operating simultaneously. This is called reciprocal regulation.

iv. H+ Ions:

PFK is inhibited by H+ ions and hence the rate of glycolysis decreases when the pH falls significantly. This prevents the excessive formation of lactate (i.e. lactic acid) under anaerobic conditions (see above) and hence prevents the medical condition known as acidosis (a deleterious drop in blood pH).

2. Hexokinase:

Hexokinase, which catalyzes the first irreversible step of glycolysis, is inhibited by glucose 6-phosphate. Thus when PFK is inhibited, fructose 6-phosphate builds up and so does glucose 6- phosphate since these two metabolites are in equilibrium via phosphoglucoisomerase. The hexokinase inhibition then reinforces the inhibition at the PFK step. At first sight this seems unusual since it is usually the first irreversible step of a pathway (the committed step) that is the main control step.

On this basis, it may appear that hexokinase should be the main control enzyme, not PFK. However, glucose 6-phosphate, the product of the hexokinase reaction, can also feed into glycogen synthesis or the pentose phosphate pathway. Thus the first irreversible step that is unique to glycolysis is that catalyzed by PFK and hence this is the main control step.

3. Pyruvate Kinase:

Pyruvate kinase catalyzes the third irreversible step in glycolysis. It is activated by fructose 1, 6-bisphosphate. ATP and the amino acid alanine allosterically inhibit the enzyme so that glycolysis slows when supplies of ATP and biosynthetic precursors (indicated by the levels of Ala) are already sufficiently high. In addition, in a control similar to that for PFK, when the blood glucose concentration is low, glucagon is released and stimulates phosphorylation of the enzyme via a cAMP cascade. This covalent modification inhibits the enzyme so that glycolysis slows down in times of low blood glucose levels.

Overview:

Gluconeogenesis synthesizes glucose from non-carbohydrate precursors, including lactate and pyruvate, citric acid cycle intermediates, the carbon skeletons of most amino acids and glycerol. This is extremely important since the brain and erythrocytes rely almost exclusively on glucose as their energy source under normal conditions.

The liver’s store of glycogen is sufficient to supply the brain with glucose for only about half a day during fasting. Thus gluconeogenesis is especially important in periods of starvation or vigorous exercise. During starvation, the formation of glucose via gluconeogenesis particularly uses amino acids from protein breakdown and glycerol from fat breakdown. During exercise, the blood glucose levels required for brain and skeletal muscle function are maintained by gluconeogenesis in the liver using lactate produced by the muscle.

The main site of gluconeogenesis is the liver, although it also occurs to a far lesser extent in the kidneys. Very little gluconeogenesis occurs in brain or muscle. Within liver cells, the first enzyme of gluconeogenesis, pyruvate carboxylase, is located in the mitochondrial matrix. The last enzyme, glucose 6-phosphatase is bound to the smooth endoplasmic reticulum. The other enzymes of the pathway are located in the cytosol.

Pathway:

In glycolysis, glucose is metabolized to pyruvate. In gluconeogenesis, pyruvate is metabolized to glucose. Thus, in principle, gluconeogenesis appears to be a reversal of glycolysis. Indeed, some of the reactions of glycolysis are reversible and so the two pathways have these steps in common. However, three steps in glycolysis are essentially irreversible; those catalyzed by the enzymes hexokinase, phosphofructokinase (PFK) and pyruvate kinase.

Comparsion of Gluconeogenesis and Glycolysis

Indeed it is the large negative free-energy change in these reactions that normally drives glycolysis forward towards pyruvate formation. Therefore, in gluconeogenesis, these three steps have to be reversed by using other reactions; gluconeogenesis is not a simple reversal of glycolysis.

Precursors for Gluconeogenesis:

Glycerol can act as a substrate for glucose synthesis by conversion to dihydroxyacetone phosphate, an intermediate in gluconeogenesis. In order for lactate, pyruvate, citric acid cycle intermediates and the carbon skeletons of most amino acids to act as precursors for gluconeogenesis, these compounds must first be converted to oxaloacetate. Some of the carbon skeletons of the amino acids give rise to oxaloacetate directly.

Others feed into the citric acid cycle as intermediates and the cycle then converts these molecules to oxaloacetate. Lactate is converted to pyruvate by the lactate dehydrogenase reaction and some amino acids also give rise to pyruvate. Therefore, for these precursors, the first step in the gluconeogenic pathway is the conversion of pyruvate to oxaloacetate.

The steps in gluconeogenesis are as follows:

1. Pyruvate is converted to oxaloacetate by carboxylation using the enzyme pyruvate carboxylase that is located in the mitochondrial matrix.

This enzyme uses biotin as an activated carrier of CO2, the reaction occurring in two stages:

E-biotin + ATP + HCO3 → E-biotin-CO2 + ADP + Pi

E-biotin-CO2 + pyruvate → E-biotin + oxaloacetate

2. The oxaloacetate is now acted on by phosphoenolpyruvate carboxykinase which simultaneously decarboxylates and phosphorylates it to form phosphoenolpyruvate (PEP), releasing CO2 and using GTP in the process.

Oxaloacetate + GTP ⇌ PEP + CO2 + GDP

Thus, reversal of the glycolytic step from PEP to pyruvate requires two reactions in gluconeogenesis, pyruvate to oxaloacetate by pyruvate carboxylase and oxaloacetate to PEP by PEP carboxykinase. Given that the conversion of PEP to pyruvate in glycolysis synthesizes ATP, it is not surprising that the overall reversal of this step needs the input of a substantial amount of energy, one ATP for the pyruvate carboxylase step and one GTP for the PEP carboxykinase step.

3. PEP is converted to fructose 1, 6-bisphosphate in a series of steps that are a direct reversal of those in glycolysis, using the enzymes enolase, phosphoglycerate mutase, phosphoglycerate kinase, glyceraldehyde 3-phosphate dehydrogenase, triose phosphate isomerase and aldolase. This sequence of reactions uses one ATP and one NADH for each PEP molecule metabolized.

4. Fructose 1, 6-bisphosphate is dephosphorylated to form fructose 6-phosphate by the enzyme fructose 1, 6-bisphosphatase, in the reaction:

fructose 1, 6-bisphosphate + H2O → fructose 6-phosphate + Pi

5. Fructose 6-phosphate is converted to glucose 6-phosphate by the glycolytic enzyme phosphoglucoisomerase.

6. Glucose 6-phosphate is converted to glucose by the enzyme glucose 6-phosphatase.

This enzyme is bound to the smooth endoplasmic reticulum and catalyzes the reaction:

glucose 6-phosphate + H2O → glucose + Pi

Energy Used:

As would be expected, the synthesis of glucose by gluconeogenesis needs the input of energy. Two pyruvate molecules are required to synthesize one molecule of glucose.

Energy is required at the following steps:

This compares with only two ATPs as the net ATP yield from glycolysis. Thus an extra four ATPs per glucose are required to reverse glycolysis. In fact, the glyceraldehyde 3-phosphate dehydrogenase reaction also consumes NADH, equivalent to two molecules of NADH for each molecule of glucose synthesized. Since each cytosolic NADH would normally be used to generate approximately two ATP molecules via the glycerol 3-phosphate shuttle and oxidative phosphorylation, this is equivalent to the input of another four ATPs per glucose synthesized.

Term Paper # 6. Transport of Oxaloacetate:

Pyruvate carboxylase is a mitochondrial matrix enzyme whereas the other enzymes of gluconeogenesis are located outside the mitochondrion. Thus oxaloacetate, produced by pyruvate carboxylase, needs to exit the mitochondrion. However the inner mitochondrial membrane is not permeable to this compound.

Transport of Oxalocetate Out of the Mitochondrion

Thus oxaloacetate is converted to malate inside the mitochondrion by mitochondrial malate dehydrogenase, the malate is transported through the mitochondrial membrane by a special transport protein and then the malate is converted back to oxaloacetate in the cytoplasm by a cytoplasmic malate dehydrogenase.

Term Paper # 7. Pyruvate Carboxylase Activation:

Oxaloacetate has two main roles. It is an intermediate that is consumed in gluconeogenesis and it is also a key intermediate in the citric acid cycle where it fuses with acetyl CoA to form citrate, eventually being regenerated by the cycle. Thus pyruvate carboxylase generates oxaloacetate for gluconeogenesis but also must maintain oxaloacetate levels for citric acid cycle function.

For the latter reason, the activity of pyruvate carboxylase depends absolutely on the presence of acetyl CoA; the biotin prosthetic group of the enzyme cannot be carboxylated unless acetyl CoA is bound to the enzyme. This allosteric activation by acetyl CoA ensures that more oxaloacetate is made when excess acetyl CoA is present. In this role of maintaining the level of citric acid cycle intermediates, the pyruvate carboxylase reaction is said to be anaplerotic that is ‘filling up’.

Term Paper # 8. Reciprocal Regulation of Glycolysis and Gluconeogenesis:

Glycolysis generates two ATPs net per glucose whereas gluconeogenesis uses four ATPs and two GTPs per glucose. Thus, if both glycolysis and gluconeogenesis were allowed to operate simultaneously, converting glucose to pyruvate and back again, the only net result would be the utilization of two ATPs and two GTPs, a so-called futile cycle. This is prevented by tight coordinate regulation of glycolysis and gluconeogenesis.

Since many of the steps of the two pathways are common, the steps that are distinct in each pathway are the sites of this regulation, in particular the inter-conversions between fructose 6-phosphate and fructose 1, 6- bisphosphate and between PEP and pyruvate.

The situation is described in detail below:

Regulation of PFK and Fructose 1, 6-Bisphosphatase:

When the level of AMP is high, this indicates the need for more ATP synthesis. AMP stimulates PFK, increasing the rate of glycolysis, and inhibits fructose 1, 6-bisphosphatase, turning off gluconeogenesis. Conversely, when ATP and citrate levels are high, this signals that no more ATP need be made. ATP and citrate inhibit PFK, decreasing the rate of glycolysis, and citrate stimulates fructose 1, 6-bisphosphatase, increasing the rate of gluconeogenesis.

Glycolysis and gluconeogenesis are made responsive to starvation by-the level of the regulatory molecule fructose 2, 6- bisphosphate (F-2, 6-BP). F-2, 6-BP is synthesized from fructose 6- phosphate and hydrolyzed back to fructose 6-phosphate by a single polypeptide with two enzymatic activities (PFK2 and FBPase2). The level of F-2, 6-BP is under hormonal control.

During starvation, when the level of blood glucose is low, the hormone glucagon is released into the bloodstream and triggers a cAMP cascade, eventually causing phosphorylation of the PFK2/FBPase2 polypeptide. This activates FBPase2 and inhibits PFK2, lowering the level of F-2, 6-BP.

Reciprocal Regulation of Glycolysis and Gluconegenesis

In the fed state, when blood glucose is at a high level, the hormone insulin is released and has the opposite effect, causing an elevation in the level of F-2, 6-BP. Since F-2, 6-BP strongly stimulates PFK and inhibits fructose 1, 6-bisphosphatase, glycolysis is stimulated and gluconeogenesis is inhibited in the fed animal. Conversely, during starvation, the low level of F-2, 6-BP allows gluconeogenesis to predominate.

Regulation of Pyruvate Kinase, Pyruvate Carboxylase and PEP Carboxykinase:

i. In liver, pyruvate kinase is inhibited by high levels of ATP and alanine so that glycolysis is inhibited when ATP and biosynthetic intermediates are already plentiful. Acetyl CoA is also abundant under these conditions and activates pyruvate carboxylase, favouring gluconeogenesis.

Conversely, when the energy status of the cell is low, the ADP concentration is high and this inhibits both pyruvate carboxylase and PEP carboxykinase, switching off gluconeogenesis. At this time, the ATP level will be low so pyruvate kinase is not inhibited and glycolysis will operate.

ii. Pyruvate kinase is also stimulated by fructose 1, 6-bisphosphate (feed forward activation) so that its activity rises when needed, as glycolysis speeds up.

iii. During starvation, the priority is to conserve blood glucose for the brain and muscle. Thus, under these conditions, pyruvate kinase in the liver is switched off. This occurs because the hormone glucagon is secreted into the bloodstream and activates a cAMP cascade that leads to the phosphorylation and inhibition of this enzyme.