Glycogen

Introduction:

 

Glycogen is a polysaccharide of glucose. Glycogen’s main function is to temporarily store energy in animal cells. It is mainly manufactured by the hepatocytes cells in the liver. Muscles also manufacture glycogen.  In addition the brain and uterus contain glycogen in minimal amounts.  In the liver hepatocytes, glycogen can amount up to 8% of the fresh weight (100–120 g in an adult) soon after a meal. Only the glycogen stored in the liver can be made available for use to other organs. (Acharya K.R, 1991) Muscles contain a much lower amount of glycogen which is approximately 1% of the muscle mass. Nevertheless the cumulative amount of glycogen in muscles exceeds that of the liver.

Small amounts of glycogen are found in the kidneys, and the glial cells in the brain and white blood cells. The uterus also stores glycogen during pregnancy for the purpose of nourishing the embryo Glycogen is similar to starch in plants, and is therefore commonly referred to as animal starch, having a similar structure to amylopectin. Many cell types contain glycogen granules in the cytosol which is vital in the glucose cycle. Glycogen forms an energy reserve which is conveniently utilized to cater for an urgent need for glucose in the body. This energy reserve is purely for immediate use and thus it is less compact than the energy reserves of triglycerides (fat).

 

 

 

 

Discussion:

.

Glycogen is a very large, highly branched polymer of glucose residues that can be broken down to yield glucose molecules whenever energy is needed. It is a dendrimer of about 60,000 glucose residues and has a molecular weight between 106 and 107 Daltons (~4.8 million). Most of the glucose residues in glycogen are linked by α-1, 4 glycosidic bonds. Approximately 1 in every 12 glucose residues also makes alpha-1, 6 glycosidic bond with a second glucose residue, which results in the creation of a branch. (Whelan Joseph W 1968). It should be noted that α (alpha) glycosidic linkages form open helical polymers, whereas β (beta) linkages produce nearly straight strands that form structural fibrils, as in cellulose

Glycogen does not have a reducing end. This is as a result of the reducing end glucose being covalently bound to the protein glycogenin as a beta-linkage to a surface tyrosine residue. Glycogenin is a glycosyltransferase and occurs as a dimer in the core of glycogen. Glycogen granules contain both glycogen and the enzymes of glycogen synthesis (glycogenesis) and degradation (glycogenolysis). The enzymes are positioned between the outer branches of the glycogen molecules and act on the non-reducing ends. Therefore the rapid synthesis and catabolism of glycogen is as a result of its multiple non-reducing end-branches.

 

Function and regulation of liver glycogen

 

As a meal containing carbohydrates is consumed and digested, blood glucose levels rise resulting in the secretion of insulin by the pancreas. Glucose from the hepatic portal vein enters the hepatocytes. Insulin acts on the hepatocytes and this stimulates the synthesis of glycogen. Glucose molecules are added to the chains of glycogen as long as both insulin and glucose remain abundant. This results in the liver absorbing more glucose from the blood than it releases.

 

After digestion, glucose levels begin to fall resulting in a decrease in insulin secretion and hence glycogen synthesis stops. This process resumes four hours later as glycogen begins to be broken down and converted again to glucose. Glycogen phosphorylase is the main enzyme that catalyses the breakdown of glycogen. For the next 8–12 hours, glucose derived from liver glycogen acts as the main source of blood glucose used to give energy to the rest of the body.

Insulin is the anabolic hormone. It enhances the storage of fuels in the body. Insulin stimulates the storage of glucose as glycogen in the liver and the muscles; Insulin also enhances the conversion of glucose into triacylglycerides and the storage of triacylglycerides in the adipose tissue. In addition it promotes the synthesis of protein in skeletal muscle. Insulin also promotes utilization of glucose as fuel. The release of insulin is regulated by the levels of glucose in the blood. The highest concentrations of insulin occur 40 to 45 minutes after a meal containing high amounts of carbohydrates. After two hours, the level of insulin goes back to the normal levels. (Acharya K.R, 1991)

Glucagon is another hormone produced by the pancreas, and acts as a counter-signal to insulin. In cases where the blood sugar begins to fall below normal, glucagon is secreted in increasing amounts. This stimulates glycogen breakdown into glucose even when insulin levels are abnormally high.

Glucagon is the hormone acts as a catalyst for the mobilization of fuels in the body. Glucagon maintains the availability of glucose in the absence of dietary glucose by stimulating the release of glucose from the liver. Glucogon stimulates glycogenolysis and gluconeogenesis. Glucagon also activates the mobilization of fatty acids from the adipose tissue. The sites of glucagon action are primarily in the liver and adipose tissue. Insulin and glucose suppress the release of glucagon and hence glucagon is at its lowest level after a high carbohydrate meal. All of glucagon’s effects are opposed by the effects of insulin.

Glucagon is synthesized by the type A cells of the pancreas in the form of preproglucagon polypeptide. The preproglucagon is produced in the endoplasmic reticulum and as it enters the lumen itunder goes proteolytic cleave to produce the mature 29 amino acidpolypeptide glucagon. Glucagon is rapidly metabolized in the liver and kidneys within a span of 3-5 minutes. (Whelan Joseph W 1968).

 

Glycogen Metabolism

 

Glycogen as stated earlier is a ready to use form of storage of glucose. It is a very large, branched polymer of glucose residues that are broken down to yield glucose molecules when energy is needed. Most of the glucose residues in glycogen are linked by α-1, 4-glycosidic bonds. Branches at about every tenth residue are created by α-1, 6-glycosidic bonds

Glycogen is not as reduced as fatty acids and this makes it not to be as energy rich as fatty acids.  Why then do animals store any energy in the form of glycogen instead of converting all excess fuel into fatty acids? Glycogen is an important for various reasons. To begin with, the systematic breakdown of glycogen and release of glucose increases the amount of glucose available in between meals. Hence, glycogen helps to ensure that the level of glucose in the blood does not fall beyond the normal level.

Glycogen’s role in maintaining blood-glucose levels is vital as in actual sense glucose is the only source of fuel used for the brain, with the exception of prolonged periods of starvation. In addition, the glucose from glycogen is always ready for use and is therefore a good source of energy for sudden, strenuous activity. Unlike fatty acids, the released glucose can provide energy in the absence of oxygen and can thus supply energy for anaerobic activity.

Glycogen is mainly stored in the liver and skeletal muscle. The concentration of glycogen is higher in the liver than in muscle where the concentration is 10% and 2% by weight respectively. (Flokin 1969).  Nevertheless more glycogen is stored in skeletal muscle because of its much greater mass. In the liver, glycogen synthesis and degradation are regulated to maintain blood-glucose levels as required to meet the needs of the organism as a whole. In contrast, in muscle, these processes are regulated to meet the energy needs of the muscle itself.

Glycogen degradation and synthesis are relatively simple biochemical processes. Glycogen degradation is made up of three steps:  the release of glucose 1-phosphate from glycogen, the remodeling of the glycogen substrate to allow further degradation, and the conversion of glucose 1-phosphate into glucose 6-phosphate for further metabolism.

The glucose 6-phosphate derived from the breakdown of glycogen has three functions. It acts as the primary substrate for glycolysis, it is processed by the pentose phosphate pathway to yield NADPH and ribose derivatives; and it is converted into glucose for release into the bloodstream. This conversion takes place primarily in the liver and to a lesser extent in the intestines and kidneys.

 

In order for glycogen to be synthesized an activated form of glucose, uridine diphosphate glucose (UDP-glucose) is needed. UDP-glucose is formed by the reaction of UTP and glucose 1-phosphate. UDP-glucose is added to the non reducing end of glycogen molecules. For glycogen degradation to occur, the glycogen molecule has to be remodeled for continued synthesis. (Whelan Joseph W 1968).

 

The regulation of these processes is quite complex. Several enzymes taking part in glycogen metabolism allosterically respond to metabolites that signal the energy needs of the cell. These allosteric responses allow the adjustment of enzyme activity to meet the needs of the cell in which the enzymes are expressed. Glycogen metabolism is also regulated by hormonally stimulated cascades that lead to the reversible phosphorylation of enzymes, which alters their kinetic properties.

Regulation by hormones allows glycogen metabolism to adjust to the needs of the entire organism. By both these mechanisms, glycogen degradation is integrated with glycogen synthesis.

Glycogen phoshorylase catalyzes the following reaction: Glycogenn + Pi Glucose-1-phosphate + glycogenn-1

Glycogen phosphorylase is a typical allosteric enzyme in that it is composed of 2 identical subunits; its dimer has symmetry and exists in only two conformations which are always in equilibrium.

Glycogen phosphorylase is dimer of two identical subunits. Each subunit has an active site which consists of a pyridoxal cofactor covalently attached via a Schiff base. The active sites are located in the center of each subunit. This enzyme is allosterically regulated.

This enzyme binds inorganic phosphate cooperatively. This allows the enzyme’s activity to increase significantly over a narrow range of substrate concentrations. Glycogen phosphorylase produces glucose-1-phosphate which is isomerized into glucose-6-phosphate and enters the glycolytic pathway to produce ATP.  ATP is a feed back inhibitor of glycogen phosphorylase. Glucose-6-phosphate is an allosteric inhibitor of the enzyme. ATP and glucose-6-phosphate suppress the cooperativity of substrate binding. (Flokin 1969).

AMP is also an allosteric effector of glycogen phosphorylase. It competes for the same allosteric binding site as ATP but stimulates glycogen phosphorylase by enhancing the cooperativity of substrate binding. An increase in the cellular concentration of AMP is an indicator that cell has low energy levels and more ATP via glycolysis needs to be produced. The reciprocal changes of ATP and AMP concentrations coupled with their competition for the allosteric binding site with reverse effects provide a mechanism for quick and reversible control over glycogenolysis.

The allosteric controls allow the cell to adjust to normal metabolic demands. In crisis conditions in which ATP is needed immediately, these allosteric controls are overridden by reversible covalent phosphorylation of glycogen phosphorylase by the enzyme, phosphorylase kinase. The reversible covalent modification converts the enzyme from a less activated, allosterically regulated form b to a more active, allosterically unresponsive form a. Thus the covalent modification is like a permanent

allosteric transition. (Acharya K.R, 1991)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Glycogen debt

 

Due to the body’s inability to hold more than around 2,000 kcal of glycogen, long-distance athletes such as marathon runners, cross-country runners and cyclists go into glycogen debt. (Flokin 1969). This occurs when a significant amount of glycogen stores are depleted after long periods of activity without replacing lost energy. This phenomenon is referred to as hitting the wall. When suffering from glycogen debt, one usually experiences extreme fatigue to the point that it is difficult to breathe or move.

 

Disorders of glycogen metabolism

 

The most common disease in which glycogen metabolism becomes abnormal is diabetes. Diabetes results from of abnormal amounts of insulin in the body which makes liver glycogen to be abnormally accumulated or depleted. Restoration of normal glucose metabolism usually normalizes glycogen metabolism as well.

In hypoglycemia caused by excessive insulin, liver glycogen levels are high, but the high insulin level prevents the glycogenolysis necessary to maintain normal blood sugar levels. Glucagon is a common treatment for this type of hypoglycemia.

Various inborn errors of metabolism are caused by deficiencies of enzymes necessary for glycogen synthesis or breakdown. These are collectively referred to as glycogen storage diseases.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

REFERENCES:

 

Acharya K.R, Glycogen Phosphorylase B: Description of the Protein Structure. World Scientific Press, 1991.

 

Whelan Joseph W, Control of Glycogen Metabolism. Academic Press, 1968.

 

Flokin, Elmer Henry S, Comprehensive Biochemistry. Elsevier, 1969.