Glycogen Metabolism

Glycogen Metabolism Topics: 1. Glycogen: An Energy Reserve 2. Introduction to Glycogen Metabolism 3. Role of Enzymes in Glycogen Degradation 4. Glycogen Breakdown: Mechanism 5. Regulation of Glycogen Breakdown and Synthesis

1. Glycogen: An Energy Reserve Glycogen: Glycogen is an energy reserve molecule which is a polysaccharide having a molecular formula of [C6H10O5]. It is stored primarily in the liver and muscle tissues. Glycogen is simply like a storage battery which is charged when glucose is present in excess. Whenever the body is in need of additional energy during conditions like fasting, strenuous exercise etc, glucose is released from this energy reserve glycogen and the necessary energy is gained. Glycogen is present as β particles, and having a size of approximately 30 nm in diameter consisting up to 60,000 glucose units. Central nervous system (CNS) depends upon the hepatic glycogen for its energy requirements. If we can compare glycogen with fats, the primary suppliers of energy in our body, glycogen can be rapidly mobilized in skeletal muscles. Even it can be utilized a fuel substrate in the absence of oxygen. Glycogen can maintain blood glucose levels for the use of certain significant tissues like the brain. One disadvantage about fats is that the carbon atoms of fat can not be used by any pathway of the body. Glycogen stores significantly more limited than adipose tissue. Increased storage of glycogen levels can double the duration of exhaustive work. Instead, if there are low or depleted glycogen stores, then it will limit exercise intensity, decreases time to exhaustion. The average person stores enough glycogen for 12 to 14 hours. The average amount of glycogen ingested daily is 400 grams. In order to maintain an adequate supply to the body, a minimum of 100 grams of carbohydrates should be consumed daily.

Structure of Glycogen: Glycogen is primarily made by the liver and the muscles, but can also be synthesized by the brain, uterus, and the vagina. Glycogen is largely α 1-4 linked glucose. Glycogen is not built by polymerizing branched monomers; it is constructed by polymerization of simple monomers. The branching is also by means of rearrangement.

Glycogen is commonly referred to as animal starch, having a similar structure to amylopectin. It is the analogue of starch, a less branched polysaccharide of glucose sugar in plants. In the liver hepatocytes, glycogen can compose up to 8% of the fresh weight of an adult soon after a meal. Even glycogen is synthesized in liver, brain and muscles, only the glycogen stored in the liver can be made accessible to other organs. In the muscles, glycogen is found in a much lower concentration, but the total amount exceeds than that of the liver. Traces of glycogen are found in the kidneys, and even smaller amounts in the brain and white blood cells. The uterus also stores glycogen during pregnancy to nourish the embryo. It is also secreted in the vagina which is ultimately converted into lactic acid to maintain the acidic environment in order to avoid outside bacterial infections.

2. Introduction to Glycogen Metabolism Glucose enters the cells in the body by facilitated diffusion. The glucose levels in blood are kept at approximately constant levels around 4-5 mM. This process does not allow the cell to contain glucose at a higher concentration than the one present in the bloodstream; the cell chemically modifies glucose by the process of phosphorylation with the help of the enzyme hexokinase.

The cell membrane is impermeable to glucose-6-phosphate molecules. Hence this process of conversion of glucose into glucose-6-phosphate effectively "traps" glucose inside the cell. It allows the recovery of more glucose from the bloodstream. Glucose-6-phosphate will be used in the synthesis of glycogen. Glycogen can either enter into pentose-phosphate pathway for the production of other carbon compounds, or degraded in order to produce energy by the process of glycolysis. Large amounts of glucose-6-phosphate inside the cell create and increase the osmotic pressure. In these conditions, water will tend to flow into the cell, increasing its volume. This eventually leads to the cell lysis. In order to prevent this, the cell stores glucose-6-phosphate as a polymer which is the glycogen. Glycogen is a sparsely soluble and this property makes it osmotically inactive. It is a branched polysaccharide, composed of glucose monomers joined through glycosidic bonds of the type α 1-4 and α 1-6 in the branching points.

In order to be used for glycogen synthesis, glucose-6-fosfato is first isomerized to glucose-1-fosfato by the enzyme fosfoglucomutase.

Addition of glucose-1-phosphate to the 4' carbon of a glycogen chain is not favored thermodynamically. Glucose-1-phosphate will therefore be activated by transformation into a species with high phosphate transfer potential. This is accomplished by reaction with uridine triphosphate (UTP) which is an analog of ATP, with uridine replacing adenine.

This reaction seems not to be thermodynamically favorable. However, pyrophosphate (PPi) released in this reaction can be hydrolyzed by the ubiquitous enzyme pyrophosphatase in a very exergonic reaction. An exergonic reaction can be coupled to an otherwise unfavourable reaction in order to make it spontaneous. Thus the removal of PPi pushes the equilibrium towards the formation of UDP-glucose. UDP-glucose has a high phosphate transfer potential, and this allows it to donate glucose to the 4' end of a glycogen chain, in a reaction catalyzed by glycogen synthase:

Glycogen synthase can only add glucose to pre-existent glycogen chains and it is unable to start the synthesis of a new glycogen molecule. Glycogen synthesis is started by the addition of a glucose molecule to a tyrosine residue present in the active site of a protein called glycogenin. After addition of around seven more glucose molecules, the new glycogen chain is ready to be acted upon by glycogen synthase. (α 1-4 → α 1-6) Branching points are created by a "branching enzyme (amylo(1,4 -->1,6)transglycosylase)". This enzyme acts upon linear stretches of glycogen with at least 11 glucose molecules. Branching enzyme transfers 7 glucose molecules-long terminal segments of glycogen to the OH group of carbon 6 of a glucose residue in the same or in another chain. Branching points must be at least 4 glucose molecules apart from each other.

3. Role of Enzymes in Glycogen Degradation UDP-glucose pyrophosphorylase: UTP-glucose-1-phosphate uridylyltransferase is an enzyme associated with glycogenesis. It synthesizes UDP-glucose from glucose-1phosphate and UTP. G-1-P + UDP → UDPG + P Pi Glycogen synthase: This enzyme converts excess glucose residues one by one into a polymeric chain for storage as glycogen. UDPG + glycogen → UDP + glycogen (n+1) Branching enzyme: Transglucosylase (α 1-4 → α 1-6)

4. Glycogen Breakdown: Mechanism Degradation of Glycogen occurs through a sequential action of three enzymes:

•

Glycogen phosphorylase: Glycogen phosphorylase cleaves α (1-4) bonds with inorganic phosphate (Pi). It can only cleave glucose residues 4 (or more) glucose residues away from a branching point. It uses pyridoxal, a vitamin B6 derivative, as cofactor.

A glycogen molecule with branches of only four glucose molecules ("limit-dextrin") cannot be further degraded by glycogen phosphorylase alone. It needs another enzyme: •

Glycogen debranching enzyme: Glycogen debranching enzyme transfers three glucose residues from a limit branch to another. The last residue in the branch (with a (α 1-6) glycosidic bond) is removed by hydrolysis, yielding free glucose and debranched glycogen. Hydrolysis of this residue is catalyzed by the same debranching enzyme.

Glycogen phosphorylase is much faster than the debranching enzyme, and therefore the outer branches of glycogen are degraded very rapidly in muscle when much energy is needed. Glycogen degradation beyond this point demands the action of the debranching enzyme and is therefore slower. •

Phosphoglucomutase: Phosphoglucomutase catalyzes the isomerization of glucose-1-P to glucose-6-P, and vice-versa:

Glucose 6-phosphate can then be used in glycolysis. Unlike muscle, and liver contains glucose-6-phosphatase, a hydrolytic enzyme catalyzing glucose-6-phosphate dephosphorylaton that allows it to supply glucose to other tissues.

5. Regulation of Glycogen Breakdown and Synthesis Since glycogen molecules can become enormously large, an inability to degrade glycogen can cause cells to become pathologically inflated. It can also lead to the functional loss of glycogen as a source of cell energy.

Diabetes mellitus: The most common disease in which glycogen metabolism becomes abnormal is diabetes mellitus. Due to abnormal amounts of insulin, liver glycogen can be abnormally accumulated or depleted. Restoration of normal glucose metabolism usually normalizes glycogen metabolism as well. Hypoglycemia: 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. Glycogenoses: Several glycogenoses are the result of deficiencies in enzymes of glycolysis whose symptoms and signs are similar to glycogen storage disease. These include deficiencies in muscle phosphglycerate kinase and muscle pyruvate kinase as well as deficiencies in fructose 1,6-bisphosphatase, lactate dehydrogenase and phosphoglycerate mutase. Various inborn errors of metabolism are caused by deficiencies of enzymes necessary for glycogen synthesis or breakdowns. These errors are collectively referred to as glycogen storage diseases. Although glycogen storage diseases are quite rare, their effects can be most dramatic. The devastating effect of many glycogen storage diseases depends on the severity of the mutation causing the deficiency. In addition, although the glycogen storage diseases are attributed to specific enzyme deficiencies, other events can cause the same characteristic symptoms.

Points to Remember: •

Glycogen is an energy reserve molecule which is a polysaccharide having a molecular formula of [C6H10O5].

•

Glycogen is stored primarily in the liver and muscle tissues.

•

Glycogen is present as β particles, and having a size of approximately 30 nm in diameter consisting up to 60,000 glucose units.

•

The average amount of glycogen ingested daily is 400 grams.

•

Glycogen is largely α 1-4 linked glucose.

•

Glycogen is not built by polymerizing branched monomers and constructed by polymerization of simple monomers.

•

Glycogen is commonly referred to as animal starch, having a similar structure to amylopectin.

•

Uterus also stores glycogen during pregnancy to nourish the embryo.

•

Glycogen is secreted in the vagina which is ultimately converted into lactic acid to maintain the acidic environment in order to avoid outside bacterial infections.

•

Glycogen can either enter into pentose-phosphate pathway for the production of other carbon compounds, or degraded in order to produce energy by the process of glycolysis.

•

Glycogen is a sparsely soluble and this property makes it osmotically inactive.

•

Glycogen is a branched polysaccharide, composed of glucose monomers joined through glycosidic bonds of the type α 1-4 and α 1-6 in the branching points.

•

Glycogen metabolism involves three major steps: Isomerization of Glucose-6-fosfato

into

Glucose-1-fosfato,

activation

of

Glucose-1-

phosphate by transformation into a species with high phosphate transfer potential and it is completed by the reaction with uridine triphosphate (UTP) which is an analog of ATP, with uridine replacing adenine. •

Glycogen synthase can only add glucose to pre-existent glycogen chains, it is unable to start the synthesis of a new glycogen molecule.

•

Glycogen synthesis is started by the addition of a glucose molecule to a tyrosine residue present in the active site of a protein called glycogenin.

•

Branching points are created by a "branching enzyme (amylo(1,4 -->1,6)transglycosylase)".

•

UTP-glucose-1-phosphate uridylyltransferase, glycogen synthase, banching enzyme Transglucosylase (α 1-4 → α 1-6) involve in the synthesis of glycogen.

•

Degradation of Glycogen occurs through a sequential action of three enzymes: Glycogen phosphorylases, Glycogen debranching enzyme and Phosphoglucomutase.

•

Glycogen phosphorylase

cleaves α (1-4) bonds with inorganic

phosphate(Pi). •

Glycogen debranching enzyme transfers three glucose residues from a

limit branch to another. •

Phosphoglucomutase catalyzes the isomerization of glucose-1-P to

glucose-6-P, and vice-versa. •

Diabetes mellitus, Hypoglycemia, Glycogenoses are some of the

glycogen storage diseases and the severity depends on the mutation causing the deficiency.