GLYCOGEN: STRUCTURE, SYNTHESIS, DEGRADATION, FUNCTIONS - BIOLOGY - 2024

The glycogen is the carbohydrate storage of most mammals. Carbohydrates are commonly called sugars and these are classified according to the number of residues caused by hydrolysis (monosaccharides, disaccharides, oligosaccharides and polysaccharides).

Monosaccharides are the simplest carbohydrates that are classified according to the number of carbons contained in their structure. There are then the trioses (3C), tetrosas (4C), pentoses (5C), hexoses (6C), heptosas (7C) and octosas (8C).

Chemical structure of glycogen showing glycosidic bonds (Source: Glykogen.svg: NEUROtiker derivative work: Marek M via Wikimedia Commons)

Depending on the presence of the aldehyde group or the ketone group, these monosaccharides are also classified as aldoses or ketoses respectively.

Disaccharides give rise, by hydrolysis, to two simple monosaccharides, while oligosaccharides produce 2 to 10 monosaccharide units and polysaccharides produce more than 10 monosaccharides.

Glycogen is, from a biochemical point of view, a polysaccharide composed of branched chains of a six-carbon aldose, that is, a hexose known as glucose. Glycogen can be represented graphically as a glucose tree. This is also called animal starch.

Glucose in plants is stored as starch and in animals as glycogen, which is stored primarily in the liver and muscle tissue.

In the liver, glycogen can make up 10% of its mass and 1% of its muscle mass. As in a 70 kg man the liver weighs about 1800 g and the muscles about 35 kg, the total amount of muscle glycogen is much higher than the liver.

Structure

The molecular weight of glycogen can reach 108 g / mol, which is equivalent to 6 × 105 glucose molecules. Glycogen is made up of multiple branched chains of α-D-glucose. Glucose (C6H12O6) is an aldohexose that can be represented in linear or cyclic form.

Glycogen has a highly branched and compact structure with chains of 12 to 14 glucose residues in the form of α-D-glucose that are linked with α- (1 → 4) glucosidic bonds. The branches of the chain are formed by α- (1 → 6) glucosidic bonds.

Glycogen, like starch in the diet, provides most of the carbohydrates that the body needs. In the intestine these polysaccharides are broken down by hydrolysis and then absorbed into the bloodstream mainly as glucose.

Three enzymes: ß-amylase, α-amylase and amyl-α- (1 → 6) -glucosidase are responsible for the intestinal breakdown of both glycogen and starch.

Α-Amylase randomly hydrolyzes the α- (1 → 4) bonds of the side chains of both glycogen and starch, and is therefore called endoglycosidase. Ss-amylase is an exoglycosidase that releases ß-maltose dimers by breaking α- (1 → 4) glycosidic bonds from the ends of the outermost chains without reaching the branches.

Since neither ß-amylase nor α-amylase degrade the branch points, the end product of their action is a highly branched structure of about 35 to 40 glucose residues called border dextrin.

The limit dextrin is finally hydrolyzed at the branch points that have α- (1 → 6) bonds by means of amyl-α- (1 → 6) -glucosidase, also known as a “debranching” enzyme. The chains released by this debranching are then degraded by ß-amylase and α-amylase.

As the ingested glycogen enters as glucose, the one found in the tissues must be synthesized by the body from glucose.

Synthesis

Glycogen synthesis is called glycogenesis and takes place primarily in muscle and liver. The glucose that enters the body with the diet passes into the bloodstream and from there into the cells, where it is immediately phosphorylated by the action of an enzyme called glucokinase.

Glucokinase phosphorylates glucose at carbon 6. ATP provides the phosphorus and energy for this reaction. As a result, glucose 6-phosphate is formed and an ADP is released. Then, glucose 6-phosphate is converted to glucose 1-phosphate by the action of a phosphoglucomutase that moves the phosphor from position 6 to position 1.

Glucose 1-phosphate is activated for the synthesis of glycogen, which involves the participation of a group of three other enzymes: UDP-glucose pyrophosphorylase, glycogen synthetase and amyl- (1,4 → 1,6) -glycosyltransferase.

Glucose-1-phosphate, together with uridine triphosphate (UTP, a nucleoside of uridine triphosphate) and by action of UDP-Glucose-pyrophosphorylase, forms the uridine diphosphate-glucose complex (UDP Glc). In the process a pyrophosphate ion is hydrolyzed.

The enzyme glycogen synthetase then forms a glycosidic bond between C1 of the UDP Glc complex and C4 of a terminal glucose residue of glycogen, and the UDP is released from the activated glucose complex. For this reaction to occur there must be a pre-existing glycogen molecule called "primordial glycogen."

Primordial glycogen is synthesized on a primer protein, glycogenin, which is 37 kDa and which is glycosylated to a tyrosine residue by the UDP Glc complex. From there, α-D-Glucose residues are linked with 1 → 4 bonds and a small chain is formed on which glycogen synthetase acts.

Once the initial chain links at least 11 glucose residues, the branching enzyme or amyl- (1,4 → 1,6) -glycosyltransferase transfers a piece of chain of 6 or 7 glucose residues to the adjacent chain in position 1 → 6, thereby establishing a branch point. The glycogen molecule thus constructed grows by additions of glucose units with 1 → 4 glycosidic bonds and more branches.

Degradation

The breakdown of glycogen is called glycogenolysis, and it is not equivalent to the reverse pathway of its synthesis. The speed of this pathway is limited by the rate of the glycogen phosphorylase catalyzed reaction.

Glycogen phosphorylase is responsible for the cleavage (phosphorolysis) of the 1 → 4 bonds of the glycogen chains, releasing glucose 1-phosphate. The enzymatic action begins at the ends of the outermost chains and they are sequentially removed until 4 glucose residues remain on each side of the branches.

Then another enzyme, α- (1 → 4) → α- (1 → 4) glucan transferase, exposes the branch point by transferring a trisaccharide unit from one branch to another. This allows amyl- (1 → 6) -glucosidase (debranching enzyme) to hydrolyze the 1 → 6 bond, removing the branch that will undergo the action of phosphorylase. The combined action of these enzymes ends up completely cleaving glycogen.

Since the initial phosphomutase reaction is reversible, glucose 6-phosphate can be formed from the cleaved glucose 1-phosphate residues of glycogen. In liver and kidney, but not in muscle, there is an enzyme, glucose-6-phosphatase, capable of dephosphorylating glucose 6-phosphate and converting it to free glucose.

Dephosphorylated glucose can diffuse into the blood, and this is how hepatic glycogenolysis is reflected in an increase in blood glucose values ​​(glycemia).

Regulation of synthesis and degradation

Of synthesis

This process is exerted on two fundamental enzymes: glycogen synthetase and glycogen phosphorylase, in such a way that when one of them is active the other is in its inactive state. This regulation prevents opposite reactions of synthesis and degradation from occurring simultaneously.

The active form and the inactive form of both enzymes is very different, and the interconversion of the active and inactive forms of phosphorylase and glycogen synthetase is strictly hormonally controlled.

Epinephrine is a hormone that is released from the adrenal medulla, and glucagon is another that is produced in the endocrine part of the pancreas. The endocrine pancreas produces insulin and glucagon. The α cells of the islets of Langerhans are the ones that synthesize glucagon.

Adrenaline and glucagon are two hormones that are released when energy is needed in response to decreased blood glucose levels. These hormones stimulate the activation of glycogen phosphorylase and inhibit glycogen synthetase, thus stimulating glycogenolysis and inhibiting glycogenesis.

While adrenaline exerts its action on the muscle and the liver, glucagon only acts on the liver. These hormones bind to specific membrane receptors on the target cell, which activates adenylate cyclase.

The activation of adenylate cyclase initiates an enzymatic cascade that, on the one hand, activates a cAMP-dependent protein kinase that inactivates glycogen synthetase and activates glycogen phosphorylase by phosphorylation (directly and indirectly, respectively).

Skeletal muscle has another mechanism of activation of glycogen phosphorylase through calcium, which is released as a consequence of the depolarization of the muscle membrane at the beginning of contraction.

Of degradation

The enzymatic cascades described above end up increasing glucose levels and when these reach a certain level, glycogenesis is activated and glycogenolysis is inhibited, also inhibiting the subsequent release of epinephrine and glucagon.

Glycogenesis is activated through the activation of phosphorylase phosphatase, an enzyme that regulates glycogen synthesis by various mechanisms, involving the inactivation of phosphorylase kinase and phosphorylase α, which is an inhibitor of glycogen synthetase.

Insulin promotes the entry of glucose into muscle cells, increasing glucose 6-phosphate levels, which stimulates dephosphorylation and activation of glycogen synthetase. Thus the synthesis begins and the degradation of glycogen is inhibited.

Features

Muscle glycogen constitutes an energy reserve for the muscle that, like reserve fats, allows the muscle to fulfill its functions. Being a source of glucose, muscle glycogen is used during exercise. These reserves increase with physical training.

In the liver, glycogen is also an important reserve source both for organ functions and for supplying glucose to the rest of the body.

This function of liver glycogen is due to the fact that the liver contains glucose 6-phosphatase, an enzyme capable of removing the phosphate group from glucose 6-phosphate and converting it to free glucose. Free glucose, unlike phosphorylated glucose, can diffuse through the membrane of hepatocytes (liver cells).

This is how the liver can provide glucose to the circulation and maintain stable glucose levels, even in conditions of prolonged fasting.

This function is of great importance, since the brain relies almost exclusively on blood glucose, so severe hypoglycemia (very low concentrations of glucose in the blood) can cause loss of consciousness.

Related diseases

Glycogen-related diseases are generically called "glycogen storage diseases."

These diseases constitute a group of hereditary pathologies characterized by the deposit in the tissues of abnormal amounts or types of glycogen.

Most glycogen storage diseases are caused by a genetic deficit of any of the enzymes involved in glycogen metabolism.

They are classified into eight types, most of which have their own names and each of them is caused by a different enzyme deficiency. Some are fatal very early in life, while others are associated with muscle weakness and deficits during exercise.

Featured examples

Some of the most prominent glycogen-related diseases are the following:

- Von Gierke's disease or Type I glycogen storage disease, is caused by a deficit of glucose 6-phosphatase in the liver and kidney.

It is characterized by the abnormal growth of the liver (hepatomegaly) due to the exaggerated accumulation of glycogen and hypoglycemia, since the liver becomes unable to supply glucose to the circulation. Patients with this condition have growth disturbances.

- Pompe or Type II disease is due to a deficiency of α- (1 → 4) -glucan 6-glycosyltranspheres in the liver, heart and skeletal muscles. This disease, like that of Andersen or Type IV, is fatal before the age of two years.

- McArdle or Type V disease presents a muscle phosphorylase deficiency and is accompanied by muscle weakness, decreased exercise tolerance, abnormal accumulation of muscle glycogen and lack of lactate during exercise.

References

1. Bhattacharya, K. (2015). Investigation and management of the hepatic glycogen storage diseases. Translational Pediatrics, 4 (3), 240–248.
2. Dagli, A., Sentner, C., & Weinstein, D. (2016). Glycogen Storage Disease Type III. Gene Reviews, 1–16.
3. Guyton, A., & Hall, J. (2006). Textbook of Medical Physiology (11th ed.). Elsevier Inc.
4. Mathews, C., van Holde, K., & Ahern, K. (2000). Biochemistry (3rd ed.). San Francisco, California: Pearson.
5. Mckiernan, P. (2017). Pathobiology of the Hepatic Glycogen Storage Diseases. Curr Pathobiol Rep.
6. Murray, R., Bender, D., Botham, K., Kennelly, P., Rodwell, V., & Weil, P. (2009). Harper's Illustrated Biochemistry (28th ed.). McGraw-Hill Medical.
7. Nelson, DL, & Cox, MM (2009). Lehninger Principles of Biochemistry. Omega Editions (5th ed.).
8. Rawn, JD (1998). Biochemistry. Burlington, Massachusetts: Neil Patterson Publishers.
9. Tarnopolsky, MA (2018). Myopathies Related to Glycogen Metabolism Disorders. Neurotherapeutics.