Glycosaminoglycans: Characteristics, Structure and Function

Carbohydrates are biopolymers composed of monomer units called monosaccharides.

Based on the number of monosaccharide units, carbohydrates can be classified into several types.

  • Monosaccharides: the monomer units can not be hydrolyzed anymore.
  • Oligosaccharide: hydrolysis of oligosaccharides gives 2-10 units of monosaccharides.
  • Polysaccharides: they are composed of 10-100 or more of these monosaccharide units.

Polysaccharides are complex carbohydrates that consist of multiple monosaccharides with other structures. They are also called glycans since the monosaccharide units are linked with glycosidic bonds.

Polysaccharides are large, branched molecules that are often insoluble in water, of amorphous nature and not sweet carbohydrates. Starch, cellulose, glycogen and chitin are the best examples of polysaccharides.

Glycogen and starch are composed of glucose units. Apart from that, starch acts as a storage form in plants, insoluble in water and digested with amylases. Glycogen is the storage form in animals.

Cellulose is the main structural component in plants, and it is indigestible to humans. Other polysaccharides such as xanthan gum are present in the capsule of a bacterium.

The polysaccharides can be classified into two types:

  1. Homopolisacáridos
  2. Heteropolisacáridos

Homopolysaccharides are composed of the same type of monosaccharide units while heteropolysaccharides have different types of monosaccharides. The general formula of polysaccharides is Cn (H2O) n-1, where n is a number between 200 and 2500.

Characteristics of glycosaminoglycans

  • Glycosaminoglycans are long, unbranched polysaccharides that are composed of repeated units of disaccharides and are also called GAGs or mucopolysaccharides because of their viscous and lubricating properties, as well as mucous secretions.
  • They consist of protein nuclei that are manufactured in the endoplasmic reticulum and are modified post-translationally by the Golgi body. Glycosaminoglycan disaccharides are added to protein cores and form proteoglycans.
  • They are essential for life and important components of the connective tissues.
  • GAG chains bind covalently to other proteins such as chemokines, cytokines, morphogens, growth factors, enzymes and adhesion molecules and form proteoglycans.
  • They are found in collagen and elastin and water adheres to GAGs, allowing pressure resistance.
  • Therefore, in the aqueous GAG solution, during compression, the water is expelled and the GAGs are forced to occupy a smaller volume. As the compression is removed, they recover their original hydrated volume due to the repulsion that arises from their negative charges.
  • The repeating units of glycosaminoglycans consist of disaccharide units; one units of monosaccharides is a hexose carbon sugar ring or a hexuronic acid that is further attached to a hexosamine; a nitrogen containing six carbon sugar and one (or both) monosaccharide units contains at least one sulfate or carboxylate group negatively charged.
  • Glycosaminoglycans are involved in a variety of extracellular and sometimes intracellular functions. For example; Heparin is a glycosaminoglycan that contains the highest negative net charge of disaccharides and acts as a natural anticoagulant substance.
  • It can bind strongly to antithrombin III (a protein involved in the termination of the clotting process) and inhibits the coagulation of blood. Another example is that the hyaluronate molecules consist of about 25,000 disaccharide units with molecular weights of up to 107.
  • They are important components of the vitreous humor in the eye and synovial fluid, which is a lubricating fluid of the joints of the body.
  • Keratin sulfate and chondroitins are also examples of glycosaminoglycans found in connective tissue such as cartilage and tendons.
  • Similarly dermatan sulfate is a component of the extracellular matrix of the skin. Apart from these glycosaminoglycans, hyaluronic acid is not bound to a protein core, while three other chondroitin sulfate, dermatan sulfate and Heparan sulfate are connected to proteoglycan via a serine residue.

Structure of glycosaminoglycans

Generally, glycosaminoglycans are negatively charged linear polysaccharides that can sulfate or not sulfate and have molecular weights of about 10-100 kilodalton.

On the basis of their structure and link units between disaccharide units; They can be classified into two types.

  1. Non-sulfated GAGs: for example, hyaluronic acid (HA).
  2. Sulphated GAGs: for example; chondroitin sulfate (CS), dermatan sulfate (DS), keratan sulfate (KS), heparin and heparin sulfate (HS).

There are disaccharides that repeat regions in chains of glycosaminoglycans that are composed of uronic acid such as D-glucuronic acid or L-iduronic acid and amino sugars such as D-galactosamine or D-glucosamine. All these glycosaminoglycans differ in the type of hexosamine, hexose or hexuronic acid units, as well as in the geometry of the glycosidic bond between these units.

For example, dermatan sulfate and chondroitin sulfate contain galactosamine and also known as galactosaminoglycans. Other glycosaminoglycans such as heparin sulfate and heparin contain one unit of glycosaminoglycan and are known as glycosaminoglycans.

Chondroitin sulfate consists of β-D-glucuronate attached to the third carbon of N-acetylgalactosamine-4-sulfate and heparin is a complex mixture of linear polysaccharides that have anticoagulant properties and vary in the degree of sulfation of the saccharide units.

  • The amino sugar in glycosaminoglycans can be sulfated in C4 or C6 or in non-acetylated nitrogen.
  • The main sugar chain of the GAGs can be sulphated in several positions; therefore, a single octasaccharide can have more than 1000 000 different sulfation sequences.
  • In the repeating unit of each glycosaminoglycan species, there are from one to two or 2 to 3 possible sulfation positions in the uronic acid and the aminosugar, respectively.
  • Since these positions are not always sulphated, there may be 16 to 48 different disaccharide units depending on the combination of sulfation positions.

Function of glycosaminoglycans

Glycosaminoglycans (GAGs) participate in many biological processes through the regulation of their various protein partners called proteoglycans. The great structural diversity of the GAG ​​makes them accessible for biochemistry, structural biology and molecular modeling and made them useful in the discovery of new drugs.

The conformational flexibility and underlying sulfation patterns of GAGs are responsible for the complexity of the GAG-protein interaction. Four negatively charged major molecules manufactured in animal cells are glycosaminoglycans (GAG), phospholipids and nucleic acids, ie, ribonucleic acid and deoxyribonucleic acid.

The negatively charged glycosaminoglycans cover the surfaces of animal cells and interact with hundreds of extracellular signaling molecules. Due to its structural complexity, it has been claimed that they are the densest biopolymers in information found in nature.

These bio molecules are related to the data of transgenic and knock-out animals of the past decade that provide convincing evidence. Currently, many new projects are underway based on different applications of glycosaminoglycans. Some of them are the following.

  1. In the regulation of FGF / FGFR signaling.
  2. Activators and inhibitors based on GAG in FGF / FGFR signaling.
  3. GAG Based on the specificity of the joint in rheumatoid arthritis.
  4. Serum GAGs and proteoglycans as biomarkers for lung cancer.

Hyaluronic acid shows many important functions in signaling activity during embryonic morphogenesis, wound healing and pulmonary and vascular diseases.

It also acts as lubrication of the synovial joints and helps in the movement of the joint, as well as in the filling of the space, the moisturizing agent and the flow barrier within the synovial membrane. It also influences the progression of cancer and protector of cartilage surfaces.

CD44, which is expressed on the surface of virtually all stem cells, including cancer stem cells, acts as the main receptor for hyaluronic acid. The interaction of hyaluronic acid with can mediate the lamination of leukocytes and extravasation in some tissues. Other glycosaminoglycans, heparin was discovered for the first time in 1917 and is used mainly for anticoagulation.

The anticoagulant property of sulfated GAGs is due to its ability to prolong the blood coagulation process, which is due to the enhancing interaction of GAGs with the natural thrombin inhibitor, antithrombin III (AT-III), with only one third of all the heparin chains that possess the structures required for AT binding.

Glycosaminoglycans play a vital role in cell signaling and development, angiogenesis, anticoagulation, tumor progression, axonal growth and metastasis. They also participate in cell proliferation since they act as co-receptors of the growth factors of the fibroblast growth factor family.

Members of the family of fibroblast growth factors need to interact with a heparin / HS chain and realize their full signaling potential by their high affinity receptor.

Sulphated glycosaminoglycans are common components in many different types of amyloid that play an important role in the pathology of amyloid diseases such as amyloid A amyloidosis, prion diseases, type 2 diabetes and Parkinson’s disease.

During these diseases, there will be deposition in tissues of fibrillar aggregates of polypeptides. Glycosaminoglycans such as Heparan sulfate can be linked with amyloidogenic peptides in vitro and in vivo to promote fibril formation and improve disease status.

Diseases such as inflammatory bowel disease and microbial infections and rheumatoid arthritis are also associated with inflammatory responses and many proteins play a role in the cascade of inflammation that leads to the activation of leukocytes and endothelial cells and finally to leukocyte extravasation and migration. of leukocytes to inflamed tissue.

Glycosaminoglycans such as heparin act as adhesion ligands in the extravasation of leukocytes and carriers of chemokines and growth factors.