Glycosaminoglycans: Characteristics, Structure and Function

Carbohydrates are biopolymers composed of monomer units called monosaccharides.

Carbohydrates can be classified into several types based on the number of monosaccharide units.

• Monosaccharides: the monomer units can not be hydrolyzed anymore.
• Oligosaccharide: hydrolysis of oligosaccharides gives 2-10 units of monosaccharides.
• Polysaccharides 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 often insoluble in water, amorphous nature, and are not sweet carbohydrates. Starch, cellulose, glycogen, and chitin are the best examples of polysaccharides.

Glycogen and starch are composed of glucose units. Also, starch is a storage form in plants, is 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 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 composed of repeated units of disaccharides and are also called GAGs or mucopolysaccharides because of their vicious and lubricating properties, as well as mucous secretions.
• They consist of protein nuclei manufactured in the endoplasmic reticulum and modified post-translationally by the Golgi body. Glycosaminoglycan disaccharides are added to protein cores and form proteoglycans.
• They are essential for life and crucial 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, the water is expelled during compression, and the GAGs are forced to occupy a smaller volume. As the reduction 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 unit of monosaccharides is a hexose carbon sugar ring or a hexuronic acid further attached to a hexosamine; a nitrogen-containing six-carbon sugar and one (or both) monosaccharide units contain 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 essential components of the vitreous humor in the eye and synovial fluid, a lubricating fluid of the body’s joints.
• Keratin sulfate and chondroitins are examples of glycosaminoglycans found in connective tissue such as cartilage and tendons.
• Similarly, dermatan sulfate is a component of the skin’s extracellular matrix. Besides these glycosaminoglycans, hyaluronic acid is not bound to a protein core. At the same time, 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.

Based on 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. Sulfated GAGs: example, chondroitin sulfate (CS), dermatan sulfate (DS), keratan sulfate (KS), Heparin and Heparin sulfate (HS).

Some disaccharides repeat regions in chains of glycosaminoglycans composed of uronic acids 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 and the geometry of the glycosidic bond between these units.

For example, dermatan sulfate and chondroitin sulfate contain galactosamine and glycosaminoglycans. Other glycosaminoglycans such as heparin sulfate and Heparin have 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. 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 non-acetylated nitrogen.
• The main sugar chain of the GAGs can be sulfated 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 sulfated, there maybe 16 to 48 different disaccharide units depending on the combination of sulfation positions.

Function of glycosaminoglycans

Glycosaminoglycans (GAGs) participate in many biological processes by regulating their various protein partners called proteoglycans. The great structural diversity of the GAG ​​made them accessible for biochemistry, structural biology, and molecular modeling and made them useful in discovering 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, i.e., 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 their structural complexity, it has been claimed that they are the densest biopolymers in information found in nature.

These biomolecules 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 vital functions in signaling activity during embryonic morphogenesis, wound healing, and pulmonary and vascular diseases.

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

CD44, which is expressed on the surface of virtually all stem cells, including cancer stem cells, acts as the primary receptor for hyaluronic acid. The interaction of hyaluronic acid 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 are vital 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.

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

There will be deposition in tissues of fibrillar aggregates of polypeptides during these diseases. 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, microbial infections, and rheumatoid arthritis are also associated with inflammatory responses. 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.