What is Glycosaminoglycans?
Glycogen and starch are both composed of glucose units. Besides, starch is a form of stored energy in plants, which is digested with amylases, and insoluble in water. In animals, glycogen exists in the form of stored energy. Cellulose is the primary structural component in plants and is indigestible by humans. Some other polysaccharides, such as xanthan gum, are present in the bacterium capsule.
They contain protein cores, made in the endoplasmic reticulum and modified post-translationally by the Golgi body. Glycosaminoglycan disaccharides are added to the protein cores and produce proteoglycans. These are the important components of connective tissues and much essential to life. Also, the GAG chains are covalently bonded to other proteins such as cytokines, chemokines, morphogens, enzyme adhesion molecules forming proteoglycans, and growth factors.
What are Carbohydrates?
Carbohydrates are the bio-polymers composed of monomer units known as monosaccharides. Carbohydrates can be classified into various types based on the number of monosaccharide units present in them.
Monosaccharides:
The monomer units cannot be further hydrolyzed.
Oligosaccharide:
Hydrolysis of oligosaccharides supplies 2-10 units of monosaccharides.
Polysaccharides:
These are composed of 10-100 or even more monosaccharide units.
Polysaccharides are described as complex carbohydrates that contain multiple monosaccharides with the other structures. They are also known as glycans because the monosaccharide units are bonded with the glycosidic linkages. Polysaccharides are branched and large molecules, which are amorphous in nature, often insoluble in water. These are non-sweet carbohydrates. Cellulose, starch, chitin, and glycogen are the best examples of polysaccharides.
Types of Glycosaminoglycans
Homopolysaccharides
Heteropolysaccharides
Homopolysaccharides are composed of similar types of monosaccharide units, whereas the heteropolysaccharides have different types of monosaccharide units. The general formula of polysaccharides can be given as Cn(H2O)n-1, where n falls between 200 and 2500.
Structure of Glycosaminoglycans
In general, glycosaminoglycans are linear and negatively charged polysaccharides that can be non-sulfate or sulfate with nearly 10-100 kilodalton molecular weights.
They can be classified into two types based on their structural units and linkage between the disaccharide units, as listed below.
Sulfated GAGs: For example, dermatan sulfate (DS), chondroitin sulfate (CS), keratan sulfate (KS), heparin, and heparin sulfate (HS),
Non-sulfated GAGs: An example is glycosaminoglycans hyaluronic acid (HA).
There are the disaccharides repeating units in the glycosaminoglycan chains, composed of uronic acid-like L-iduronic acid or D-glucuronic acid and amino sugar such as D-glucosamine or D-galactosamine. All these glycosaminoglycans differ in the hexosamine type, hexuronic or hexose acid unit, and the geometry of the glycosidic linkage between them.
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For example, the chondroitin sulfate and dermatan sulfate contain galactosamine and also called glycosaminoglycans. A few other glycosaminoglycans like heparin and heparin sulfate also contain glycosaminoglycan units.
Chondroitin sulfate contains beta-D-glucuronate, which is linked to the 3rd carbon of N-acetylgalactosamine-4-sulfate. In contrast, heparin is a complex mixture of linear polysaccharides with anticoagulant properties and varies in the saccharide units' sulfation degree.
The amino sugar in the glycosaminoglycans can be sulfated either on the non-acetylated nitrogen or C4 or C6.
The sugar structure of GAGs can be sulfated at different positions; hence a simple octasaccharide contains over 1000,000 various sulfation sequences.
There exist either 2-3 or 1-2 possible sulfation positions on the amino sugar and on the uronic acid, respectively, in the repeating unit of every glycosaminoglycan species.
Since these positions are not always sulfated, 16 to 48 multiple disaccharide units can exist based on the sulfation position combination.
Function of Glycosaminoglycans
Glycosaminoglycans (otherwise called GAGs) participate in various biological processes through the regulation of their different protein partners known as proteoglycan.
The GAG's large structural diversity makes them approachable for structural, biochemical, molecular modeling, and biology and made them useful in the new drug discovery.
The underlying sulfation patterns and conformational flexibility of GAGs are responsible for the complexity of GAG-protein interaction.
Primarily negatively charged molecules prepared in animal cells are phospholipids, glycosaminoglycans (GAGs), and nucleic acids or ribonucleic deoxyribonucleic acid.
The glycosaminoglycans, which are negatively charged, cover the animal cell surfaces and interact with hundreds of extracellular signaling molecules.
Due to their structural complexity, they have been claimed to exist as the most information-dense biopolymers that are found in nature. These biomolecules are related to the transfer of genetic information in animals.
Applications of Glycosaminoglycans
There are many new projects currently going on, based on different applications of glycosaminoglycans. Some of them are as follows.
Inhibitors in FGF/FGFR Signaling and GAG-based Activators.
In the regulation of FGFR/FGF Signaling.
Proteoglycans and Serum GAGs as biomarkers for lung cancer.
Joint Specificity in Rheumatoid Arthritis, on the basis of GAG.
Hyaluronic acid represents various essential functions in signaling activity during wound healing, embryonic morphogenesis, and vascular & pulmonary diseases. Also, it acts as synovial joint lubrication and helps in joint movement and as a wetting agent, space filler, and flow barrier within the synovium. It influences cancer progression and protects cartilage surfaces.
FAQs on Glycosaminoglycans
1. What are glycosaminoglycans (GAGs)?
Glycosaminoglycans, also known as mucopolysaccharides, are long, unbranched polysaccharides. They consist of repeating disaccharide units, where each unit is typically composed of an amino sugar (like N-acetylglucosamine or N-acetylgalactosamine) and a uronic acid (like glucuronic acid). Due to their structure, they are highly polar and act as the body's natural lubricants.
2. What are the main types and examples of glycosaminoglycans?
Glycosaminoglycans are classified into several major types based on their specific sugar residues, linkage types, and the presence and location of sulfate groups. The primary examples include:
- Hyaluronic acid: A non-sulfated GAG found in synovial fluid, skin, and connective tissues, crucial for lubrication and hydration.
- Chondroitin sulfate: A sulfated GAG that is a major structural component of cartilage, providing resistance to compression.
- Dermatan sulfate: Found mainly in the skin, blood vessels, and heart valves.
- Keratan sulfate: Present in cartilage, bone, and the cornea of the eye.
- Heparin: A highly sulfated GAG, well-known for its role as a natural anticoagulant (blood thinner).
3. What are the primary functions of glycosaminoglycans in the body?
Glycosaminoglycans perform a wide range of essential biological functions, including:
- Structural Support: They are key components of the extracellular matrix (ECM), providing structural integrity and cushioning to connective tissues like cartilage and tendons.
- Hydration and Lubrication: Their ability to bind large amounts of water helps hydrate tissues and lubricate joints.
- Cell Signalling and Regulation: GAGs interact with hundreds of proteins, including growth factors and cytokines, to regulate processes like cell growth, proliferation, and adhesion.
- Anticoagulation: Heparin is a specific GAG that plays a critical role in preventing blood clotting by activating antithrombin III.
4. How does the chemical structure of glycosaminoglycans contribute to their role in cushioning joints?
The cushioning ability of GAGs stems directly from their unique chemical structure. They possess a high density of negative charges from carboxylate and sulfate groups. These negative charges repel each other, forcing the GAG chains to remain extended and occupy a large volume. Furthermore, these charges attract and bind a vast number of water molecules, forming a hydrated, gel-like substance. When a joint is compressed, this water is squeezed out, but the repulsion between the fixed negative charges prevents the tissue from collapsing. When the pressure is released, the GAGs rapidly rehydrate, providing the resilience and shock-absorbing properties essential for cartilage.
5. What is the main difference between glycosaminoglycans (GAGs) and proteoglycans?
The primary difference lies in their composition and structure. A glycosaminoglycan is an individual, long chain of repeating disaccharides. A proteoglycan is a much larger macromolecule where one or more GAG chains are covalently attached to a central 'core protein'. Essentially, GAGs are the carbohydrate components that make up a proteoglycan. The only exception is hyaluronic acid, which is a massive GAG that does not typically bind covalently to a core protein but instead forms non-covalent complexes with them.
6. Where are glycosaminoglycans primarily found in the human body?
Glycosaminoglycans are most abundant in the extracellular matrix (ECM) of all connective tissues. Key locations include:
- Cartilage: Providing shock absorption in joints.
- Synovial Fluid: Acting as a lubricant in joints.
- Skin: Contributing to hydration, turgor, and elasticity.
- Tendons and Ligaments: Providing structural strength.
- Blood Vessels and Heart Valves: Ensuring structural integrity.
- Cell Surfaces: Where they are involved in cell adhesion and signalling.
7. Why is the synthesis of glycosaminoglycans considered a non-template process?
Unlike the synthesis of proteins or DNA which follows a precise genetic template (mRNA or DNA), GAG synthesis is a non-template process. It occurs in the Golgi apparatus through the sequential action of various enzymes, such as glycosyltransferases and sulfotransferases. The final structure of a GAG chain (its length, exact disaccharide sequence, and sulfation pattern) is determined by the availability and specificity of these enzymes in a particular cell at a particular time. This results in significant heterogeneity, meaning GAGs of the same type can have slight structural variations, allowing for a diverse range of biological activities.
