Carbohydrate Chemistry, Polysaccharides, and Clinical Importance

Basics of Carbohydrate Chemistry and Polysaccharides

• Presented by: Dr. B.K. Manjunatha Goud, MBBS MD, Professor and Chairperson of Biochemistry

• Date: 23/01/2025

Learning Outcomes

• List the physiological functions of glycosaminoglycans (GAGs).

• Justify the clinical importance of:

  • Hyaluronic Acid

  • Chondroitin 4- and 6-sulfate

  • Anticoagulants (Heparin)

Heteropolysaccharides

• Glycosaminoglycans are present in connective tissue.

• Due to negative charges, they fix a large quantity of water molecules onto the cartilage, ensuring tissue visco-elasticity.

• Essential for the proper functioning of the locomotive system.

• Important constituents of ECM (extracellular matrix):

  • Ground substances

  • Cartilages

  • Tendons, ligaments

  • Vascular wall, skin, lung, cornea

• Functions:

  • Mechanical support

  • Lubrication

  • Cushioning

Extracellular Matrix (ECM)

• Composed of 3 major classes of biomolecules:

  1. Structural proteins: collagen and elastin.

  2. Specialized proteins: e.g., fibrillin, fibronectin, and laminin.

  3. Proteoglycans: GAGs

Synthesis and Degradation

• Synthesized in the endoplasmic reticulum (ER).

• Modifications like sulfation occur in the Golgi complex.

• Degraded mainly by lysosomal enzymes.

• Clinical condition: Lysosomal storage disease or mucopolysaccharidoses.

Classification of GAGs

1. Hyaluronic acid

2. Chondroitin sulfate

3. Heparin

4. Dermatan sulfate

5. Keratan sulfate

• All GAGs are covalently attached to a protein, forming a proteoglycan.

Resilience of GAGs

• Negatively charged $\text{COO}^-$ and $\text{SO}_4^-$ groups on GAGs bind to positively charged hydrogen ions of water molecules, creating a hydrated gel.

• Negative charge imparts high viscosity and low compressibility, ideal for lubricating fluid in joints.

Constituents of GAGs

• Repeating sugar derivatives:

  1. Amino sugar: (N-acetyl glucosamine / galactosamine)

  2. Uronic acid: (Glucuronic / iduronic acid)

Specific GAGs

• Hyaluronic Acid

  • Disaccharide unit: N-acetyl glucosamine & Glucuronic acid.

  • Found in Synovial fluid, vitreous humor of eyes, connective tissue, and forms gel around the ovum.

  • Only GAG not sulfated.

  • Serves as a lubricant and shock absorbent in joints.

• Chondroitin 4- and 6-sulfate

  • Most abundant GAG in the body.

  • Found in cartilage (Chondros), tendons, ligaments, and aorta.

  • Disaccharide unit: N-acetyl galactosamine (with sulfate on either C-4 or C-6) and Glucuronic acid.

  • Loss of Chondroitin sulfate from the cartilage causes osteoarthritis.

• Heparin

  • Disaccharide unit: Glucosamine sulfated at C2 and C6 & Glucuronic acid sulfated at C2.

  • Found as an intracellular component of mast cells that line arteries of the liver, lung, & skin.

  • Acts as an anticoagulant.

• Dermatan sulfate

  • Disaccharide unit: N-acetyl galactosamine and L-iduronic acid.

  • Found in skin, blood vessels, and heart valves.

• Keratan sulfate

  • Disaccharide unit: N-acetyl glucosamine & galactose; sulfate may be present on C6 of either sugar.

  • Does not contain uronic acid.

  • Found in cornea; responsible for transparency of cornea.

Pathogenesis of Edema in Hypothyroidism

• Characteristic finding is the accumulation of glycosaminoglycans (mostly hyaluronic acid) in interstitial tissue.

• Results in interstitial edema (e.g., in skin, heart muscle, etc.).

• The accumulation is due to decreased destruction of glycosaminoglycans.

Proteoglycans

• Proteoglycans have a very high carbohydrate to protein ratio, often 95:5, and are found in the extracellular matrix.

• GAG chains are linked to core proteins by N- and O-glycosidic links.

Glycoproteins

• If the carbohydrate content is less than 10% (e.g., Antibody).

• The carbohydrate part of the glycoprotein plays a role in determining the part of the antigen molecule to which the antibody binds.

Structure of Proteoglycans

• Essential parts of the extracellular matrix.

• The majority of GAGs in the body are linked to core proteins, forming Proteoglycans.

• The linkage of GAGs to the protein core involves a specific trisaccharide composed of two Galactose residues and a xylose residue (GAG-GalGalXyl-$\text{O-CH}_2$- protein).

• Linked to the protein core through an O-glycosidic bond.

Lysosomal Storage Disorders (LSD)

Diagnosis of GAG related issues

• Widespread deposits of a particular GAG in tissues.

• Excessive excretion of GAG in urine.

• Detection of GAG in urine via:

  • Dimethylmethylene Blue (DMB) Assay

  • Cetyl trimethyl ammonium bromide test

  • Thin-Layer Chromatography (TLC)

  • High-Performance Liquid Chromatography (HPLC)