Biochemistry Chapter 14: Glycosaminoglycans

Overview of Glycosaminoglycans

• Glycosaminoglycans (GAGs) are large, negatively charged heteropolysaccharide chains associated with a small amount of protein ("core protein") to form proteoglycans.
• Proteoglycans typically consist of up to 95% carbohydrate and 5% core protein.
• GAGs have the ability to bind large amounts of water, producing a gel-like matrix that forms the basis of the body's ground substance.
• The hydrated GAGs serve as a flexible support for the extracellular matrix (ECM), interacting with structural and adhesive proteins.

Structure of Glycosaminoglycans

• Proteoglycans are found in the ECM and on the outer surface of cells.
• GAGs are associated with a small amount of protein ("core protein") by an O-glycosidic bond, forming proteoglycans.
• Proteoglycans contain a greater amount of carbohydrate than do glycoproteins, which consist primarily of protein with a variable amount of carbohydrate.
• GAGs are long, unbranched heteropolysaccharide chains composed of a repeating disaccharide unit ([acidic sugar–amino sugar]n).
• Keratan sulfate is an exception, containing galactose instead of an acidic sugar.
• The amino sugar is either D-glucosamine or D-galactosamine, which may be acetylated, sulfated, or non-acetylated.
• The acidic sugar is either D-glucuronic acid or L-iduronic acid (C-5 epimer of D-glucuronic acid).

Relationship between Glycosaminoglycan Structure and Function

• Being negatively charged, GAG chains are extended in solution and repel each other, producing the "slippery" consistency of mucous secretions and synovial fluid.
• When a solution of GAGs is compressed, the water is "squeezed out" and the GAGs are forced to occupy a smaller volume.

Structure of Proteoglycan Monomers

• A proteoglycan monomer found in cartilage consists of a core protein and up to 100 linear chains of GAGs covalently attached to the core protein.
• Each GAG chain contains up to 200 disaccharide units.
• The resulting structure resembles a "bottle brush".

Degradation of Glycosaminoglycans

• Lysosomal degradation of GAGs involves the removal of the last group added during synthesis, followed by the action of sulfatases or exoglycosidases.
• Endo- and exoglycosidases are also involved in the lysosomal degradation of glycoproteins and glycolipids.
• Deficiencies in these enzymes result in the accumulation of partially degraded carbohydrates, leading to tissue damage.

Mucopolysaccharidoses

• Mucopolysaccharidoses are hereditary diseases characterized by the accumulation of glycosaminoglycans in various tissues, causing progressive symptoms such as skeletal and extracellular matrix deformities, and mental retardation.
• These diseases are caused by a deficiency of any one of the lysosomal hydrolases normally involved in the degradation of heparan sulfate and/or dermatan sulfate.
• This results in the presence of oligosaccharides in the urine, due to incomplete lysosomal degradation of glycosaminoglycans.