Glycosaminoglycans

The most abundant heteropolysaccharides in the body are the glycosaminoglycans (GAGs). These molecules are long unbranched polysaccharides containing a repeating disaccharide unit. The disaccharide units contain either of two modified sugars--- N-acetylgalactosamine (GalNAc) or N-acetylglucosamine (GlcNAc) and a uronic acid such as glucuronate or iduronate. GAGs are highly negatively charged molecules, with extended conformation that imparts high viscosity to the solution. GAGs are located primarily on the surface of cells or in the extracellular matrix (ECM). Along with the high viscosity of GAGs comes low compressibility, which makes these molecules ideal for a lubricating fluid in the joints. At the same time, their rigidity provides structural integrity to cells and provides passageways between cells, allowing for cell migration. The specific GAGs of physiological significance are hyaluronic acid, dermatan sulfate, chondroitin sulfate, heparin, heparan sulfate, and keratan sulfate. Although each of these GAGs has a predominant disaccharide component (see Table below), heterogeneity does exist in the sugars present in the make-up of any given class of GAG.

Hyaluronic is unique among the GAGs in that it does not contain any sulfate and is not found covalently attached to proteins as a proteoglycan. It is, however, a component of non-covalently formed complexes with proteoglycans in the ECM. Hyaluronic acid polymers are very large (with molecular weights of 100,000 - 10,000,000) and can displace a large volume of water. This property makes them excellent lubricators and shock absorbers.

	Hyaluronates: composed of D-glucuronate + GlcNAc linkage is b(1, 3)
	Dermatan sulfates: composed of L-iduronate (many are sulfated) + GalNAc-4-sulfate linkages is b(1, 3)
	Chondroitin 4- and 6-sulfates : composed of D-glucuronate + GalNAc-4- or 6-sulfate linkage is b(1, 3) (the figure contains GalNAc 4-sulfate)
	Heparin and Heparan sulfates: composed of D-glucuronate-2-sulfate (or iduronate-2-sulfate) + N-sulfo-D-glucosamine-6-sulfate linkage is a(1, 4) (heparans have less sulfate than heparins)
	Keratan sulfates: composed of galactose + GlcNAc-6-sulfate linkage is b(1, 4)

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Characteristics of GAGs

GAG	Localization	Comments
Hyaluronate	synovial fluid, vitreous humor, ECM of loose connective tissue	large polymers, shock absorbing
Chondroitin sulfate	cartilage, bone, heart valves	most abundant GAG
Heparan sulfate	basement membranes, components of cell surfaces	contains higher acetylated glucosamine than heparin
Heparin	component of intracellular granules of mast cells lining the arteries of the lungs, liver and skin	more sulfated than heparan sulfates
Dermatan sulfate	skin, blood vessels, heart valves
Keratan sulfate	cornea, bone, cartilage aggregated with chondroitin sulfates

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Proteoglycans

The majority of GAGs in the body are linked to core proteins, forming proteoglycans (also called mucopolysaccharides). The GAGs extend perpendicularly from the core in a brush-like structure. The linkage of GAGs to the protein core involves a specific trisaccharide composed of two galactose residues and a xylulose residue (GAG-GalGalXyl-O-CH₂-protein). The trisaccharide linker is coupled to the protein core through an O-glycosidic bond to a S residue in the protein. Some forms of keratan sulfates are linked to the protein core through an N-asparaginyl bond. The protein cores of proteoglycans are rich in S and T residues, which allows multiple GAG attachments.

Structure of the GAG linkage to protein in proteoglycans

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Clinical Significance

Proteoglycans and GAGs perform numerous vital functions within the body, some of which still remain to be studied. One well-defined function of the GAG heparin is its role in preventing coagulation of the blood. Heparin is abundant in granules of mast cells that line blood vessels. The release of heparin from these granules, in response to injury, and its subsequent entry into the serum leads to an inhibition of blood clotting, in the following manner. Free heparin complexes with and activates antithrombin III, which in turn inhibits all the serine proteases of the coagulation cascade. This phenomenon has been clinically exploited in the use of heparin injection for anti-coagulation therapies.

Several genetically inherited diseases, for example the lysosomal storage diseases, result from defects in the lysosomal enzymes responsible for the metabolism of complex membrane-associated GAGs. These specific diseases, termed mucopolysaccharidoses (MPS) (in reference to the earlier term, mucopolysaccharide, used for glycosaminoglycans) lead to an accumulation of GAGs within cells. There are at least 14 known types of lysosomal storage diseases that affect GAG catabolism; some of the more commonly encountered examples are Hurler's syndrome, Hunter's syndrome, Sanfilippo syndrome, Maroteaux-Lamy syndrome and Morquio's syndrome. All of these disorders, excepting Hunter's syndrome, are inherited in an autosomal recessive manner.
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Diseases of Glycosaminoglycan (Mucopolysaccharides) Metabolism

Type:Syndrome	Enzyme Defect	Affected GAG	Symptoms
MPS I H: Hurler's	a-L-iduronidase	dermatan sulfate, heparan sulfate	corneal clouding, dystosis multiplex, organomegaly, heart disease, dwarfism, mental retardation; early mortality
MPS I S: Scheie's	a-L-iduronidase	dermatan sulfate, heparan sulfate	corneal clouding; aortic valve disease; joint stiffening; normal intelligence and life span
MPS I H/S: Huler/Scheie	a-L-iduronidase	dermatan sulfate, heparan sulfate	intermediate between I H and I S
MPS II: Hunter's	L-iduronate-2-sulfatase	dermatan sulfate, heparan sulfate	mild and severe forms, only X-linked MPS, dystosis multiplex, organomegaly, facial and physical deformities, no corneal clouding, mental retardation, death before 15 except in mild form then survival to 20 - 60
MPS III A: Sanfilippo A	Heparan N-sulfatase	heparan sulfate	profound mental deterioration, hyperactivity, skin, brain, lungs, heart and skeletal muscle are affected in all 4 types of MPS-III
MPS III B: Sanfilippo B	a-N-acetyl-D-glucosaminidase	heparan sulfate	phenotype similar to III A
MPS III C: Sanfilippo C	AcetylCoA: a-glucosaminide-acetyltransferase	heparan sulfate	phenotype similar to III A
MPS III D: Sanfilippo D	N-acetylglucosamine-6-sulfatase	heparan sulfate	phenotype similar to III A
MPS IV A: Morquio A	Galactose-6-sulfatase	keratan sulfate, chondroitin 6-sulfate	corneal clouding, odontoid hypoplasia, aortic valve disease, distinctive skeletal abnormalities
MPS IV B: Morquio B	b-Galactosidase	keratan sulfate	severity of disease similar to IV A
MPS V, a designation no longer used
MPS VI: Maroteaux-Lamy	N-acetylgalactosamine-4-sulfatase also called arylsulfatase B	dermatan sulfate	3 distinct forms from mild to severe, aortic valve disease, dystosis multiplex, normal intelligence, corneal clouding, coarse facial features
MPS VII: Sly	b-Glucuronidase	heparan sulfate, dermatan sulfate, chondroitin 4-, 6-sulfates	hepatosplenomegaly, dystosis multiplex, wide spectrum of severity, hydrops fetalis
MPS VIII, a designation no longer used

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This article has been modified by Dr. M. Javed Abbas.
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20:44 21/12/2002