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Glycosaminoglycans (GAGs) are distinct from other sugars/oligosaccharides in that they are polymers of disaccharide units composed of an amino sugar, N-acetylglucosamine (GlcNAc), or N-acetylgalactosamine (GalNAc), and uronic acid, glucuronic acid (GlcUA), or iduronic acid (IdUA). The exception is keratan sulfate (KS) in which the uronic acid is replaced by the neutral sugar galactose. Initially, GAGs were thought to be just part of an extracellular glue or ground substance that held tissues together and provided a liquid-like space between cells for the transport of nutrients. However, research using new technologies and techniques over the last two decades has revealed that the effects of GAGs on cells are more dynamic than previously thought. In addition to their structural roles, GAGs are fundamentally important as modifiers of cell behaviors that range from leukocyte recruitment during inflammation to the complex signaling events that help cancer cells survive during homing and metastasis. Cellular behaviors and responses depend in part on chain length of the GAG as well as GAG-sugar modifications such as sulfation and acetylation. Longer GAGs tend to be part of the extracellular matrix (ECM) in which long cable-like structures and networks may support tissue structure through cross-linking with other ECM components. Shorter GAGs or small oligosaccharides of less than 30-50 sugars may interact with cellular receptors to promote cell signaling involving antiapoptosis or immunostimulation.
There are four classes of GAGs (Figure 1): Chondroitin (Chon) sulfate (CS) A through E, heparin (HP) and heparan sulfate (HS), KS, and hyaluronan (HA). CS is a polymer of the disaccharide GlcUA-β1, 3-GalNAc-β1, 4 that can be sulfated at one or more positions: GalNAc-4 (type A), Gal- NAc-4 (type B), GalNAc-6 (type C), GalNAc-6, GlcUA-2 (type D), and GalNAc-4, 6 (type E). CS-B, which is now called dermatan sulfate (DS), is an unusual CS family member in which iduronic acid substitutes for some, but not all, glucuronic acid (as in HP and HS) and GlcUA is in an alpha-1, 3 linkage with GlcNAc. HP and HS are polymers of the disaccharide β1, 4-GlcUA-β1, 4-GlcNAc, in which some of the glucuronic acid is converted to iduronic acid. HS differs from HP in that the Nacetylglucosamine is de-N-acetylated and N-sulfated at position 2. HP is typically more highly sulfated than HS and is primarily found in mast cells of the immune system. In contrast, HS is ubiquitous throughout the body and its sugars are highly sulfated in patches along the chain, allowing differing ligands to bind to regions of higher or lower anionic charge density. Although KS does not contain uronic acid, it is grouped with the family of GAGs because of its repeating disaccharide containing GlcNAc. It is assembled on a core protein with either an O-linkage to serine (Ser) or threonine (Thr) or an N-linkage to asparagine (Asn). KS is a major component of lumican and keratocan, proteoglycans that are important in the clarity of corneal matrix as well as aggrecan, a structural molecule in cartilage and during brain development.
Unlike the other GAGs, HA is a “free” polysaccharide that is not assembled covalently onto a proteoglycan core protein in the normal biosynthetic organelles (Golgi and ER), but is often bound to proteins after its extrusion from the plasma membrane by HA synthase. After it is released by the synthase, HA is never sulfated, de-N-acetylated, or modified in any way (except by IαI as described below). All of the GAGs, except HA and some KS chains (as noted above), are attached to and assembled as O-linked glycans on proteoglycan core proteins and are sulfated to various degrees. CS, HP, and HS are attached to proteoglycans via Ser, or sometimes Thr residues, and their assembly starts with the common tetrasaccharide: GlcUA(β1, 3)Gal(β1, 3)Gal(β1, 4)Xyl(β1)→Ser.
CS, HP, and HS often act as concomitant molecular signatures for their respective proteoglycans. Receptors or binding proteins for the GAGs can be grouped into three different classes. Receptors in the first class are soluble proteins that are ECM organizers, such as versican, aggrecan, and neurocan. The second class of receptors (e.g., CD44, RHAMM, and TSG6) is associated with cell-mediated processes stimulated by GAGs such as inflammation and cellular motility. The third class of receptors (e.g., CD44, HARE/Stabilin-2) is involved in GAG scavenging and turnover and is responsible for proper homeostasis of GAG levels in the plasma, tissues, and lymphatic fluids. CD44 is in two classes due its functional diversity.