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Varki A, Cummings R, Esko J, et al., editors. Essentials of Glycobiology. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 1999.

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Essentials of Glycobiology.

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Chapter 11Proteoglycans and Glycosaminoglycans

Primary contributions to this chapter were made by J.D. Esko (University of California at San Diego).

THE FOCUS OF THIS CHAPTER IS on the structure, biosynthesis, and general biology of proteoglycans. Topics include a description of the major families of proteoglycans, their characteristic polysaccharide chains (glycosaminoglycans), and the pathways involved in their biosynthesis.

Historical Perspective (1–4)

The study of proteoglycans dates back to the turn of the twentieth century with investigations of “chondromucoid” from cartilage and anticoagulant preparations from liver (heparin). From 1930 to 1950, great strides were made in analyzing the chemistry of the polysaccharides of these preparations (also known as “mucopolysaccharides”), notably by Karl Meyer and his associates, who described the structure of hyaluronic acid, dermatan sulfate, keratan sulfate, and different isomeric forms of chondroitin sulfate. During this period, Jorpes and Gardell in Sweden described the chemical structure of heparin and heparan sulfate. These polysaccharides eventually came to be known as glycosaminoglycans to indicate the presence of amino sugars and other sugars in a polymeric form. Subsequent studies by Rodén and Lindahl provided insights into the linkage of the chains to core proteins, and these structural studies together paved the way for the biosynthetic studies that followed.

The 1970s marked a turning point in the field, when improved isolation and chromatographic procedures were developed to purify and analyze tissue proteoglycans and glycosaminoglycans. Sajdera and Hascall developed a density gradient method for separating the large aggregating proteoglycans, which revealed that the extracellular matrix was much more organized than previously appreciated (Figure 11.1). Also during this period, P.F. Kraemer showed that the production of proteoglycans was a general property of animal cells and that proteoglycans and glycosaminoglycans were present on the cell surface. This observation led to a rapid expansion of the field and the eventual appreciation of proteoglycan function in cell adhesion and signaling, as well as a host of other biological activities (for greater details, see Chapter 29). Today, studies using somatic cell genetics, molecular cloning, and gene knockouts are under way using organisms as diverse as flies, worms, and mice to better understand the physiological role of proteoglycans. In turn, human diseases associated with aberrant biosynthesis of proteoglycans have been discovered (see Chapters 3137). By understanding the pathways in greater detail, novel ways to intervene with proteoglycan assembly may emerge that may have therapeutic value (see Chapters 40 and 41).

Figure 11.1. The large cartilage CS proteoglycan (aggrecan) forms an aggregate using hyaluronic acid as a scaffold and link protein to stabilize the complex.

Figure 11.1

The large cartilage CS proteoglycan (aggrecan) forms an aggregate using hyaluronic acid as a scaffold and link protein to stabilize the complex. In addition, cartilage matrix contains collagen (not shown) and various glycoproteins (partially filled circles). (more...)

Proteoglycans and Glycosaminoglycans Are Components of Extracellular Matrices and Cell Surfaces (3,5–12)

Proteoglycans consist of a core protein and one or more covalently attached GAG chains (Figure 11.2). GAGs are linear polysaccharides, whose building blocks (disaccharides) consist of an amino sugar (either GlcNAc or GalNAc) and an uronic acid (GlcA and IdoA). Virtually all mammalian cells produce proteoglycans and either secrete them into the ECM, insert them into the plasma membrane, or store them in secretory granules. The matrix proteoglycans include small interstitial proteoglycans (decorin, biglycan, fibromodulin), a proteoglycan form of type IX collagen, and one or more members of the aggrecan family of proteoglycans (aggrecan, brevican, neurocan, or versican). Some of these proteoglycans contain only one GAG chain (e.g., decorin), whereas others have more than 100 chains (e.g., aggrecan). The matrix proteoglycans typically contain the GAGs known as CS or DS. Exceptions to this generalization exist, since the HS proteoglycans perlecan and agrin are major species found in basement membranes.

Figure 11.2. Glycosaminoglycans consist of repeating disaccharide units.

Figure 11.2

Glycosaminoglycans consist of repeating disaccharide units. HA lacks any sulfate groups, but the rest of the GAGs contain sulfates at various positions. As described in the text, considerable variations occur in the positions of sulfation and IdoA.

The ECM determines the physical characteristics of tissues and many of the biological properties of cells embedded in it. The major components of the ECM are fibrous proteins that provide tensile strength (e.g., various collagens and elastin), adhesive glycoproteins (e.g., fibronectin, laminin, and tenascin), and proteoglycans that provide a hydrated gel which resists compressive forces.

Cells also elaborate a diverse group of membrane proteoglycans. These typically have type I orientations and have either single membrane-spanning domains or a GPI anchor (see Chapter 10). Membrane proteoglycans tend to contain mostly HS (e.g., the glypicans), but many are hybrid structures containing both HS and CS (e.g., the syndecans and betaglycan). A few membrane proteoglycans contain exclusively CS (e.g., CD44 and NG2).

In addition, cells with storage granules concentrate proteoglycans along with other secretory products. These proteoglycans typically contain highly sulfated forms of CS, although the secretory granules of connective tissue mast cells contain mostly heparin. Secretory granule proteoglycans are thought to help sequester and regulate the availability of positively charged components, such as proteases and bioactive amines.

It should be kept in mind that most proteoglycans also contain O- and N-glycans typically found on glycoproteins (see Chapters 7 and 8). The GAG chains are much larger than these other types of glycans (e.g., a 20-kD GAG chain contains ~80 sugar residues, whereas a typical biantennary N-glycan may contain 10–12 residues). Therefore, the properties of the GAGs tend to predominate, but the other glycans may also have biological activities.

Proteoglycans Interact with a Variety of Ligands (11–14)

Table 11.1 lists some of the proteins known to interact with GAGs (see Chapter 29). Most of the proteins bind to HS, which may reflect the greater chemical diversity and capacity of HS to interact with proteins through varied arrangements of sulfated sugar residues. These interactions have profound physiological effects. For example, injection of heparin into the bloodstream results in rapid anticoagulation due to binding and activation of antithrombin. Ligand binding to GAGs may result in (1) immobilization of proteins at sites of production, (2) regulation of enzyme activity, (3) binding to a signaling receptor, (4) protection of ligands against degradation, and (5) a reservoir of ligands for future mobilization. In some cases, the interaction depends on a very specific sequence of modified sugars in the GAG chain. The best-studied example is antithrombin-heparin, which depends on a specific pentasaccharide sequence (Figure 11.3)

Table 11.1. Examples of proteins that bind to GAGs.

Table 11.1

Examples of proteins that bind to GAGs.

Figure 11.3. The antithrombin-binding sequence in heparin consists of a very specific arrangement of sulfated sugar residues and uronic acid epimers.

Figure 11.3

The antithrombin-binding sequence in heparin consists of a very specific arrangement of sulfated sugar residues and uronic acid epimers.

Proteoglycans Exhibit Great Structural Diversity (14–17)

Proteoglycans exhibit tremendous structural variation due to a number of factors. First, proteoglycans that contain more than one GAG chain usually exhibit variation in the number of attached chains. For example, syndecan-1 has five attachment sites for GAGs, but not all of the sites are used equally. In addition, some sites contain either CS or HS. The length of the chains also varies and the arrangement of sulfated residues along the chains differs. Thus, a preparation of syndecan-1 represents a diverse population of molecules. Finally, syndecan-1 from different cell types exhibits differences in the number of chains, their lengths, and their fine structures. This characteristic of all proteoglycans presumably reflects the way GAGs are made, as described below.

Hyaluronan Is the Simplest Glycosaminoglycan (18–24)

The HA disaccharide consists of GlcNAcβ1-3GlcAβ1-4 and is repeated many times in each chain. HA is distributed widely in nature, from the capsules of Streptococcus to tissues of invertebrate and vertebrate organisms. In mammals, HA is abundant in skin, skeletal tissues, the vitreous of the eye, umbilical cord, and synovial fluid. A typical polymer might contain 104 disaccharides (mass 105 to 107 daltons). In solution, HA has an extended structure—when stretched end to end, a polymer of 106 daltons is about 2 μm. Because of its length, it tends to entangle into a mesh-like structure. At a concentration of 10 mg/ml, its viscosity (η) is about 5000 that of water, which confers rigidity to tissues when HA is present at high concentrations (e.g., rooster combs and the vitreous of the eye). Under shear stress, the viscosity drops rapidly, but it remains quite elastic. Thus, HA has the property of a biological lubricant, reducing friction during movement and providing resiliency under static conditions. The uniform structure of HA would seem to obviate specific biological interactions, but in fact, several HA-binding proteins have evolved. For more details, see Chapter 29.

The biosynthesis of HA involves copolymerization of GlcNAc and GlcA from of their respective high-energy nucleotide donors, UDP-GlcNAc and UDP-GlcA. Unlike all the other GAGs, HA is never covalently linked to protein. Its synthesis appears to occur at the plasma membrane in cells, which is an exception to the rule that glycosylation generally occurs in the Golgi. Furthermore, the polymer is thought to assemble from the reducing end, resulting in its extrusion from the cell surface. Cells expressing an HA-binding protein on its surface (e.g., CD44) will retain the extruded material as a pericellular coat one or two cell diameters thick.

Three HA synthetases have been cloned, and these constitute a family of homologous enzymes (HAS 1–3). Isozymes have been identified in a number of organisms, including DG42 in Xenopus, a homolog in a virus that infects a Chlorella-like green algae, and Streptococcus. The HA synthetases vary in size from 42 to 65 kD, depending on isoform and species. Hydropathy plots indicate that the enzyme may span the membrane as many as 12 times, but the functional form of the enzyme is unknown. Its catalytic activity is impressive, since it can polymerize about 100 monosaccharides/sec in vitro, or about 106 daltons of polysaccharide in less than 1 minute.

Hyaluronidases are enzymes that degrade HA. Several types of hyaluronidases are known that generate either tetrasaccharides (testicular hyaluronidase) or disaccharides (bacterial) as end products. In addition, endothelial cells express a receptor that facilitates clearance of HA from the blood. After entering lysosomes, the polymer can be completely degraded to GlcNAc, which can be recycled (see Chapter 18), and GlcA, which is catabolized by the pentose pathway.

Keratan Sulfate, a Sulfated Polylactosamine (25–30)

KS is a sulfated polylactosamine chain identical to the type found on conventional glycoproteins and mucins (see Chapters 7 and 8). Their linkage to protein distinguishes two types of KS. KS I, originally described in cornea, is linked through a core glycan structure found in the N-glycosylated glycoproteins. KS II (skeletal KS) is an O-glycan linked through GalNAc to Ser/Thr, like the linkage found in mucins (see Chapter 8). Examples of KS proteoglycans are shown in Figure 11.4 and Table 11.2. In the cornea, KS proteoglycans maintain the even spacing of type I collagen fibrils, allowing the passage of light without scattering. Defects in sulfation (macular corneal dystrophy) or chain formation (keratoconus) cause distortions in fibril organization and corneal opacity. In cartilage, the function of the KS II is unclear. In humans and cows, the large CS proteoglycan found in cartilage (aggrecan) contains a segment of 4–23 hexapeptide repeats where the KS chains are located (E-E-P-S,F-P-S), but rats and other rodents lack this motif and do not contain KS.

Figure 11.4. Keratan sulfates consist of a sulfated polylactosamine linked either to Asn or Ser/Thr residues.

Figure 11.4

Keratan sulfates consist of a sulfated polylactosamine linked either to Asn or Ser/Thr residues. The actual order of the various sulfated and nonsulfated disaccharides occurs somewhat randomly along the chain. Not shown are sialic acid and fucose residues (more...)

Table 11.2. Examples of keratan sulfate proteoglycans.

Table 11.2

Examples of keratan sulfate proteoglycans.

The polylactosamine of KS I can be quite long (~50 disaccharides, 20–25 kD) and contain a mixture of nonsulfated, monosulfated (Gal-GlcNAc6S), and disulfated disaccharides (Gal6S-GlcNAc6S).

The biosynthesis of the polylactosamine and the underlying linkage structure is covered in Chapters 7 and 8. At least two sulfotransferases, GlcNAc 6-O-sulfotransferase, and Gal 6-O-sulfotransferase, both of which have been cloned, catalyze the sulfation reactions. These enzymes, like other sulfotransferases, utilize activated sulfate, PAPS (3′-phosphoadenyl-5′-phosphosulfate), as a high-energy donor (see Chapter 6). Studies of lung mucin biosynthesis have suggested a scheme for coordinating polymer elongation and sulfation: GlcNAc 6-O-sulfotransferase will act only on terminal GlcNAc residues, whereas Gal transferase will act on both sulfated and nonsulfated GlcNAc (Figure 11.5). Thus, failure to add sulfate to a terminal GlcNAc residue results in a disaccharide unit devoid of sulfate or having at most one sulfate group located on the GlcNAc residue. The relationship of enzymes involved in KS I and KS II sulfation is unclear at this time.

Figure 11.5. The pathway depicts a mechanism for generating fully sulfated (left) or partially sulfated disaccharides (right) during KS biosynthesis.

Figure 11.5

The pathway depicts a mechanism for generating fully sulfated (left) or partially sulfated disaccharides (right) during KS biosynthesis. The inability of the GlcNAc 6-O-sulfotransferase to act on internal residues means that polymerization and sulfation (more...)

Bacterial keratanases degrade KS at characteristic positions (Table 11.3). In animals, KS is degraded in lysosomes by the sequential action of exoglycosidases (β-galactosidase and β-hexosaminidase) after removal of the sulfate groups on the terminal residue by sulfatases (see Chapter 18).

Table 11.3. Keratanases.

Table 11.3


Heparan Sulfate and Chondroitin Sulfate Are Linked by Xylose to Serine (31–33)

Two classes of GAG chains, CS and HS, are linked to serine residues in core proteins by way of xylose (Figure 11.6). Xylosyltransferase initiates the process using UDP-xylose as donor. A glycine residue almost invariably lies to the carboxy-terminal side of the serine, but a perfect consensus sequence does not exist for the attachment site. In addition, at least two acidic amino acid residues are usually present, and they can be located on one or both sides of the serine, usually within a few residues. Several proteoglycans contain clustered GAG attachment sites, raising the possibility that xylosyltransferase could act in a processive manner. Xylosylation is an incomplete process in some proteoglycans, which may explain why proteoglycans with multiple attachment sites contain different numbers of chains in different cells. Variation in the degree of GAG substitution also might result from low levels of UDP-xylose, low activity of xylosyltransferase, or competing reactions, such as phosphorylation, acylation, or other forms of glycosylation.

Figure 11.6. Chondroitin and heparan sulfate biosynthesis initiates by the formation of a linkage region tetrasaccharide.

Figure 11.6

Chondroitin and heparan sulfate biosynthesis initiates by the formation of a linkage region tetrasaccharide. Addition of the first hexosamine residue commits the intermediate to either CS or HS.

After xylose addition, a linkage tetrasaccharide is generated (Figure 11.6), which can undergo phosphorylation at C-2 of xylose and sulfation of the galactose residues. In general, phosphorylation and sulfation occur substoichiometrically. The lack of chain specificity for phosphorylation would seem to exclude it as a signal for controlling composition. However, phosphorylation may be transient, suggesting a role in processing or sorting. Additional studies are needed to determine whether any relationship exists between galactose sulfation and chain initiation, polymerization, and turnover.

The linkage tetrasaccharide lies at a bifurcation in the biosynthetic pathway. Three types of reactions have been detected: addition of β-GalNAc (initiation of CS), addition of α-GlcNAc (initiation of HS), and addition of α-GalNAc (Figure 11.6). These reactions are thought to be catalyzed by three independent transferases. The α-GalNAc reaction is unusual and gives rise to a pentasaccharide or heptasaccharide containing one CS disaccharide that has not yet been found in a natural proteoglycan. These enzymes are important control points because they ultimately regulate the type of GAG chain that will assemble. Control over the addition of β-GalNAc or α-GlcNAc appears to be manifested at the level of enzyme recognition for linear amino acid sequences immediately adjacent to the attachment site in the core protein. α-GlcNAc addition involves recognition of the amino acid sequences flanking attachment sites for HS. These usually contain a cluster of acidic residues within seven to nine residues of the site. In the example shown below (syndecan-2), the underlined sequence indicates the sites of GAG attachment and the boldface letters refer to the clustered acidic residues.


Although CS and HS chains usually assemble on the linkage region tetrasaccharide described above, some cells also can generate these GAGs as N-glycans. These were detected in oligosaccharide preparations released with N-glycanase, which liberates glycans linked to asparagine. However, the structure of the “linkage fragment” (i.e., the underlying core glycan) is not known.

Chondroitin Sulfate/Dermatan Sulfate Biosynthesis (2,34–36)

CS consists of repeating units of GalNAc-GlcA disaccharides (see Figure 11.1) polymerized into long chains with an average size of 20 kD (~40 disaccharides). On the basis of the structure of CS, at least five enzyme activities could be predicted, including three transferases (the initiating GalNAc transferase described above and the polymerizing GalNAc and GlcA transferases) and two sulfotransferases (GalNAc 4-sulfotransferase and GalNAc 6-sulfotransferase). Additional enzymes exist for epimerization of GlcA to IdoA in DS, sulfation at C-2 of the uronic acids, and other patterns of sulfation found in unusual species of chondroitin. The conversion of GlcA to IdoA in DS is unusual since it takes place after the polymer has formed (cf. Chapter 6). To date, only the GalNAc 6-sulfotransferase has been purified and cloned, although progress in this area is expected to accelerate with recent advances in genome analysis and cloning techniques.

CS assembly can occur on virtually all proteoglycans, depending on the cell in which the core protein is expressed. The major proteoglycans that typically contain CS or DS chains in vivo are shown in Table 11.4. CSs from different sources vary in the location of sulfate groups. This is easily assessed using bacterial chondroitinases, which cleave the chains into disaccharides. Separation of the products reveals that many types of CS exist in nature (Table 11.5), but many chains are hybrid structures containing more than one type of disaccharide. For example, DS refers to a glycan that contains one or more IdoA-containing disaccharides (chondroitin sulfate B) as well as GlcA-containing disaccharides. Animal cells also degrade CS in lysosomes using a series of exoglycolytic activities (see Chapter 18).

Table 11.4. Examples of chondroitin sulfate proteoglycans.

Table 11.4

Examples of chondroitin sulfate proteoglycans.

Table 11.5. Types of chondroitin sulfates.

Table 11.5

Types of chondroitin sulfates.

Heparin and Heparan Sulfate Biosynthesis (3,14,17,37–39)

Heparin and HS consist of the disaccharide unit, GlcNAcα1-4GlcAβ1-4 (see Figure 11.1). Heparin is produced exclusively by mast cells and differs from HS in the degree of modification of the sugar residues, as described below. Virtually all cells express HS proteoglycans, and several major families of core proteins have been cloned and analyzed biochemically, genetically, and biologically (Table 11.6).

Table 11.6. Examples of heparan sulfate proteoglycans.

Table 11.6

Examples of heparan sulfate proteoglycans.

As the polysaccharides polymerize, they undergo a series of modification reactions catalyzed by at least four families of sulfotransferases, and one epimerase (Figure 11.7). A GlcNAc N-deacetylase/N-sulfotransferase acts on a subset of GlcNAc residues in a cluster along the chain. Generally, the enzyme deacetylates and rapidly adds sulfate to the free amino groups to form GlcNSO3, but some of the deacetylated GlcN residues can escape N-sulfation. An epimerase, such as the one involved in DS synthesis, then acts on GlcA residues immediately adjacent to the GlcNS, followed by 2-O-sulfation of the IdoA that is generated. Next, a sulfotransferase adds sulfate groups to the 6-OH of the GlcN residues adjacent to the uronic acid. Finally, certain arrangements of sulfated sugar residues and uronic acid epimers act as a target for the 3-O-sulfotransferase. The modifications tend to occur in clusters along the chain, with regions devoid of sulfate separating the modified tracts. In general, the reactions proceed in the order indicated, but they fail to go to completion, resulting in tremendous chemical heterogeneity within the modified regions. The specific arrangement of sulfated residues and uronic acid epimers in heparin and HS gives rise to specific binding sequences for ligands. A major question concerns how the enzymes and pathway of HS/heparin biosynthesis are regulated to achieve tissue-specific expression of ligand-binding sequences.

Figure 11.7. HS biosynthesis involves a series of modification reactions including sulfation and epimerization of GlcA.

Figure 11.7

HS biosynthesis involves a series of modification reactions including sulfation and epimerization of GlcA. Chain polymerization and modification are thought to occur simultaneously. (PAPS) 3′-phosphoadenyl-5′-phosphosulfate, the high-energy (more...)

During the last decade, nearly all of the enzymes involved with HS synthesis have been purified or molecularly cloned. Several important features have emerged from these studies, which may shed light on how different binding sequences arise.

  • Several of the enzymes appear to have dual catalytic activities. Thus, a single protein bearing two catalytic domains catalyzes N-deacetylation of GlcNAc residues and subsequent N-sulfation. The same is true of the copolymerase, which transfers GlcNAc and GlcA from the corresponding UDP sugars to the growing polymer. In contrast, the epimerase, 2-O-sulfotransferase, and 6-O-sulfotransferase(s) appear to be unique properties of independent enzymes.
  • In several cases, multiple isozymes exist that can catalyze a single or pair of reactions. Thus, four N-deacetylase/N-sulfotransferases exist, three 6-O-sulfotransferases have been described, and five 3-O-sulfotransferases have been identified. Their tissue distribution varies, which may cause differences in the pattern of sulfation. However, some overlap exists as well, suggesting that individual isozymes may act on different sub-sequences within the chain.
  • The polymer modification reactions probably colocalize in the same stacks of the Golgi complex. Thus, the enzymes may form a supramolecular complex that coordinates the modification reactions. The composition of these complexes may play a part in regulating the fine structure of the chains.
  • In general, the composition of HS varies more between cell types than between core proteins expressed in the same cell. This observation suggests that each cell type may express a unique array of enzymes and potential regulatory factors.

The Difference between Heparin and Heparan Sulfate (14,34)

Considerable confusion exists over the definition of heparin and HS. The major differences are summarized in Table 11.7. Heparin is produced by mast cells and sold by pharmaceutical companies as an anticoagulant. In contrast, HS is made by virtually all cells. It also can contain anticoagulant activity, but the crude preparations have much less activity than heparin. During biosynthesis, heparin undergoes more extensive sulfation and uronic acid epimerization, such that more than 85% of the GlcNAc residues are N-deacetylated and N-sulfated and more than 70% of the uronic acid is converted to IdoA.

Table 11.7. Major differences between heparin and heparan sulfate.

Table 11.7

Major differences between heparin and heparan sulfate.

Table 11.8. Heparin lyases.

Table 11.8

Heparin lyases.

Another way to distinguish heparin from HS is by susceptibility to bacterial (Flavobacterium) heparin lyases. These enzymes, like the bacterial chondroitinases, are eliminases and produce an unusual unsaturated uronic acid on the nonreducing end of the oligosaccharide products.

Proteoglycans Turn Over Continuously (9,40,41)

Cells secrete proteoglycans directly into the extracellular environment, and some are shed from the cell surface through proteolytic cleavage of the core protein. Cells also internalize a large fraction of cell surface proteoglycans by endocytosis (Figure 11.8). These internalized proteoglycans first encounter heparanases that cleave the chains at a limited number of sites, probably dependent on the sequence. These smaller fragments eventually appear in the lysosome and undergo complete degradation by way of a series of exoglycosidases and sulfatases (see Chapter 18). The purpose of intracellular heparanases is not clear, but they may be involved in release of bound ligands from the internalized proteoglycan prior to the lysosome. CS proteoglycans follow a similar route, but endoglycosidases that degrade the chains prior to the lysosome have not been described.

Figure 11.8. HS proteoglycans turn over both by shedding from the cell surface and by endocytosis and step-wise degradation inside lysosomes.

Figure 11.8

HS proteoglycans turn over both by shedding from the cell surface and by endocytosis and step-wise degradation inside lysosomes. (Adapted, with permission, from [9] Yanagishita and Hascall 1992.)

Genetic Studies of Proteoglycan Structure, Function, and Metabolism (42–48)

A variety of mutant cell lines altered in GAG biosynthesis have been isolated and biochemically characterized (see Chapter 31). In addition, Drosophila mutants with lesions in growth-factor-dependent signaling have been described that turn out to have defects in GAG formation or nucleotide precursors. With cDNA clones available for many core proteins and biosynthetic enzymes, targeted disruption of genes is now a possibility. For greater detail of these subjects, see Chapters 3133.

Future Prospects

The last two decades have seen a tremendous increase in the number of glycoproteins found to contain glycosaminoglycans. Furthermore, many of the details of the biosynthetic pathways have been described. This information in turn has led to the purification and cloning of genes encoding the core proteins and the biosynthetic enzymes, which have revealed that the relevant proteins belong to families of presumably related function. Recombinant proteins can be produced readily, which should permit the analysis of enzyme structure and function. The availability of these reagents will revolutionize the way we study the biology of these glycoconjugates in the future. With the genes in hand, genetic ablation experiments can now be undertaken to study how proteoglycans participate in normal and pathophysiology. Already, mutants have been characterized in cultured cell lines (see Chapter 31), in lower organisms (see Chapter 19), and to a lesser extent in mice (see Chapter 33). Such models provide insights into inborn errors in proteoglycan assembly in humans, and they define targets for potential pharmaceutical intervention.


Lindahl U, Höök M. Glycosaminoglycans and their binding to biological macromolecules. Annu. Rev. Biochem. 1978;47:385–417. [PubMed: 354500]
Rodén L. 1980. Structure and metabolism of connective tissue proteoglycans. In The biochemistry of glycoproteins and proteoglycans (ed. Lennarz W.J.), pp. 267–271. Plenum Press, New York.
Kjellén L, Lindahl U. Proteoglycans: Structures and interactions. Annu. Rev. Biochem. 1991;60:443–475. [PubMed: 1883201]
Yanagishita M. A brief history of proteoglycans. Experientia. 1993;49:366–368. [PubMed: 8500592]
Gallagher J T, Lyon M, Steward W P. Structure and function of heparan sulphate proteoglycans. Biochem. J. 1986;236:313–325. [PMC free article: PMC1146843] [PubMed: 2944511]
Gallagher J T. The extended family of proteoglycans: Social residents of the pericellular zone. Curr. Opin. Cell Biol. 1989;1:1201–1218. [PubMed: 2517581]
Kolset S O, Gallagher J T. Proteoglycans in haemopoietic cells. Biochim. Biophys. Acta. 1990;1032:191–211. [PubMed: 2261494]
Bernfield M, Kokenyesi R, Kato M, Hinkes M T, Spring J, Gallo R L, Lose E J. Biology of the syndecans: A family of transmembrane heparan sulfate proteoglycans. Annu. Rev. Cell Biol. 1992;8:365–393. [PubMed: 1335744]
Yanagishita M, Hascall V. Cell surface heparan sulfate proteoglycans. J. Biol. Chem. 1992;267:9451–9454. [PubMed: 1577788]
David G. Integral membrane heparan sulfate proteoglycans. FASEB J. 1993;7:1023–1030. [PubMed: 8370471]
Iozzo R V, Murdoch A D. Proteoglycans of the extracellular environment: Clues from the gene and protein side offer novel perspectives in molecular diversity and function. FASEB J. 1996;10:598–614. [PubMed: 8621059]
Iozzo R V. Matrix proteoglycans: From molecular design to cellular function. Annu. Rev. Biochem. 1998;67:609–652. [PubMed: 9759499]
Jackson R L, Busch S J, Cardin A D. Glycosaminoglycans: Molecular properties, protein interactions, and role in physiological processes. Physiol. Rev. 1991;71:481–539. [PubMed: 2006221]
Conrad H.E. 1998. Heparin-binding proteins. Academic Press, San Diego.
Turnbull J E, Gallagher J T. Sequence analysis of heparan sulphate indicates defined location of N-sulphated glucosamine and iduronate 2-sulphate residues proximal to the protein-linkage region. Biochem. J. 1991;277:297–303. [PMC free article: PMC1151232] [PubMed: 1859357]
Lyon M, Deakin J A, Gallagher J T. Liver heparan sulfate structure. A novel molecular design. J. Biol. Chem. 1994;269:11208–11215. [PubMed: 8157650]
Maccarana M, Sakura Y, Tawada A, Yoshida K, Lindahl U. Domain structure of heparan sulfates from bovine organs. J. Biol. Chem. 1996;271:17804–17810. [PubMed: 8663266]
Fraser J R, Laurent T C. Turnover and metabolism of hyaluronan. Ciba Found. Symp. 1989;143:41–53. [PubMed: 2680348]
DeAngelis P L, Papaconstantinou J, Weigel P H. Molecular cloning, identification, and sequence of the hyaluronan synthase gene from group A Streptococcus pyrogenes. J. Biol. Chem. 1993;268:19181–19184. [PubMed: 8366070]
Kreil G. Hyaluronidases— A group of neglected enzymes. Protein Sci. 1995;4:1666–1669. [PMC free article: PMC2143229] [PubMed: 8528065]
DeAngelis P L, Achyuthan A M. Yeast-derived recombinant DG42 protein of Xenopus can synthesize hyaluronan in vitro. J. Biol. Chem. 1996;271:23657–23660. [PubMed: 8798586]
DeAngelis P L, Jing W, Graves M V, Burbank D E, Van Etten J L. Hyaluronan Synthase of Chlorella Virus Pbcv-1. Science. 1997;278:1800–1803. [PubMed: 9388183]
Fraser J R E, Laurent T C, Laurent U B G. Hyaluronan: Its nature, distribution, functions and turnover. J. Intern. Med. 1997;242:27–33. [PubMed: 9260563]
Spicer A P, McDonald J A. Characterization and molecular evolution of a vertebrate hyaluronan synthase gene family. J. Biol. Chem. 1998;273:1923–1932. [PubMed: 9442026]
Greiling H. and Scott J.E., eds. 1989. Keratan sulphate: Chemistry, biology, chemical pathology. Biochemical Society, London.
Brown G M, Huckerby T N, Morris H G, Abram B L, Nieduszynski I A. Oligosaccharides derived from bovine articular cartilage keratan sulfates after keratanase II digestion: Implications for keratan sulfate structural fingerprinting. Biochemistry. 1994;33:4836–4846. [PubMed: 8161543]
Greiling H. Structure and biological functions of keratan sulfate proteoglycans. EXS. 1994;70:101–122. [PubMed: 8298243]
Tai G H, Huckerby T N, Nieduszynski I A. Multiple non-reducing chain termini isolated from bovine corneal keratan sulfates. J. Biol. Chem. 1996;271:23535–23546. [PubMed: 8798563]
Degroote S, Lo-Guidice J M, Strecker G, Ducourouble M P, Roussel P, Lamblin G. Characterization of an N-acetylglucosamine-6-O-sulfotransferase from human respiratory mucosa active on mucin carbohydrate chains. J. Biol. Chem. 1997;272:29493–29501. [PubMed: 9368010]
Fukuta M, Inazawa J, Torii T, Tsuzuki K, Shimada E, Habuchi O. Molecular cloning and characterization of human keratan sulfate Gal-6-sulfotransferase. J. Biol. Chem. 1997;272:32321–32328. [PubMed: 9405439]
Rodén L, Koerner T, Olson C, Schwartz N B. Mechanisms of chain initiation in the biosynthesis of connective tissue polysaccharides. Fed. Proc. 1985;44:373–380. [PubMed: 3917944]
Sundblad G, Holojda S, Roux L, Varki A, Freeze H H. Sulfated N-linked oligosaccharides in mammalian cells. II. Identification of glycosaminoglycan-like chains attached to complex-type glycans. J. Biol. Chem. 1988;263:8890–8896. [PubMed: 3379051]
Zhang L, Esko J D. Amino acid determinants that drive heparan sulfate assembly in a proteoglycan. J. Biol. Chem. 1994;269:19295–19299. [PubMed: 8034692]
Linhardt R.J. 1995. Analysis of glycosaminoglycans with polysaccharide lyases. In Current protocols in molecular biology (eds. Ausubel F. et al.), pp. 17.13.17–17.13.32. Greene Publishing and Wiley Interscience, New York.
Silbert J E, Sugumaran G. Intracellular membranes in the synthesis, transport, and metabolism of proteoglycans. Biochim. Biophys. Acta. 1995;1241:371–384. [PubMed: 8547301]
Silbert J E. Organization of glycosaminoglycan sulfation in the biosynthesis of proteochondroitin sulfate and proteodermatan sulfate. Glycoconjugate J. 1996;13:907–912. [PubMed: 8981081]
Lindahl U, Kusche M, Lidholt K, Oscarsson L G. Biosynthesis of heparin and heparan sulfate. Ann. N.Y. Acad. Sci. 1989;556:36–50. [PubMed: 2525361]
Salmivirta M, Lidholt K, Lindahl U. Heparan sulfate: A piece of information. FASEB J. 1996;10:1270–1279. [PubMed: 8836040]
Rosenberg R D, Shworak N W, Liu J, Schwartz J J, Zhang L J. Heparan sulfate proteoglycans of the cardiovascular system. Specific structures emerge but how is synthesis regulated. J. Clin. Invest. 1997;99:2062–2070. [PMC free article: PMC508034] [PubMed: 9151776]
Williams K J, Fuki I V. Cell-surface heparan sulfate proteoglycans: Dynamic molecules mediating ligand catabolism. Curr. Opin. Lipidol. 1997;8:253–262. [PubMed: 9335948]
Bai X M, Bame K J, Habuchi H, Kimata K, Esko J D. Turnover of heparan sulfate depends on 2-O-sulfation of uronic acids. J. Biol. Chem. 1997;272:23172–23179. [PubMed: 9287321]
Esko J D. Genetic analysis of proteoglycan structure, function and metabolism. Curr. Opin. Cell Biol. 1991;3:805–816. [PubMed: 1931081]
Wallis G A. Cartilage disorders. The importance of being sulphated. Curr. Biol. 1995;5:225–227. [PubMed: 7780725]
Pilia G, Hughes-Benzie R M, MacKenzie A, Baybayan P, Chen E Y, Huber R, Neri G, Cao A, Forabosco A, Schlessinger D. Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome [see comments] Nat. Genet. 1996;12:241–247. [PubMed: 8589713]
Superti-Furga A, Hästbacka J, Rossi A, Van der Harten J J, Wilcox W R, Cohn D H, Rimoin D L, Steinmann B, Lander E S, Gitzelmann R. A family of chondrodysplasias caused by mutations in the diastrophic dysplasia sulfate transporter gene and associated with impaired sulfation of proteoglycans. Ann. N.Y. Acad. Sci. 1996;785:195–201. [PubMed: 8702127]
Danielson K G, Baribault H, Holmes D F, Graham H, Kadler K E, Iozzo R V. Targeted disruption of decorin leads to abnormal collagen fibril morphology and skin fragility. J. Cell Biol. 1997;136:729–743. [PMC free article: PMC2134287] [PubMed: 9024701]
Häcker U, Lin X H, Perrimon N. The Drosophila sugarless gene modulates Wingless signaling and encodes an enzyme involved in polysaccharide biosynthesis. Development. 1997;124:3565–3573. [PubMed: 9342049]
Jackson S M, Nakato H, Sugiura M, Jannuzi A, Oakes R, Kaluza V, Golden C, Selleck S B. dally, a Drosophila glypican, controls cellular responses to the TGF-β-related morphogen, Dpp. Development. 1997;124:4113–4120. [PubMed: 9374407]
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