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Heparan sulfate (HS) is a linear
polysaccharide Polysaccharides (), or polycarbohydrates, are the most abundant carbohydrates found in food. They are long chain polymeric carbohydrates composed of monosaccharide units bound together by glycosidic linkages. This carbohydrate can react with wa ...
found in all animal tissues. It occurs as a
proteoglycan Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan (GAG) chain(s). The point of attachment is a serine (Ser) residue to whic ...
(HSPG, i.e. Heparan Sulfate ProteoGlycan) in which two or three HS chains are attached in close proximity to cell surface or
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
proteins. It is in this form that HS binds to a variety of protein
ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
s, including Wnt, and regulates a wide range of biological activities, including developmental processes,
angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
, blood coagulation, abolishing detachment activity by GrB (Granzyme B), and tumour
metastasis Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
. HS has also been shown to serve as cellular receptor for a number of viruses, including the
respiratory syncytial virus Respiratory syncytial virus (RSV), also called human respiratory syncytial virus (hRSV) and human orthopneumovirus, is a common, contagious virus that causes infections of the respiratory tract. It is a negative-sense, single-stranded RNA virus. ...
. One study suggests that cellular heparan sulfate has a role in SARS-CoV-2 Infection, particularly when the virus attaches with ACE2.


Proteoglycans

The major cell membrane HSPGs are the transmembrane
syndecans Syndecans are single transmembrane domain proteins that are thought to act as coreceptors, especially for G protein-coupled receptors. More specifically, these core proteins carry three to five heparan sulfate and chondroitin sulfate chains, i.e. ...
and the
glycosylphosphatidylinositol Glycosylphosphatidylinositol (), or glycophosphatidylinositol, or GPI in short, is a phosphoglyceride that can be attached to the C-terminus of a protein during posttranslational modification. The resulting GPI-anchored proteins play key roles in ...
(GPI) anchored glypicans. Other minor forms of membrane HSPG include
betaglycan Betaglycan also known as Transforming growth factor beta receptor III (TGFBR3), is a cell-surface chondroitin sulfate / heparan sulfate proteoglycan >300 kDa in molecular weight. Betaglycan binds to various members of the TGF-beta superfamily of ...
and the V-3 isoform of
CD44 The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the ''CD44'' gene on chromosome 11. CD44 has been referred to as HCAM (homing cell adhes ...
present on
keratinocytes Keratinocytes are the primary type of cell found in the epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells. Basal cells in the basal layer (''stratum basale'') of the skin are sometimes referred ...
and activated
monocytes Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also infl ...
. In the extracellular matrix, especially
basement membrane The basement membrane is a thin, pliable sheet-like type of extracellular matrix that provides cell and tissue support and acts as a platform for complex signalling. The basement membrane sits between Epithelium, epithelial tissues including mesot ...
s and fractones, the multi-domain
perlecan Perlecan (PLC) also known as basement membrane-specific heparan sulfate proteoglycan core protein (HSPG) or heparan sulfate proteoglycan 2 (HSPG2), is a protein that in humans is encoded by the ''HSPG2'' gene. The HSPG2 gene codes for a 4,391 ami ...
,
agrin Agrin is a large proteoglycan whose best-characterised role is in the development of the neuromuscular junction during embryogenesis. Agrin is named based on its involvement in the aggregation of acetylcholine receptors during synaptogenesis. ...
and collagen XVIII core proteins are the main HS-bearing species.


Structure and differences from heparin

Heparan sulfate is a member of the
glycosaminoglycan Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units (i.e. two-sugar units). The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case ...
family of carbohydrates and is very closely related in structure to
heparin Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Since heparins depend on the activity of antithrombin, they are considered anticoagulants. Specifically it is also used in the treatm ...
. Heparin, commonly known as an anticoagulant, is a highly sulfated form of HS which, in contrast to HS, is mainly found in mast cell secretory granules. Both consist of a variably sulfated repeating
disaccharide A disaccharide (also called a double sugar or ''biose'') is the sugar formed when two monosaccharides are joined by glycosidic linkage. Like monosaccharides, disaccharides are simple sugars soluble in water. Three common examples are sucrose, lact ...
unit. The main disaccharide units that occur in heparan sulfate and heparin are shown below. The most common disaccharide unit within heparan sulfate is composed of a
glucuronic acid Glucuronic acid (from Greek γλεῦκος "''wine, must''" and οὖρον "''urine''") is a uronic acid that was first isolated from urine (hence the name). It is found in many gums such as gum arabic (c. 18%), xanthan, and kombucha tea and ...
(GlcA) linked to ''N''-acetylglucosamine (GlcNAc), typically making up around 50% of the total disaccharide units. Compare this to heparin, where IdoA(2S)-GlcNS(6S) makes up 85% of heparins from beef lung and about 75% of those from porcine intestinal mucosa. Problems arise when defining hybrid GAGs that contain both 'heparin-like' and 'HS-like' structures. It has been suggested that a GAG should qualify as heparin only if its content of N-sulfate groups largely exceeds that of N-acetyl groups and the concentration of O-sulfate groups exceeds those of N-sulfate. Not shown below are the rare disaccharides containing a 3-O-sulfated glucosamine (GlcNS(3S,6S) or a free
amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituen ...
group (GlcNH3+). Under physiological conditions the
ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...
and
amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is ...
sulfate groups are deprotonated and attract positively charged counterions to form a salt. It is in this form that HS is thought to exist at the cell surface. File:GlcA-GlcNAc.png, GlcA-GlcNAc File:GlcA-GlcNS.png, GlcA-GlcNS File:IdoA-GlcNS.png, IdoA-GlcNS File:IdoA(2S)-GlcNS.png, IdoA(2S)-GlcNS File:IdoA-GlcNS(6S).png, IdoA-GlcNS(6S) File:IdoA(2S)-GlcNS(6S).png, IdoA(2S)-GlcNS(6S)


Abbreviations

*GlcA = β-D-
glucuronic acid Glucuronic acid (from Greek γλεῦκος "''wine, must''" and οὖρον "''urine''") is a uronic acid that was first isolated from urine (hence the name). It is found in many gums such as gum arabic (c. 18%), xanthan, and kombucha tea and ...
*IdoA = α-L-
iduronic acid -Iduronic acid (IUPAC abbr.: IdoA) is the major uronic acid component of the glycosaminoglycans (GAGs) dermatan sulfate, and heparin. It is also present in heparan sulfate, although here in a minor amount relative to its carbon-5 epimer glucuro ...
*IdoA(2S) = 2-''O''-sulfo-α-L-iduronic acid *GlcNAc = 2-deoxy-2-acetamido-α-D-glucopyranosyl *GlcNS = 2-deoxy-2-sulfamido-α-D-glucopyranosyl *GlcNS(6S) = 2-deoxy-2-sulfamido-α-D-glucopyranosyl-6-''O''-sulfate


Biosynthesis

Many different cell types produce HS chains with many different primary structures. Therefore, there is a great deal of variability in the way HS chains are synthesised, producing structural diversity encompassed by the term "heparanome" - which defines the full range of primary structures produced by a particular cell, tissue or organism. However, essential to the formation of HS regardless of primary sequence is a range of biosynthetic enzymes. These enzymes consist of multiple
glycosyltransferases Glycosyltransferases (GTFs, Gtfs) are enzymes ( EC 2.4) that establish natural glycosidic linkages. They catalyze the transfer of saccharide moieties from an activated nucleotide sugar (also known as the " glycosyl donor") to a nucleophilic gly ...
,
sulfotransferase Sulfotransferases (SULTs) are transferase enzymes that catalyze the transfer of a sulfo group from a donor molecule to an acceptor alcohol or amine. The most common sulfo group donor is 3'-phosphoadenosine-5'-phosphosulfate (PAPS). In the case o ...
s and an
epimerase Epimerases and racemases are isomerase enzymes that catalyze the inversion of stereochemistry in biological molecules. Racemases catalyze the stereochemical inversion around the asymmetric carbon atom in a substrate having only one center of asymm ...
. These same enzymes also synthesize
heparin Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Since heparins depend on the activity of antithrombin, they are considered anticoagulants. Specifically it is also used in the treatm ...
. In the 1980s,
Jeffrey Esko Jeffrey David Esko, Ph.D.,M.D. (h.c) is currently a Distinguished Professor of Cellular and Molecular Medicine and Co-Director of the Glycobiology Research and Training Center at the University of California, San Diego. His research has focuses on ...
was the first to isolate and characterize animal cell mutants altered in the assembly of heparan sulfate. Many of these enzymes have now been purified, molecularly cloned and their expression patterns studied. From this and early work on the fundamental stages of HS/heparin biosynthesis using a mouse mastocytoma cell free system a lot is known about the order of enzyme reactions and specificity.


Chain initiation

HS synthesis initiates with the transfer of
xylose Xylose ( grc, ξύλον, , "wood") is a sugar first isolated from wood, and named for it. Xylose is classified as a monosaccharide of the aldopentose type, which means that it contains five carbon atoms and includes an aldehyde functional gro ...
from UDP-xylose by
xylosyltransferase Xylosyltransferase are transferase enzymes which act upon xylose and are classified under EC 2.4.2. More specifically, they can refer to: * Dolichyl-phosphate D-xylosyltransferase * Dolichyl-xylosyl-phosphate-protein xylosyltransferase * Flavon ...
(XT) to specific
serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...
residues within the protein core. Attachment of two
galactose Galactose (, '' galacto-'' + '' -ose'', "milk sugar"), sometimes abbreviated Gal, is a monosaccharide sugar that is about as sweet as glucose, and about 65% as sweet as sucrose. It is an aldohexose and a C-4 epimer of glucose. A galactose molec ...
(Gal) residues by galactosyltransferases I and II (GalTI and GalTII) and
glucuronic acid Glucuronic acid (from Greek γλεῦκος "''wine, must''" and οὖρον "''urine''") is a uronic acid that was first isolated from urine (hence the name). It is found in many gums such as gum arabic (c. 18%), xanthan, and kombucha tea and ...
(GlcA) by glucuronosyltransferase I (GlcATI) completes the formation of a ''
tetrasaccharide A tetrasaccharide is a carbohydrate which gives upon hydrolysis four molecules of the same or different monosaccharides. For example, stachyose upon hydrolysis gives one molecule each of glucose and fructose and two molecules of galactose Gala ...
primer'' ''O''-linked to a serine of the core-protein: βGlcUA-(1→3)-βGal-(1→3)-βGal-(1→4)-βXyl-''O''-Ser.
Xylose Xylose ( grc, ξύλον, , "wood") is a sugar first isolated from wood, and named for it. Xylose is classified as a monosaccharide of the aldopentose type, which means that it contains five carbon atoms and includes an aldehyde functional gro ...
attachment to the core protein is thought to occur in the
endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...
(ER) with further assembly of the linkage region and the remainder of the chain occurring in the
Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles ins ...
. The pathways for HS/heparin or
chondroitin sulfate Chondroitin sulfate is a sulfated glycosaminoglycan (GAG) composed of a chain of alternating sugars ( N-acetylgalactosamine and glucuronic acid). It is usually found attached to proteins as part of a proteoglycan. A chondroitin chain can have ove ...
(CS) and
dermatan sulfate Dermatan sulfate is a glycosaminoglycan (formerly called a mucopolysaccharide) found mostly in skin, but also in blood vessels, heart valves, tendons, and lungs. It is also referred to as chondroitin sulfate B, although it is no longer classifie ...
(DS) biosynthesis diverge after the formation of this common tetrasaccharide linkage structure. The next enzyme to act, GlcNAcT-I or GalNAcT-I, directs synthesis, either to HS/heparin or CS/DS, respectively.


Chain elongation

After attachment of the first ''N''-acetylglucosamine (GlcNAc) residue, elongation of the tetrasacchride linker is continued by the stepwise addition of GlcA and GlcNAc residues. These are transferred from their respective UDP-sugar nucleotides. This is carried out by one or more related enzymes whose genes are members of the exostoses (EXT) gene family of tumour suppressors. Mutations at the EXT1-3 gene loci in humans lead to an inability of cells to produce HS and to the development of the disease
Multiple Hereditary Exostoses Hereditary multiple osteochondromas (HMO), also known as hereditary multiple exostoses, is a disorder characterized by the development of multiple benign osteocartilaginous masses ( exostoses) in relation to the ends of long bones of the lower li ...
(MHE). MHE is characterized by cartilage-capped tumours, known as osteochondromas or exostoses, which develop primarily on the long bones of affected individuals from early childhood until puberty.


Chain modification

As an HS chain polymerises, it undergoes a series of modification reactions carried out by four classes of sulfotransferases and an epimerase. The availability of the sulfate donor PAPS is crucial to the activity of the sulfotransferases.


N-deacetylation/N-sulfation

The first polymer modification is the N-deacetylation/N-sulfation of GlcNAc residues into GlcNS. This is a prerequisite for all subsequent modification reactions, and is carried out by one or more members of a family of four GlcNAc N-deacetylase/N-sulfotransferase enzymes (NDSTs). In early studies, it was shown that modifying enzymes could recognize and act on any N-acetylated residue in the forming polymer. Therefore, the modification of GlcNAc residues should occur randomly throughout the chain. However, in HS, N-sulfated residues are mainly grouped together and separated by regions of N-acetylation where GlcNAc remains unmodified. There are four isoforms of NDST (NDST1–4). Both N-deacetylase and N-sulfotransferase activities are present in all NDST-isoforms but they differ significantly in their enzymatic activities.


Generation of GlcNH2

Due to the N-deacetylase and N-sulfotransferase being carried out by the same enzyme N-sulfation is normally tightly coupled to N-acetylation. GlcNH2 residues resulting from apparent uncoupling of the two activities have been found in heparin and some species of HS.


Epimerisation and 2-O-sulfation

Epimerisation In stereochemistry, an epimer is one of a pair of diastereomers. The two epimers have opposite absolute configuration, configuration at only one stereogenic center out of at least two. All other stereogenic centers in the molecules are the same in ...
is catalysed by one enzyme, the GlcA C5 epimerase or heparosan-N-sulfate-glucuronate 5-epimerase (). This enzyme epimerises GlcA to
iduronic acid -Iduronic acid (IUPAC abbr.: IdoA) is the major uronic acid component of the glycosaminoglycans (GAGs) dermatan sulfate, and heparin. It is also present in heparan sulfate, although here in a minor amount relative to its carbon-5 epimer glucuro ...
(IdoA). Substrate recognition requires that the GlcN residue linked to the non-reducing side of a potential GlcA target be N-sulfated. Uronosyl-2-O-sulfotransferase (2OST) sulfates the resulting IdoA residues.


6-O-sulfation

Three glucosaminyl 6-O-transferases (6OSTs) have been identified that result in the formation of GlcNS(6S) adjacent to sulfated or non-sulfated IdoA. GlcNAc(6S) is also found in mature HS chains.


3-O-sulfation

Currently seven glucosaminyl 3-''O''-sulfotransferases (3OSTs, HS3STs) are known to exist in mammals (eight in zebrafish). The 3OST enzymes create a number of possible 3-''O''-sulfated disaccharides, including GlcA-GlcNS(3S±6S) (modified by
HS3ST1 Heparan sulfate glucosamine 3-O-sulfotransferase 1 is an enzyme that in humans is encoded by the ''HS3ST1'' gene. Function Heparan sulfate biosynthetic enzymes are key components in generating a myriad of distinct heparan sulfate fine structur ...
and HS3ST5), IdoA(2S)-GlcNH2(3S±6S)(modified by
HS3ST3A1 Heparan sulfate glucosamine 3-O-sulfotransferase 3A1 is an enzyme that in humans is encoded by the ''HS3ST3A1'' gene. Heparan sulfate biosynthetic enzymes are key components in generating myriad distinct heparan sulfate fine structures that carr ...
,
HS3ST3B1 Heparan sulfate glucosamine 3-O-sulfotransferase 3B1 is an enzyme that in humans is encoded by the ''HS3ST3B1'' gene. Heparan sulfate biosynthetic enzymes are key components in generating myriad distinct heparan sulfate fine structures that carry ...
, HS3ST5 and HS3ST6) and GlcA/IdoA(2S)-GlcNS(3S) (modified by
HS3ST2 Heparan sulfate glucosamine 3-O-sulfotransferase 2 is an enzyme that in humans is encoded by the ''HS3ST2'' gene. Heparan sulfate biosynthetic enzymes are key components in generating a myriad of distinct heparan sulfate fine structures that carr ...
and HS3ST4). As with all other HS sulfotransferases, the 3OSTs use 3'-phosphoadenosine-5'-phosphosulfate (PAPS) as a sulfate donor. Despite being the largest family of HS modification enzymes, the 3OSTs produce the rarest HS modification, the 3-''O''-sulfation of specific glucosamine residues at the C3-OH moiety. The 3OSTs are divided into two functional subcategories, those that generate an antithrombin III binding site (
HS3ST1 Heparan sulfate glucosamine 3-O-sulfotransferase 1 is an enzyme that in humans is encoded by the ''HS3ST1'' gene. Function Heparan sulfate biosynthetic enzymes are key components in generating a myriad of distinct heparan sulfate fine structur ...
and HS3ST5) and those that generate a herpes simplex virus 1 glycoprotein D (HSV-1 gD) binding site (
HS3ST2 Heparan sulfate glucosamine 3-O-sulfotransferase 2 is an enzyme that in humans is encoded by the ''HS3ST2'' gene. Heparan sulfate biosynthetic enzymes are key components in generating a myriad of distinct heparan sulfate fine structures that carr ...
,
HS3ST3A1 Heparan sulfate glucosamine 3-O-sulfotransferase 3A1 is an enzyme that in humans is encoded by the ''HS3ST3A1'' gene. Heparan sulfate biosynthetic enzymes are key components in generating myriad distinct heparan sulfate fine structures that carr ...
,
HS3ST3B1 Heparan sulfate glucosamine 3-O-sulfotransferase 3B1 is an enzyme that in humans is encoded by the ''HS3ST3B1'' gene. Heparan sulfate biosynthetic enzymes are key components in generating myriad distinct heparan sulfate fine structures that carry ...
, HS3ST4, HS3ST5 and HS3ST6). As the 3OSTs are the largest family of HS modification enzymes and their actions are rate-limiting, substrate specific and produce rare modifications, it has been hypothesized that 3OST modified HS plays an important regulatory role in biological processes. It has been demonstrated that 3-''O''-sulfation can enhance the binding of Wnt to the glypican and may play a role in regulating Wnt in cancer.


Ligand binding

Heparan sulfate binds with a large number of extracellular proteins. These are often collectively called the “heparin interactome” or "heparin-binding proteins", because they are isolated by affinity chromatography on the related polysaccharide heparin, though the term “heparan sulfate interactome” is more correct. The functions of heparan sulfate binding proteins ranges from extracellular matrix components, to enzymes and coagulation factors, and most growth factors, cytokines, chemokines and morphogens The laboratory of Dr. Mitchell Ho at the NCI isolated the HS20 human monoclonal antibody with high affinity for heparan sulfate by phage display. The antibody binds heparan sulfate, not chondroitin sulfate. The binding of HS20 to heparan sulfate requires sulfation at both the C2 position and C6 position. HS20 blocks the Wnt binding on heparan sulfate and also inhibits infectious entry of pathogenic JC polyomavirus.


Interferon-γ

The cell surface receptor binding region of
Interferon-γ Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...
overlaps with the HS binding region, near the protein's C-terminal. Binding of HS blocks the receptor binding site and as a result, protein-HS complexes are inactive.


Wnt

Glypican-3 (GPC3) interacts with both Wnt and
Frizzled Frizzled is a family of atypical G protein-coupled receptors that serve as receptors in the Wnt signaling pathway and other signaling pathways. When activated, Frizzled leads to activation of Dishevelled in the cytosol. Species distribution Fr ...
to form a complex and triggers downstream signaling. It has been experimentally established that Wnt recognizes a heparan sulfate motif on GPC3, which contains IdoA2S and GlcNS6S, and that the 3-O-sulfation in GlcNS6S3S enhances the binding of Wnt to the glypican. The HS-binding properties of a number of other proteins are also being studied: * Antithrombin III *
Fibroblast Growth Factors Fibroblast growth factors (FGF) are a family of cell signalling proteins produced by macrophages; they are involved in a wide variety of processes, most notably as crucial elements for normal development in animal cells. Any irregularities in their ...
*
Hepatocyte Growth Factor Hepatocyte growth factor (HGF) or scatter factor (SF) is a paracrine cellular growth, motility and morphogenic factor. It is secreted by mesenchymal cells and targets and acts primarily upon epithelial cells and endothelial cells, but also acts o ...
*
Interleukin-8 Interleukin 8 (IL-8 or chemokine (C-X-C motif) ligand 8, CXCL8) is a chemokine produced by macrophages and other cell types such as epithelial cells, airway smooth muscle cells and endothelial cells. Endothelial cells store IL-8 in their storage ...
*
Vascular Endothelial Growth Factor Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...
* Wnt/Wingless *
Endostatin Endostatin is a naturally occurring, 20-kDa C-terminal fragment derived from type XVIII collagen. It is reported to serve as an anti-angiogenic agent, similar to angiostatin and thrombospondin. Endostatin is a broad-spectrum angiogenesis inhibi ...


Heparan sulfate analogue

Heparan sulfate analogues are thought to display identical properties as heparan sulfate with exception of being stable in a proteolytic environment like a wound. Because heparan sulfate is broken down in chronic wounds by heparanase, the analogues only bind sites where natural heparan sulfate is absent and cannot be broken down by any known heparanases and glycanases. Also the function of the heparan sulfate analogues is the same as heparan sulfate, protecting a variety of protein ligands such as growth factors and cytokines. By holding them in place, the tissue can then use the different protein ligands for proliferation.


References

{{DEFAULTSORT:Heparan Sulfate Glycosaminoglycans Sulfate esters