Heparan sulfate

[9][10] Other minor forms of membrane HSPG include betaglycan[11] and the V-3 isoform of CD44 present on keratinocytes and activated monocytes.

[12] In the extracellular matrix, especially basement membranes and fractones,[13] the multi-domain perlecan,[14] agrin[15] and collagen XVIII[16] core proteins are the main HS-bearing species.

Heparan sulfate is a member of the glycosaminoglycan (GAG) family of carbohydrates and is very closely related in structure to heparin.

Under physiological conditions the ester and amide sulfate groups are deprotonated and attract positively charged counterions to form a salt.

In the 1980s, Jeffrey Esko was the first to isolate and characterize animal cell mutants altered in the assembly of heparan sulfate.

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.

[21] HS synthesis initiates with the transfer of xylose from UDP-xylose by xylosyltransferase (XT) to specific serine residues within the protein core.

Attachment of two galactose (Gal) residues by galactosyltransferases I and II (GalTI and GalTII) and glucuronic acid (GlcA) by glucuronosyltransferase I (GlcATI) completes the formation of a tetrasaccharide primer O-linked to a serine of the core-protein:[22] βGlcUA-(1→3)-βGal-(1→3)-βGal-(1→4)-βXyl-O-Ser.

[22][24] 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 (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.

[25] As an HS chain polymerises, it undergoes a series of modification reactions carried out by four classes of sulfotransferases and an epimerase.

In early studies, it was shown that modifying enzymes could recognize and act on any N-acetylated residue in the forming polymer.

Substrate recognition requires that the GlcN residue linked to the non-reducing side of a potential GlcA target be N-sulfated.

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 [45] The laboratory of Mitchell Ho at the NCI isolated the HS20 human monoclonal antibody with high affinity for heparan sulfate by phage display.

HS20 blocks the Wnt binding on heparan sulfate[5] and also inhibits infectious entry of pathogenic JC polyomavirus.