title: Structural features in heparin which modulate specific biological activities mediated by basic fibroblast growth factor.
abstract: The biological activity of basic fibroblast growth factor (bFGF) is influenced greatly by direct binding to heparin and heparan sulphate (HS). Heparin-derived oligosaccharides have been utilized to determine the structural requirements present in the polymer that account for binding to bFGF. We had previously demonstrated that fragments > 6 mer can inhibit the interaction between cell surface heparan sulphate proteoglycan (HSPG) and bFGF, and bFGF-induced proliferation of adrenocortical endothelial (ACE) cells. In contrast, oligosaccharides > 10 mer can enhance the binding of bFGF to its high-affinity receptor or support bFGF-induced mitogenesis in ACE cells (Ishihara et al., J. Biol. Chem., 268, 4675-4683, 1993). We have extended these studies to size- and structure-defined oligosaccharides from heparin, 2-O-desulphated (2-O-DS-) heparin, 6-O-desulphated (6-O-DS-) heparin, carboxy-reduced (CR-) heparin and carboxy-amidomethylsulphonated (AMS-) heparin. Oligosaccharides from these polymers were fractionated on a bFGF-affinity column and were assessed as inhibitors or enhancers of specific bFGF-derived biological activities. The results of these studies indicate that both 2-O-sulphate and the negative charge of the carboxy group [L-iduronic acid (IdoA) residues] are required for specific interactions of heparin-derived oligosaccharides with bFGF and for modulation of bFGF mitogenic activity. In addition, the charge of the carboxy groups in uronic acids can be replaced by other functional groups with a negative charge, such as the amidomethyl sulphonate moiety described here.
authors: Glycomed Inc., Alameda, CA 94501.
authors: M
authors: M
authors: Ishihara
authors: P N
authors: PN
authors: Shaklee
authors: Z
authors: Z
authors: Yang
authors: W
authors: W
authors: Liang
authors: Z
authors: Z
authors: Wei
authors: R J
authors: RJ
authors: Stack
authors: K
authors: K
authors: Holme
mesh_terms: D000818:Animals; D001665:Binding Sites; D002240:Carbohydrate Sequence; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002846:Chromatography, Affinity; D004187:Disaccharides / Q000737:chemistry; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism* / Q000494:pharmacology; D006493:Heparin / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009844:Oligosaccharides / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism
chemical_list: D004187:Disaccharides; D009844:Oligosaccharides; D016222:Fibroblast Growth Factor 2; D006493:Heparin