Structural features in heparin which modulate specific biological activities mediated by basic fibroblast growth factor.
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.
Ishihara
M
M
Glycomed Inc., Alameda, CA 94501.
Shaklee
P N
PN
Yang
Z
Z
Liang
W
W
Wei
Z
Z
Stack
R J
RJ
Holme
K
K
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
D004187:Disaccharides; D009844:Oligosaccharides; D016222:Fibroblast Growth Factor 2; D006493:Heparin