title: The activation of fibroblast growth factors by heparin: synthesis, structure, and biological activity of heparin-like oligosaccharides.
abstract: An effective strategy has been designed for the synthesis of oligosaccharides of different sizes structurally related to the regular region of heparin; this is illustrated by the preparation of hexasaccharide 1 and octasaccharide 2. This synthetic strategy provides the oligosaccharide sequence containing a D-glucosamine unit at the nonreducing end that is not available either by enzymatic or chemical degradation of heparin. It may permit, after slight modifications, the preparation of oligosaccharide fragments with different charge distribution as well. NMR spectroscopy and molecular dynamics simulations have shown that the overall structure of 1 in solution is a stable right-hand helix with four residues per turn. Hexasaccharide 1 and, most likely, octasaccharide 2 are, therefore, chemically well-defined structural models of naturally occurring heparin-like oligosaccharides for use in binding and biological activity studies. Both compounds 1 and 2 induce the mitogenic activity of acid fibroblast growth factor (FGF1), with the half-maximum activating concentration of 2 being equivalent to that of heparin. Sedimentation equilibrium analysis with compound 2 suggests that heparin-induced FGF1 dimerization is not an absolute requirement for biological activity.
authors.affiliation: Grupo de Carbohidratos, Instituto de Investigaciones Químicas, CSIC, Isla de la Cartuja, Américo Vespucio s/n, 41092 Seville, Spain.
authors.forename: J L
authors.initials: JL
authors.lastname: de Paz
authors.forename: J
authors.initials: J
authors.lastname: Angulo
authors.forename: J M
authors.initials: JM
authors.lastname: Lassaletta
authors.forename: P M
authors.initials: PM
authors.lastname: Nieto
authors.forename: M
authors.initials: M
authors.lastname: Redondo-Horcajo
authors.forename: R M
authors.initials: RM
authors.lastname: Lozano
authors.forename: G
authors.initials: G
authors.lastname: Giménez-Gallego
authors.forename: M
authors.initials: M
authors.lastname: Martín-Lomas
mesh_terms: D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001711:Biotransformation / Q000187:drug effects; D002240:Carbohydrate Sequence; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006493:Heparin / Q000737:chemistry / Q000494:pharmacology*; D007067:Iduronic Acid / Q000737:chemistry; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008934:Mitogens / Q000494:pharmacology; D008958:Models, Molecular; D009844:Oligosaccharides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013056:Spectrophotometry, Ultraviolet
chemical_list: D000925:Anticoagulants; D007202:Indicators and Reagents; D008934:Mitogens; D009844:Oligosaccharides; D007067:Iduronic Acid; D005346:Fibroblast Growth Factors; D006493:Heparin