Glycobiology Advance Access originally published online on June 15, 2005
Glycobiology 2005 15(10):1008-1015; doi:10.1093/glycob/cwi091
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Dynamic properties of biologically active synthetic heparin-like hexasaccharides
2 Grupo de Carbohidratos, Instituto de Investigaciones Químicas, CSIC, Américo Vespucio 49, Isla de la Cartuja, 41092 Sevilla, Spain; 3 Institute of Chemistry, Slovak Academy of Sciences, 845 38 Bratislava, Slovakia; 4 Unitat de RMN, Serveis Cientificotècnics, Universitat de Barcelona, Parc Científic de Barcelona, Josep Samitier 1-5, 08028-Barcelona, Spain; and 5 Institute for Chemical and Biochemical Research "G. Ronzoni", via G. Colombo 81, 20133 Milan, Italy
1 To whom correspondence should be addressed; e-mail: pedro.nieto{at}iiq.csic.es
Received on March 29, 2005; revised on May 16, 2005; accepted on June 7, 2005
A complete study of the dynamics of two synthetic heparin-like hexasaccharides, D-GlcNHSO3-6-SO4-
-(1
4)-L-IdoA-2-SO4--(14)-D-GlcNHSO3-6-SO4--(14)-L-IdoA-2-SO4--(14)-D-GlcNHSO3-6-SO4--(14)-L-IdoA-2-SO4--1iPr (1) and 4)-L-IdoA-2-SO4--(14)-D-GlcNHAc-6-SO4--(14)-L-IdoA--(14)-D-GlcNHSO3--(14)-L-IdoA-2-SO4--1iPr (2), has been performed using 13C-nuclear magnetic resonance (NMR) relaxation parameters, T1, T2, and heteronuclear nuclear Overhauser effect (NOEs). Compound 1 is constituted from sequences corresponding to the major polysaccharide heparin region, while compound 2 contains a sequence never found in natural heparin. They differ from each other only in sulphation patterns, and are capable of stimulating fibroblast growth factors (FGFs)-1 induced mitogenesis. Both oligosaccharides exhibit a remarkable anisotropic overall motion in solution as revealed by their anisotropic ratios (
/||), 4.0 and 3.0 respectively. This is a characteristic behaviour of natural glycosaminoglycans (GAG) which has also been observed for the antithrombin (AT) binding pentasaccharide D-GlcNHSO3-6-SO4--(14)-D-GlcA-ß-(14)-D-GlcNHSO3-(3,6-SO4)--(14)-L-IdoA-2-SO4--(14)-D-GlcNHSO3-6-SO4--1Me (3) (Hricovíni, M., Guerrini, M., Torri, G., Piani, S., and Ungarelli, F. (1995) Conformational analysis of heparin epoxide in aqueous solution. An NMR relaxation study. Carbohydr. Res., 277, 11–23). The motional properties observed for 1 and 2 provide additional support to the suitability of these compounds as heparin models in agreement with previous structural (de Paz, J.L., Angulo, J., Lassaletta, J.M., Nieto, P.M., Redondo-Horcajo, M., Lozano, R.M., Jiménez-Gallego, G., and Martín-Lomas, M. (2001) The activation of fibroblast growth factors by heparin: synthesis, structure and biological activity of heparin-like oligosaccharides. Chembiochem, 2, 673–685; Ojeda, R., Angulo, J., Nieto, P.M., and Martin-Lomas. M. (2002) The activation of fibroblast growth factors by heparin: synthesis and structural study of rationally modified heparin-like oligosaccharides. Can. J. Chem,. 80, 917–936; Lucas, R., Angulo, J., Nieto, P.M., and Martin-Lomas, M. (2003) Synthesis and structural studies of two new heparin-like hexasaccharides. Org. Biomol. Chem., 1, 2253–2266) and biological data (Angulo, J., Ojeda, R., de Paz, J.L., Lucas, R., Nieto, P.M., Lozano, R.M., Redondo-Horcajo, M., Giménez-Gallego, G., and Martín-Lomas, M. (2004) The activation of fibroblast growth factors (FGFs) by glycosaminoglycans: influence of the sulphation pattern on the biological activity of FGF-1. Chembiochem, 5, 55–61). Fast internal motions observed for the less sulphated compound 2, as compared with 1, may be related to their different behavior in stimulating FGF1-induced mitogenic activity.
Key words: anisotropy / FGF interaction / heparan sulphate / heparin / NMR relaxation
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