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具有生物活性的合成类肝素六糖的动态特性

Dynamic properties of biologically active synthetic heparin-like hexasaccharides.

作者信息

Angulo Jesús, Hricovíni Milos, Gairi Margarida, Guerrini Marco, de Paz José Luis, Ojeda Rafael, Martín-Lomas Manuel, Nieto Pedro M

机构信息

Grupo de Carbohidratos, Instituto de Investigaciones Químicas, CSIC, Américo Vespucio 49, Isla de la Cartuja, 41092 Sevilla, Spain.

出版信息

Glycobiology. 2005 Oct;15(10):1008-15. doi: 10.1093/glycob/cwi091. Epub 2005 Jun 15.

DOI:10.1093/glycob/cwi091
PMID:15958415
Abstract

A complete study of the dynamics of two synthetic heparin-like hexasaccharides, D-GlcNHSO3-6-SO4-alpha-(1-->4)-L-IdoA-2-SO4-alpha-(1-->4)-D-GlcNHSO3-6-SO4-alpha-(1-->4)-L-IdoA-2-SO4-alpha-(1-->4)-D-GlcNHSO3-6-SO4-alpha-(1-->4)-L-IdoA-2-SO4-alpha-1-->iPr (1) and -->4)-L-IdoA-2-SO4-alpha-(1-->4)-D-GlcNHAc-6-SO4-alpha-(1-->4)-L-IdoA-alpha-(1-->4)-D-GlcNHSO3-alpha-(1-->4)-L-IdoA-2-SO4-alpha-1-->iPr (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 (tau /tau||), 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-alpha-(1-->4)-D-GlcA-beta-(1-->4)-D-GlcNHSO3-(3,6-SO4)-alpha-(1-->4)-L-IdoA-2-SO4-alpha-(1-->4)-D-GlcNHSO3-6-SO4-alpha-1-->Me (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.

摘要

利用13C核磁共振（NMR）弛豫参数T1、T2和异核Overhauser效应（NOE），对两种合成类肝素六糖，即D-GlcNHSO3-6-SO4-α-(1→4)-L-IdoA-2-SO4-α-(1→4)-D-GlcNHSO3-6-SO4-α-(1→4)-L-IdoA-2-SO4-α-(1→4)-D-GlcNHSO3-6-SO4-α-(1→4)-L-IdoA-2-SO4-α-1→iPr（1）和→4)-L-IdoA-2-SO4-α-(1→4)-D-GlcNHAc-6-SO4-α-(1→4)-L-IdoA-α-(1→4)-D-GlcNHSO3-α-(1→4)-L-IdoA-2-SO4-α-1→iPr（2）进行了全面研究。化合物1由对应于主要多糖肝素区域的序列组成，而化合物2含有天然肝素中从未发现的序列。它们彼此之间仅硫酸化模式不同，且都能够刺激成纤维细胞生长因子（FGFs）-1诱导的有丝分裂。两种低聚糖在溶液中均表现出显著各向异性的整体运动，其各向异性比率（τ/τ||）分别为4. 和3.0。这是天然糖胺聚糖（GAG）的特征行为，抗凝血酶（AT）结合五糖D-GlcNHSO3-6-SO4-α-(1→4)-D-GlcA-β-(1→4)-D-GlcNHSO3-(3,6-SO4)-α-(1→4)-L-IdoA-2-SO4-α-(1→4)-D-GlcNHSO3-6-SO4-α-1→Me（3）也观察到这种行为（Hricovíni，M.，Guerrini，M.，Torri，G.，Piani，S.和Ungarelli，F.（1995）水溶液中肝素环氧化物的构象分析。NMR弛豫研究。碳水化合物研究，277，11 - 23）。对1和2观察到的运动性质为这些化合物作为肝素模型的适用性提供了额外支持，这与先前的结构研究（de Paz，J.L.，Angulo，J.，Lassaletta，J.M.，Nieto，P.M.，Redondo-Horcajo，M.，Lozano，R.M.，Jiménez-Gallego，G.和Martín-Lomas，M.（2001）肝素对成纤维细胞生长因子的激活作用：类肝素低聚糖的合成、结构和生物活性。化学生物化学杂志, 2, 673 - 685；Ojeda，R.，Angulo，J.，Nieto，P.M.和Martin-Lomas，M.（2002）肝素对成纤维细胞生长因子的激活作用：合理修饰的类肝素低聚糖的合成和结构研究。加拿大化学杂志, 80, 917 - 936；Lucas，R.，Angulo，J.，Nieto，P.M.和Martin-Lomas，M.（2003）两种新的类肝素六糖的合成和结构研究。有机生物分子化学杂志, 1, 2253 - 2266）以及生物学数据（Angulo，J.，Ojeda，R.，de Paz，J.L.，Lucas，R.，Nieto，P.M.，Lozano，R.M.，Redondo-Horcajo，M.，Giménez-Gallego，G.,和Martín-Lomas，M.（2004）糖胺聚糖对成纤维细胞生长因子（FGFs）的激活作用：硫酸化模式对FGF-1生物活性的影响。化学生物化学杂志, 5, 55 - 61）一致。与化合物1相比，硫酸化程度较低的化合物2中观察到的快速内部运动可能与其在刺激FGF1诱导的有丝分裂活性方面的不同行为有关。

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