Abstract
The main sites of calcium binding were determined for the low molecular weight heparin drug enoxaparin and the synthetic pentasaccharide Arixtra (fondaparinux). [1H,13C] HSQC pH titrations were carried out to characterize the acid–base properties of these samples both in the presence and absence of calcium. The differences in the titration curves were used to determine the structural components of enoxaparin and fondaparinux responsible for Ca2+ binding. In enoxaparin both unsubstituted and 2-O-sulfated iduronic acid residues are important in calcium binding and the presence of the 2-O-sulfo group does not seem to influence the Ca2+ binding capability of the iduronate ring. In fondaparinux changes in chemical shifts upon Ca2+ binding were smaller than observed for enoxaparin, and were observed for both the glucuronic acid and 2-O-sulfated iduronic acid residues. In enoxaparin significant perturbations of the chemical shift of the N-sulfoglucosamine anomeric carbon in residues connected to 2-O-sulfated iduronic acid were detected on Ca2+ binding, however it was not possible to determine whether these changes reflect direct involvement in calcium complexation or result from through space interactions or conformational changes.
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