Further evidence for the critical role of a non-chair conformation of L-iduronic acid in the activation of antithrombin
L-iduronic acid, a conformationally flexible monosaccharide, imparts a remarkable protein adaptability to the glycosaminoglycans heparin, heparan sulfate, and dermatan sulfate. The pentasaccharide representing the antithrombin binding site of heparin contains one such L-iduronic acid residue, the co...
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| Autores principales: | , , , , , , , , |
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| Formato: | JOUR |
| Materias: | |
| Acceso en línea: | http://hdl.handle.net/20.500.12110/paper_1434193X_v_n21_p3595_Kovensky |
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| Sumario: | L-iduronic acid, a conformationally flexible monosaccharide, imparts a remarkable protein adaptability to the glycosaminoglycans heparin, heparan sulfate, and dermatan sulfate. The pentasaccharide representing the antithrombin binding site of heparin contains one such L-iduronic acid residue, the conformation of which has been suspected for a long time to be a critical factor in the interaction with antithrombin. We have recently synthesized pentasaccharides containing an L-iduronic acid residue conformationally forced to exist within a restricted arc (2S0 ⇄ 2,5B ⇄ 5S1) of the overall pseudorotational circle. We could thus demonstrate that the 2S0 conformation is adopted upon binding to the protein. In the present work, we now describe the synthesis of a similar pentasaccharide containing a slightly more flexible L-iduronic acid unit with a three-atom bridge between C-2 and C5 of the hexopyranose ring. This pentasaccharide is a better activator of AT-III with respect to blood coagulation factor Xa inhibition. These results confirm that L-iduronic acid adopts an unusual non-chair conformation close to 2S0 and clearly explains how the unique conformational behavior of L-iduronic acid is the key to heparin's interaction with AT-III. © Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002. |
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