Further Evidence for the Critical Role of a Non-Chair Conformation of L-Iduronic Acid in the Activation of Antithrombin

Autor: Jean-Marc Herbert, José Kovensky, Jean-Maurice Mallet, Maurice Petitou, Jean-Pascal Herault, Jacques Esnault, Pierre Sinaÿ, Pierre-Alexandre Driguez, Philippe Sizun
Rok vydání: 2002
Předmět:
Zdroj: Scopus-Elsevier
ISSN: 1099-0690
1434-193X
DOI: 10.1002/1099-0690(200211)2002:21<3595::aid-ejoc3595>3.0.co;2-f
Popis: 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)
Databáze: OpenAIRE
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