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Further Evidence for the Critical Role of a Non‐Chair Conformation of L ‐Iduronic Acid in the Activation of Antithrombin
Author(s) -
Kovensky José,
Mallet JeanMaurice,
Esnault Jacques,
Driguez PierreAlexandre,
Sizun Philippe,
Hérault JeanPascal,
Herbert JeanMarc,
Petitou Maurice,
Sinaÿ Pierre
Publication year - 2002
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/1099-0690(200211)2002:21<3595::aid-ejoc3595>3.0.co;2-f
Subject(s) - chemistry , iduronic acid , antithrombin , stereochemistry , biochemistry , heparin , heparan sulfate
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 ( 2 S 0 ⇄ 2,5 B ⇄ 5 S 1 ) of the overall pseudorotational circle. We could thus demonstrate that the 2 S 0 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 2 S 0 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)