An unusual antithrombin-binding heparin octasaccharide with an additional 3-O-sulfated glucosamine in the active pentasaccharide sequence

作者：Guerrini Marco^*; Elli Stefano; Mourier Pierre; Rudd Timothy R; Gaudesi Davide; Casu Benito; Boudier Christian; Torri Giangiacomo; Viskov Christian

来源：Biochemical Journal, 2013, 449(2): 343-351.

DOI：10.1042/BJ20121309

• antithrombin
• heparin
• NMR
• 3-O-sulfation
• 3-O-sulfotransferase (3-OST)

The 3-O-sulfation of N-sulfated glucosamine is the last event in the biosynthesis of heparin/heparan sulfate, giving rise to the antithrombin-binding pentasaccharide sequence AGA*IA, which is largely associated with the antithrombotic activity of these molecules. The aim of the present study was the structural and biochemical characterization of a previously unreported AGA*IA*-containing octasaccharide isolated from the very-low-molecular-mass heparin semuloparin, in which both glucosamine residues of the pentasaccharide moiety located at the non-reducing end bear 3-O-sulfate groups. Two-dimensional and STD (saturation transfer difference) NMR experiments clearly confirmed its structure and identified its ligand epitope binding to antithrombin. The molecular conformation of the octasaccharide-antithrombin complex has been determined by NMR experiments and docking/energy minimization. The presence of the second 3-O-sulfated glucosamine in the octasaccharide induced more than one order of magnitude increase in affinity to antithrombin compared to the pentasaccharide AGA*IA.

• 出版日期2013-1-15