Structural variation in the antithrombin III binding site region and its occurrence in heparin from different sources

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Abstract
A tetrasaccharide possessing a biosynthetically permissible structural variability in and adjacent to the antithrombin III (ATIII) binding site has been isolated from heparin lyase depolymerized bovine lung heparin by using strong anion-exchange high-pressure liquid chromatography (SAX-HPLC). On the basis of two-dimensional 500-MHz 1H NMR experiments, including phase-sensitive correlated spectroscopy (COSY) and rotating frame nuclear Overhauser enhancement spectroscopy (ROESY), and fast-atom bombardment mass spectrometry (FAB-MS), the primary structure of his tetrasaccharide was unambiguously established as .DELTA.Ap2S (1.fwdarw.4)-.alpha.-D-GlcNp2S6S(1.fwdarw.4)-.beta.-D-GlcaP(1.fwdarw.4)-.alpha.-D-GlcNp2S3S6S (where .DELTA.UA represents 4-deoxy-.alpha.-L-threo-hex-4-enopyranosyluronic acid). The 1H NMR ROESY experiment proved to be particularly valuable in offering sequence information. Heparins from a variety of species and tissue sources were examined by oligosaccharide mapping using SAX-HPLC and gradient polyacrylamide gel electrophoresis. Two of the heparins are used as anticoagulants; they are porcine intestinal mucosal heparin and bovine lung heparin. The predominant ATIII-binding site in porcine heparin contained an N-acetylated glucosamine residue. We now report the structure of the predominant ATIII-binding site in bovine heparin as .fwdarw.4)-.alpha.-D-GlcNp2S6S(1.fwdarw.4)-.beta.-D-GlcAp(1.fwdarw.4)-.alpha.-D-GlcNp2S3S6S(1.fwdarw.4)-.alpha.-L-IdoAp2S(1.fwdarw.4)-.alpha.-D-GlcNp2S6S(1.fwdarw.. This study shows the presence of one or both types of TIII-binding-site variants in all of the heparins that were examined.
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