Structure and antithrombin-binding properties of heparin isolated from the clams Anomalocardia brasiliana and Tivela mactroides.

Pejler, Gunnar; Danielsson, Åke; Björk, Ingemar; Lindahl, Ulf; Nader, Helena B.; Dietrich, Carl P.

doi:10.1016/s0021-9258(18)60822-1

Cited by 97 publications

(18 citation statements)

References 49 publications

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“…The highly sulphated analogues heparin and HS have been studied extensively (7) due to their well understood functions in anti-coagulation. Heparin is known to be highly evolutionarily conserved with similar structures found in a broad range of vertebrate and invertebrate organisms (51) such as turkey (52), whale (53), camel (54), mouse (55), human (56), lobster (57), shrimp (58), mussel (59), marine clam species (60), and crab (61). The difference between HS and heparin is quantitative and not qualitative (62), as can be seen in Table 3.…”

Section: Sulphated Gags: Heparin/heparan Sulphatementioning

confidence: 99%

Free energy calculations of glycosaminoglycan–protein interactions

Gandhi¹,

Mancera²

2009

Glycobiology

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Glycosaminoglycans (GAGs) are complex highly charged linear polysaccharides that have a variety of roles in biological processes. We report the first use of molecular dynamics (MD) free energy calculations using the MM/PBSA method to investigate the binding of GAGs to protein molecules, namely the platelet endothelial cell adhesion molecule 1 (PECAM-1) and annexin A2. Calculations of the free energy of the binding of heparin fragments of different sizes reveal the existence of a region of low GAG-binding affinity in domains 5-6 of PECAM-1 and a region of high affinity in domains 2-3, consistent with experimental data and ligand-protein docking studies. A conformational hinge movement between domains 2 and 3 was observed, which allows the binding of heparin fragments of increasing size (pentasaccharides to octasaccharides) with an increasingly higher binding affinity. Similar simulations of the binding of a heparin fragment to annexin A2 reveal the optimization of electrostatic and hydrogen bonding interactions with the protein and protein-bound calcium ions. In general, these free energy calculations reveal that the binding of heparin to protein surfaces is dominated by strong electrostatic interactions for longer fragments, with equally important contributions from van der Waals interactions and vibrational entropy changes, against a large unfavorable desolvation penalty due to the high charge density of these molecules.

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Section: Sulphated Gags: Heparin/heparan Sulphatementioning

confidence: 99%

Free energy calculations of glycosaminoglycan–protein interactions

Gandhi¹,

Mancera²

2009

Glycobiology

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“…wt %) were taken into account, 91 wt % of heparin's mass could be ascribed to oligosaccharides of known structure (Linhardt et al, 1988). Porcine mucosal heparin and bovine Structures of heparin's ATIII-binding site (R = H or S03") including the permissible structural variation where R" = S03" or COCH3 (Pejler et al, 1987), hexasaccharide 7 (Linhardt et al, 1986), and tetrasaccharide 6. lung heparin showed distinctly different oligosaccharide maps.…”

Section: Resultsmentioning

confidence: 99%

“…0006-2960/90/0429-4362$02.50/0 site (Lindahl et al, 1984;Pejler et al, 1987;Guo & Conrad, 1989). The precise structure of the ATIII-binding site within bovine heparin has not been reported, despite the fact that bovine heparin is used as frequently as porcine heparin in clinical anticoagulation.…”

mentioning

confidence: 99%

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

Loganathan

Wang²,

Mallis³

et al. 1990

Biochemistry

133

104

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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 this tetrasaccharide was unambiguously established as delta UAp2S (1----4)-alpha-D-GlcNp2S6S(1----4)-beta-D-GlcAp(1----4)-alph a-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 these 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----4)-alpha-D-GlcNp2S6S(1----4)-beta-D-GlcAp(1----4)-alph a-D- GlcNp2S3S6S(1----4)-alpha-L-IdoAp2S(1----4)-alpha-D-GlcNp 2S6S(1----. This study shows the presence of one or both types of ATIII-binding-site variants in all of the heparins that were examined.

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“…In invertebrates, heparin is found in some species of mollusk, crustacean, annelid, echinodermate, tunicate and urochordate life (Cassaro & Dietrich, 1977;Cavalcante et al, 2000;Dietrich et al, 1985;Luppi, Cesaretti, & Volpi, 2005;Medeiros et al, 2000;Pejler et al, 1987;Sampaio et al, 2006). In some invertebrates, the presence of heparin-like structures with similarities to heparin but, with some structural peculiarities, have been described (Brito et al, 2008;Chavante et al, 2000;Dietrich et al, 1999a;Nader et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

A heparin-like compound isolated from a marine crab rich in glucuronic acid 2-O-sulfate presents low anticoagulant activity

Andrade

Lima

Souza

et al. 2013

Carbohydrate Polymers

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A natural heparin-like compound isolated from the crab Goniopsis cruentata was structurally characterized and its anticoagulant and hemorrhagic activities were determined. Enzymatic and nuclear magnetic resonance analysis revealed that its structure is rich in disulfated disaccharides, possessing significant amounts of 2-O-sulfated-β-D-glucuronic acid units. Furthermore, low amounts of trisulfated disaccharide units containing 2-O-sulfated-α-L-iduronic acid were detected, when compared to mammalian heparin. In addition, this heparin-like structure showed negligible in vitro anticoagulant activity and low bleeding potency, facts that make it a suitable candidate for the development of structure-driven, heparin based therapeutic agents with fewer undesirable effects.

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Structure and antithrombin-binding properties of heparin isolated from the clams Anomalocardia brasiliana and Tivela mactroides.

Cited by 97 publications

References 49 publications

Free energy calculations of glycosaminoglycan–protein interactions

Free energy calculations of glycosaminoglycan–protein interactions

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

A heparin-like compound isolated from a marine crab rich in glucuronic acid 2-O-sulfate presents low anticoagulant activity

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