Antithrombin-binding oligosaccharides: structural diversities in a unique function?

Guerrini, Marco; Mourier, Pierre; Torri, Giangiacomo; Viskov, Christian

doi:10.1007/s10719-014-9543-9

Cited by 30 publications

(24 citation statements)

References 55 publications

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“…The currently known AT-binding sequence comprises a disaccharide –GlcA-GlcNS3S±6S-unit 34 (Supplementary Fig S3). The substitution of the –GlcA-GlcNS3S6S- disaccharide unit with the –IdoA2S-GlcNS3S6S- disaccharide unit in HS was perceived to abolish AT-binding affinity 35–36 .…”

Section: Resultsmentioning

confidence: 99%

“…The AT-binding sequences isolated so far all consist of the –GlcA-GlcNS3S6S- disaccharide repeating unit, which is a product of 3-OST-1 enzyme modification 34, 40 . Although Compound 5 , which is a product of 3-OST-3 enzyme modification, does not contain the –GlcA-GlcNS3S6S- disaccharide unit, it binds to AT and displays anticoagulant activity.…”

Section: Discussionmentioning

confidence: 99%

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Synthesis of 3-O-Sulfated Oligosaccharides to Understand the Relationship between Structures and Functions of Heparan Sulfate

Wang

Hsieh

et al. 2017

J. Am. Chem. Soc.

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The sulfation at the 3-OH position of glucosamine is an important modification in forming structural domains for heparan sulfate to enable its biological functions. Seven 3-O-sulfotransferase isoforms in the human genome are involved in the biosynthesis of 3-O-sulfated heparan sulfate. As a rare modification present in heparan sulfate, the availability of 3-O-sulfated oligosaccharides is very limited. Here, we report the use of a chemoenzymatic synthetic approach to synthesize six 3-O-sulfated oligosaccharides, including three hexasaccharides and three octasaccharides. The synthesis was achieved by rearranging the enzymatic modification sequence to accommodate the substrate specificity of 3-O-sulfotransferase 3. We studied the impact of 3-O-sulfation on the conformation of the pyranose ring of 2-O-sulfated iduronic acid using NMR, and on the correlation between ring conformation and anticoagulant activity. We identified a novel octasaccharide that interacts with antithrombin and displays anti factor Xa activity. Interestingly, the octasaccharide displays a faster clearance rate than fondaparinux, an FDA approved pentasaccharide drug, in a rat model, making this octasaccharide a potential short acting anticoagulant drug candidate that could reduce bleeding risk. Having access to a set of critically important 3-O-sulfated oligosaccharides offers the potential to develop new heparan sulfate-based therapeutics.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Synthesis of 3-O-Sulfated Oligosaccharides to Understand the Relationship between Structures and Functions of Heparan Sulfate

Wang

Hsieh

et al. 2017

J. Am. Chem. Soc.

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“…In fact, other types of carbohydrate structures, distinct from GAGs, including those with low or no activity, have also been identified that can fulfil the structural requirements of AT binding [72] and a proposal has been made that the stabilization of AT is the key determinant of its activity [73]. It has also been shown that N-acetylation or N-sulfation is permitted in the substitution pattern of residues adjacent to and within, the first glucosamine residue, the pentasaccharide and that specific residues outside of the pentasaccharide region active for AT can influence AT activity [74][75][76][77][78]. This reinforces the idea that binding, even with low affinity, does not necessarily equate to activity.…”

Section: Antithrombin-heparin Pentasaccharide: An Exception That Doesmentioning

confidence: 99%

Heparan sulfate and heparin interactions with proteins

Meneghetti

Hughes

Rudd

et al. 2015

J. R. Soc. Interface.

256

241

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Heparan sulfate (HS) polysaccharides are ubiquitous components of the cell surface and extracellular matrix of all multicellular animals, whereas heparin is present within mast cells and can be viewed as a more sulfated, tissuespecific, HS variant. HS and heparin regulate biological processes through interactions with a large repertoire of proteins. Owing to these interactions and diverse effects observed during in vitro, ex vivo and in vivo experiments, manifold biological/pharmacological activities have been attributed to them. The properties that have been thought to bestow protein binding and biological activity upon HS and heparin vary from high levels of sequence specificity to a dependence on charge. In contrast to these opposing opinions, we will argue that the evidence supports both a level of redundancy and a degree of selectivity in the structure-activity relationship. The relationship between this apparent redundancy, the multi-dentate nature of heparin and HS polysaccharide chains, their involvement in protein networks and the multiple binding sites on proteins, each possessing different properties, will also be considered. Finally, the role of cations in modulating HS/heparin activity will be reviewed and some of the implications for structure-activity relationships and regulation will be discussed.

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“…[2]) this sequence was reproduced by total chemical synthesis, which led to the anticoagulant drug Fondaparinux and several follow up compounds. [3,4] The availability of homogeneous synthetic compounds allowed X-ray crystallography [5][6][7][8] and NMR studies [9][10][11][12][13][14] for ap lethora of heparinb inding oligosaccharides. All these results supported the strict specificity of the AGA*IA sequence in the heparin-AT recognition.B ased on theses tudies and on enzyme kinetics,a modelw as proposed to explain the two-stepA Tb inding and activation by heparin.…”

Section: Introductionmentioning

confidence: 99%

Degeneracy of the Antithrombin Binding Sequence in Heparin: 2‐O‐Sulfated Iduronic Acid Can Replace the Critical Glucuronic Acid

Elli

Stancanelli

Wang

et al. 2020

Chemistry A European J

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Heparin binds to and activates antithrombin (AT) through a specific pentasaccharide sequence, in which a trisaccharide subsite, containing glucuronic acid (GlcA), has been considered as the initiator in the recognition of the polysaccharide by the protein. Recently it was suggested that sulfated iduronic acid (IdoA2S) could replace this “canonical” GlcA. Indeed, a heparin octasaccharidic sequence obtained by chemoenzymatic synthesis, in which GlcA is replaced with IdoA2S, has been found to similarly bind to and activate antithrombin. By using saturation‐transfer‐difference (STD) NMR, NOEs, transferred NOEs (tr‐NOEs) NMR and molecular dynamics, we show that, upon binding to AT, this IdoA2S unit develops comparable interactions with AT as GlcA. Interestingly, two IdoA2S units, both present in a 1C4‐2S0 equilibrium in the unbound saccharide, shift to full 2S0 and full 1C4 upon binding to antithrombin, providing the best illustration of the critical role of iduronic acid conformational flexibility in biological systems.

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Antithrombin-binding oligosaccharides: structural diversities in a unique function?

Cited by 30 publications

References 55 publications

Synthesis of 3-O-Sulfated Oligosaccharides to Understand the Relationship between Structures and Functions of Heparan Sulfate

Synthesis of 3-O-Sulfated Oligosaccharides to Understand the Relationship between Structures and Functions of Heparan Sulfate

Heparan sulfate and heparin interactions with proteins

Degeneracy of the Antithrombin Binding Sequence in Heparin: 2‐O‐Sulfated Iduronic Acid Can Replace the Critical Glucuronic Acid

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