Chemical Approaches to Define the Structure-Activity Relationship of Heparin-like Glycosaminoglycans

Noti, Christian; Seeberger, Peter H.

doi:10.1016/j.chembiol.2005.05.013

Cited by 129 publications

(94 citation statements)

References 162 publications

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“…It contains five O-sulfate groups, three N-sulfate groups, and two carboxylate moieties. In the antithrombin-pentasaccharide complex, these acidic groups are completely ionized and interact with the complementary amino acid side chains (Arg, Lys, Glu, and Asn) on the protein [11][12][13][14][15]. Despite its importance, the 3D molecular structure of native heparin and its simpler derivatives are not known.…”

Section: Introductionmentioning

confidence: 99%

Molecular structure of basic oligomeric building units of heparan-sulfate glycosaminoglycans

2010

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This study reports in detail the results of systematic large-scale theoretical investigations of the acidic dimeric structural units (D-E, E-F, F-G, and G-H) and pentamer D-E-F-G-H (fondaparinux) of the glycosaminoglycan heparin, and their anionic forms. The geometries and energies of these oligomers have been computed using HF/6-31G(d), Becke3LYP/6-31G(d), and Becke3LYP/ 6-311?G(d,p) methods. The optimized geometries indicate that the most stable structure of these units in the neutral state is stabilized via a system of intramolecular hydrogen bonds. The equilibrium structure of these species changed appreciably upon dissociation. Water has a remarkable effect on the geometry of the anions studied. Because of high negative charge, the solvent effect also resulted in an appreciable energetic stabilization of biologically active anionic forms of these glycosaminoglycans. The stable energy conformations around glycosidic bonds found for dimers and pentamer investigated are compared and discussed with the available experimental X-ray structural data for the structurally related heparinderived pentasaccharides in cocrystals with proteins.

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Section: Introductionmentioning

confidence: 99%

Molecular structure of basic oligomeric building units of heparan-sulfate glycosaminoglycans

2010

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“…GAGs are negatively charged molecules characterized by long, unbranched polysaccharide chains that contain a repeating disaccharide unit. The disaccharide units contain either of two modified sugars, N-acetylgalactosamine or N-acetylglucosamine, and a uronic acid such as glucuronate or iduronate (26,43,56).…”

Section: Introductionmentioning

confidence: 99%

Sulodexide: A Renewed Interest in This Glycosaminoglycan

Lauver

Lucchesi

2006

Cardiovascular Drug Reviews

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Glycosaminoglycans (GAGs) are the most abundant group of heteropolysaccharides found in the body. These long unbranched molecules contain a repeating disaccharide unit. GAGs are located primarily in the extracellular matrix or on the surface of cells. These molecules serve as lubricants in the joints while at the same time providing structural rigidity to cells. Sulodexide is a highly purified glycosaminoglycan composed of a fast mobility heparin fraction as well as dermatan sulfate. Sulodexide differs from other glycosaminoglycans, like heparin, by having a longer half-life and a reduced effect on systemic clotting and bleeding. In addition, sulodexide demonstrates a lipolytic activity that is increased in comparison to heparin. Oral administration of sulodexide results in the release of tissue plasminogen activator and an increase in fibrinolytic activities. An increasing body of research has demonstrated the safety and efficacy of sulodexide in a wide range of vascular pathologies.

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“…Heparin is produced exclusively in mast cells, cleaved to 15-kDa fragments, and sequestered in intracellular granules. Alternatively, HS is expressed by virtually all cell types as the glycan module of HS proteoglycans (9,10). Depending on the protein core, HS proteoglycans are either secreted or tethered to the plasma membrane, displaying their HS on the outer face (9,11).…”

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confidence: 99%

CCR2 Chemokines Bind Selectively to Acetylated Heparan Sulfate Octasaccharides

Schenauer

Sweeney

et al. 2007

Journal of Biological Chemistry

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Chemokines participate in well documented interactions with glycosaminoglycans (GAGs). Although many chemokine amino acid residues involved in binding have been identified, much less is known about the bound regions of GAG. Heparan sulfate (HS) is the predominant cell surface GAG, and its heterogeneous nature offers proteins a variety of structural motifs with which to interact. In the present study, we describe the interactions of three CC chemokines, MCP-1/CCL2, MCP-2/CCL8, and MCP-3/CCL7, with HS-derived oligosaccharides. To this end, we generated and characterized a complex HS octasaccharide library containing 17 different octasaccharide compositions based on acetyl and sulfate group content. Electrospray ionization mass spectrometry was used to detect chemokine-HS octasaccharide complexes in the bound state, and an affinity purification protocol was used to select and identify chemokine-binding octasaccharides from the complex mixture. The results indicate that HS octasaccharide sulfation is the foremost requirement for chemokine binding. However, within octasaccharides of constant charge density, acetylation is also observed to augment binding, suggesting that there may be as yet undiscovered specificity in the chemokine-HS interaction.Chemokines are a large class of cytokines that direct leukocyte migration during various physiological processes, including routine immune surveillance, development, and inflammation (1). These proteins exert their various functions by binding to and signaling through G-protein-coupled receptors within the leukocyte plasma membrane. Prior to signal transduction, chemokines are retained near their site of production by a separate interaction with cell surface and extracellular matrix glycosaminoglycans (GAGs).2 The interaction with GAGs is thought to maintain the required chemokine concentration gradient in the face of vascular flow and draining lymph nodes (2, 3). Moreover, GAG binding was recently shown to be essential for in vivo chemokine activity (4). Furthermore, many chemokines are capable of forming oligomeric structures. This property also seems to be required for in vivo activity, and can be induced by GAG binding (4 -7).GAGs are complex, linear, anionic, polysaccharides composed of repeating disaccharide units (8, 9). GAGs are broadly classified into four families, based on sugar composition, glycosidic bond linkage, and presence of specific structural modifications. These four families are as follows: heparan sulfate (HS)/heparin, chondroitin sulfate/dermatan sulfate, keratan sulfate, and hyaluronan. Heparin and HS (along with hyaluronan) are the principle protein-binding GAGs (9). Due to differences in localization of the heparinoids (heparin and HS), HS is thought to be the more relevant protein binding GAG. Heparin is produced exclusively in mast cells, cleaved to 15-kDa fragments, and sequestered in intracellular granules. Alternatively, HS is expressed by virtually all cell types as the glycan module of HS proteoglycans (9, 10). Depending on the protein core,...

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Chemical Approaches to Define the Structure-Activity Relationship of Heparin-like Glycosaminoglycans

Cited by 129 publications

References 162 publications

Molecular structure of basic oligomeric building units of heparan-sulfate glycosaminoglycans

Molecular structure of basic oligomeric building units of heparan-sulfate glycosaminoglycans

Sulodexide: A Renewed Interest in This Glycosaminoglycan

CCR2 Chemokines Bind Selectively to Acetylated Heparan Sulfate Octasaccharides

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