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Biomolecules Jan 2023Glycosaminoglycans (GAGs) are a class of linear anionic periodic polysaccharides containing disaccharide repetitive units. These molecules interact with a variety of...
Glycosaminoglycans (GAGs) are a class of linear anionic periodic polysaccharides containing disaccharide repetitive units. These molecules interact with a variety of proteins in the extracellular matrix and so participate in biochemically crucial processes such as cell signalling affecting tissue regeneration as well as the onset of cancer, Alzheimer's or Parkinson's diseases. Due to their flexibility, periodicity and chemical heterogeneity, often termed "sulfation code", GAGs are challenging molecules both for experiments and computation. One of the key questions in the GAG research is the specificity of their intermolecular interactions. In this study, we make a step forward to deciphering the "sulfation code" of chondroitin sulfates-4,6 (CS4, CS6, where the numbers correspond to the position of sulfation in NAcGal residue) and dermatan sulfate (DS), which is different from CSs by the presence of IdoA acid instead of GlcA. We rigorously investigate two sets of these GAGs in dimeric, tetrameric and hexameric forms with molecular dynamics-based descriptors. Our data clearly suggest that CS4, CS6 and DS are substantially different in terms of their structural, conformational and dynamic properties, which contributes to the understanding of how these molecules can be different when they bind proteins, which could have practical implications for the GAG-based drug design strategies in the regenerative medicine.
Topics: Dermatan Sulfate; Molecular Dynamics Simulation; Chondroitin Sulfates; Glycosaminoglycans; Sulfates
PubMed: 36830616
DOI: 10.3390/biom13020247 -
Carbohydrate Polymers Jun 2014The lumpsucker, Cyclopterus lumpus, a cottoid teleost fish found in the cold waters of the North Atlantic, and North Pacific, was identified as a possible source of...
The lumpsucker, Cyclopterus lumpus, a cottoid teleost fish found in the cold waters of the North Atlantic, and North Pacific, was identified as a possible source of GAGs. The GAGs present in the C. lumpus dorsal hump and body wall tissue were isolated and purified. Two fractions were analysed by NMR and their GAG structures determined as hyaluronic acid and CS/DS chains. The latter fraction contained GlcA (65% of the total uronic acids) and IdoA (the remaining 35%). All uronic acid residues were unsulfated, whilst 86% of the GalNAc was 4-sulfated and 14% was 6-sulfated. The presence of GlcA-GalNAc4S, IdoA-GalNAc4S and GlcA-GalNAc6S disaccharide fragments was confirmed. The isolated GAGs obtained from each tissue were biochemically characterised. The lumpsucker offers a high yield source of GAGs, which compares favourably with other sources such as shark cartilage.
Topics: Animals; Chondroitin Sulfates; Dermatan Sulfate; Fishes; Hyaluronic Acid; Magnetic Resonance Spectroscopy; Oxidation-Reduction; Polymers
PubMed: 24721047
DOI: 10.1016/j.carbpol.2014.01.090 -
Human Mutation Dec 2011
A response to: loss of dermatan-4-sulfotransferase 1 (D4ST1/CHST14) function represents the first dermatan sulfate biosynthesis defect, "dermatan sulfate-deficient Adducted Thumb-Clubfoot Syndrome". Which name is appropriate, "Adducted Thumb-Clubfoot Syndrome" or "Ehlers-Danlos syndrome"?
Topics: Dermatan Sulfate; Humans; Sulfotransferases
PubMed: 21964831
DOI: 10.1002/humu.21586 -
The Journal of Biological Chemistry Nov 1985A dermatan sulfate proteoglycan has been isolated from a murine parietal yolk sac cell line, which in culture synthesizes basement membrane components. The proteoglycan...
A dermatan sulfate proteoglycan has been isolated from a murine parietal yolk sac cell line, which in culture synthesizes basement membrane components. The proteoglycan has a molecular weight of 200,000-300,000 with 10-15 dermatan sulfate chains of Mr = 14,000-16,000. The glycosaminoglycan chains carry sulfate residues predominantly attached to C-4 of the galactosamine unit; less than 10% of the sulfate groups occur as 6-sulfated galactosamine units. About 60% of the uronic acid residues are of the glucuronic configuration, the rest being iduronic acid. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of chondroitinase ABC-treated 125I-labeled proteoglycan reveals two polypeptides with molecular weights of 34,000 and 27,000. Results from papain digestion of the proteoglycan suggest that most of the polysaccharide chains are clustered at a papain-resistant segment of the core protein (Mr = 8,000). This proteoglycan is distinctly different from the large cartilage proteoglycan in the smaller size of its core protein, and its relationship to other small chondroitin and dermatan sulfate proteoglycans and to the chondroitin sulfate proteoglycan recently located in rat tissue basement membranes will be discussed.
Topics: Animals; Antibodies, Monoclonal; Basement Membrane; Cell Line; Chondroitin; Chromatography, Gel; Chromatography, Ion Exchange; Dermatan Sulfate; Mice; Molecular Weight; Proteins; Yolk Sac
PubMed: 4055755
DOI: No ID Found -
Blood Coagulation & Fibrinolysis : An... Jan 1996Low-molecular-weight (LMW)-dermatan sulfate (Desmin) with the mean molecular weight of 5600 Da has been obtained by limited depolymerization of natural dermatan sulfate....
Low-molecular-weight (LMW)-dermatan sulfate (Desmin) with the mean molecular weight of 5600 Da has been obtained by limited depolymerization of natural dermatan sulfate. The pharmacokinetic and pharmacodynamic data of 100 and 200 mg were analyzed after intravenous injection and of 50, 100 and 200 mg after subcutaneous injection on tissue factor pathway inhibitor (TFPI) antigen and activity, heparin cofactor (HC) II activity, HeptestTM coagulation value, chromogenic S-2222 anti-factor Xa (aXa) assay, activated partial thromboplastin time (APTT), thrombin clotting time (TCT), plasminogen, tissue plasminogen activator activity (t-PA) and plasminogen activator inhibitor (PAI). After i.v.injection of 100 mg and 200 mg Desmin TFPI antigen and activity increased 2.2- and 2.7-fold, and returned to normal values within 60 and 90 min, respectively. Using the HC II assay the elimination half-lives (T1/2 el) increased from 1.9 h to 3.3 h with increasing doses of LMW-dermatan sulfate. T1/2 el were 4.3 and 6.9 h with the Heptest assay and 3.3 and 5.1 with the aXa method, respectively. APTT, TCT and the fibrinolytic parameters were not modified by either dose of i.v. LMW-dermatan sulfate. After s.c. administration of 100 mg or 200 mg LMW-dermatan sulfate no increase of TFPI antigen or activity was detected. T1/2 el was 5.6 h using HC II method, 11.1 h using Heptest and 7.8 h with the aXa activity. The total clearance was about ten-fold higher when determined by the HC II method compared with Heptest and aXa method. The volume of distribution (VD) increased with increasing doses of s.c. LMW-dermatan sulfate and was highest with the HC II method. Intravenous administration of 100 mg protamine chloride 15 min after i.v. dosing of 100 mg LMW-dermatan sulfate did not modify TFPI, coagulation or fibrinolytic parameters. Further analysis of the complex mechanism of action has to include studies which should explain the low release of TFPI in relation to the antithrombotic effects of LMW-dermatan sulfate.
Topics: Anticoagulants; Biological Availability; Dermatan Sulfate; Female; Fibrinolytic Agents; Humans; Injections, Intravenous; Injections, Subcutaneous; Lipoproteins; Male; Molecular Weight; Protamines; Reference Values
PubMed: 8845462
DOI: 10.1097/00001721-199601000-00006 -
Comparative antithrombotic and hemorrhagic effects of dermatan sulfate, heparan sulfate and heparin.Thrombosis Research Nov 1990Dermatan sulfate and heparan sulfate are currently under development as potential antithrombotic drugs. In our studies we have evaluated the relative antithrombotic and... (Comparative Study)
Comparative Study
Dermatan sulfate and heparan sulfate are currently under development as potential antithrombotic drugs. In our studies we have evaluated the relative antithrombotic and bleeding effects of these two agents in comparison to heparin, the commonly used anticoagulant. In a rabbit model of stasis thrombosis, a 500 micrograms/kg IV dose of dermatan or heparan produced 50-60% inhibition of induced in vivo thrombosis. At 750 micrograms/kg, both agents produced greater than 75% inhibition of thrombosis. Ex vivo measurement of plasma samples obtained from these animals demonstrated variable clotting effects at the lower dose and a proportional increase in the clotting activity at the higher dose. No anti-Xa or anti-IIa activity was observed in any sample. In contrast, animals treated with only 100 micrograms/kg heparin showed complete inhibition of induced thrombosis with significant anti-Xa and anti-IIa activities as well as prolongation of the clotting assays (APTT, TT and HeptestR). In the hemorrhagic studies utilizing a rabbit ear blood loss model, a 5.0 mg/kg IV dose of dermatan or heparan produced much less blood loss than heparin. On a gravimetric basis, dermatan and heparan were 10 fold less hemorrhagic than heparin. These results indicate that the relative contribution of plasmatic and cellular sites to the mediation of the antithrombotic action of heparin, dermatan and heparan differ. Although the antithrombotic dosages of dermatan and heparan are higher than heparin, due to the different mechanisms of action of each agent, a better safety index may be provided by dermatan and heparan than heparin.
Topics: Animals; Blood Coagulation Tests; Dermatan Sulfate; Dose-Response Relationship, Drug; Fibrinolytic Agents; Hemorrhage; Heparin; Heparitin Sulfate; Rabbits
PubMed: 2084948
DOI: 10.1016/0049-3848(90)90180-k -
Expert Opinion on Pharmacotherapy May 2000Danaparoid sodium (Orgaran, Organon) is a heparinoid glycosamino-glycuronan antithrombotic agent approved for the prophylaxis of post-operative deep vein thrombosis... (Review)
Review
Danaparoid sodium (Orgaran, Organon) is a heparinoid glycosamino-glycuronan antithrombotic agent approved for the prophylaxis of post-operative deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE) in patients undergoing elective hip replacement surgery. Danaparoid is a low molecular weight heparinoid consisting of a mixture of heparan sulphate (84%), dermatan sulphate (12%) and small amounts of chondroitin sulphate (4%), whose antithrombotic activity has been well established. Its pharmacological effect is exerted primarily by inhibiting Factors Xa (FXa) and IIa (FIIa) at a ratio greater than heparin, with a minimal effect on platelet function. Danaparoid exhibits low cross-reactivity with heparin-induced antibodies when compared with heparin or low molecular weight heparins (LMWH), thereby making it an excellent choice for the management of heparin-induced thrombocytopenia (HIT). It has excellent bioavailability following s.c. injection. Danaparoid has little effect on routine coagulation tests (activated partial thromboplastin time [aPTT], prothrombin time [PT], and thrombin time [TT]). Patients with elevated serum creatinine should be monitored carefully. For its FDA approved indication (DVT prophylaxis during hip replacement surgery), its cost per day is approximately eight times more than LMWH. Even though monitoring is not routinely necessary according to the manufacturer for its approved indication, monitoring is frequently necessary when it is used in other clinical scenarios. Its higher cost than comparable therapies for DVT prophylaxis and the low availability of the FXa assay in most non-tertiary care hospitals has limited the widespread use of danaparoid. Danaparoid has been found to be effective in the treatment of HIT although this is an off label use, despite being the most frequent reason why danaparoid is used.
Topics: Anticoagulants; Blood Coagulation Disorders; Chondroitin Sulfates; Clinical Trials as Topic; Dermatan Sulfate; Drug Combinations; Fibrinolytic Agents; Heparitin Sulfate; Humans; Thrombocytopenia
PubMed: 11249517
DOI: 10.1517/14656566.1.4.803 -
Glycoconjugate Journal Dec 2000Dermatan sulfate was partially depolymerized with chondroitin ABC lyase to obtain an oligosaccharide mixture from which an unsaturated disulfated tetrasaccharide was...
Dermatan sulfate was partially depolymerized with chondroitin ABC lyase to obtain an oligosaccharide mixture from which an unsaturated disulfated tetrasaccharide was purified and characterized using nuclear magnetic resonance spectroscopy and electrospray ionization mass spectrometry. Chemical removal of the unsaturated uronate residue with mercuric acetate, followed by de-4-O-sulfation with arylsulfatase B (N-acetylgalactosamine 4-sulfatase) and N- acetylhexosaminidase catalyzed removal of the 2-acetamido-2-deoxy-D-galactospyranosyl residue at the non-reducing end afforded a monosulfated disaccharide of the structure alpha-L-idopyranosyluronic acid (1-->3)-alpha,beta-D-2-acetamido-2-deoxy-4-O-sulfo galactopyranose. This monosulfated disaccharide serves as a substrate for mammalian alpha-L-iduronidase as demonstrated using fluorophore assisted carbohydrate electrophoresis.
Topics: Animals; Chondroitin ABC Lyase; Dermatan Sulfate; Electrophoresis, Polyacrylamide Gel; Fluorescence; Iduronidase; Intestinal Mucosa; Magnetic Resonance Spectroscopy; Molecular Structure; N-Acetylgalactosamine-4-Sulfatase; Oligosaccharides; Spectrometry, Mass, Electrospray Ionization; Swine
PubMed: 11511807
DOI: 10.1023/a:1010956926518 -
Thrombosis and Haemostasis Aug 1987
Topics: Chondroitin; Dermatan Sulfate; Drug Contamination; Heparin
PubMed: 3672433
DOI: No ID Found -
Biochemical Society Transactions Nov 1991
Review
Topics: Animals; Chondroitin Sulfate Proteoglycans; Collagen; Connective Tissue; Dermatan Sulfate; Eye; Humans; Molecular Structure
PubMed: 1794574
DOI: 10.1042/bst0190866