8,737 results on '"Iduronic Acid"'
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2. Synthesis of a Heparinoid Pentasaccharide Containing l-Guluronic Acid Instead of l-Iduronic Acid with Preserved Anticoagulant Activity.
- Author
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Herczeg M, Demeter F, Lisztes E, Racskó M, Tóth BI, Timári I, Bereczky Z, Kövér KE, and Borbás A
- Subjects
- Oligosaccharides pharmacology, Anticoagulants pharmacology, Mannose, Iduronic Acid, Heparinoids
- Abstract
l-Iduronic acid is a key constituent of heparin and heparan sulfate polysaccharides due to its unique conformational plasticity, which facilitates the binding of polysaccharides to proteins. At the same time, this is the synthetically most challenging unit of heparinoid oligosaccharides; therefore, there is a high demand for its replacement with a more easily accessible sugar unit. In the case of idraparinux, an excellent anticoagulant heparinoid pentasaccharide, we demonstrated that l-iduronic acid can be replaced by an easier-to-produce l-sugar while maintaining its essential biological activity. From the inexpensive d-mannose, through a highly functionalized phenylthio mannoside, the l-gulose donor was prepared by C-5 epimerization in 10 steps with excellent yield. This unit was incorporated into the pentasaccharide by α-selective glycosylation and oxidized to l-guluronic acid. The complete synthesis required only 36 steps, with 21 steps for the longest linear route. The guluronate containing pentasaccharide inhibited coagulation factor Xa by 50% relative to the parent compound, representing an excellent anticoagulant activity. To the best of our knowledge, this is the first biologically active heparinoid anticoagulant which contains a different sugar unit instead of l-iduronic acid.
- Published
- 2022
- Full Text
- View/download PDF
3. An N-linked tetrasaccharide from Halobacterium salinarum presents a novel modification, sulfation of iduronic acid at the O-3 position.
- Author
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Notaro A, Vershinin Z, Guan Z, Eichler J, and De Castro C
- Subjects
- Glycoproteins metabolism, Glycosylation, Oligosaccharides metabolism, Polysaccharides chemistry, Halobacterium salinarum metabolism, Iduronic Acid
- Abstract
Halobacterium salinarum, a halophilic archaeon that grows at near-saturating salt concentrations, provided the first example of N-glycosylation outside Eukarya. Yet, almost 50 years later, numerous aspects of such post-translational protein processing in this microorganism remain to be determined, including the architecture of glycoprotein-bound glycans. In the present report, nuclear magnetic resonance spectroscopy was used to define a tetrasaccharide N-linked to both archaellins, building blocks of the archaeal swimming device (the archaellum), and the S-layer glycoprotein that comprises the protein shell surrounding the Hbt. salinarum cell as β-GlcA(2S)-(1 → 4)-α-IdoA(3S)-(1 → 4)-β-GlcA-(1 → 4)-β-Glc-Asn. The structure of this tetrasaccharide fills gaps remaining from previous studies, including confirmation of the first known inclusion of iduronic acid in an archaeal N-linked glycan. At the same time, the sulfation of this iduronic acid at the O-3 position has not, to the best of our knowledge, been previously seen. As such, this may represent yet another unique facet of N-glycosylation in Archaea., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
4. TREM2 on microglia cell surface binds to and forms functional binary complexes with heparan sulfate modified with 6-O-sulfation and iduronic acid
- Author
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McMillan, Ilayda Ozsan, Liang, Li, Su, Guowei, Song, Xuehong, Drago, Kelly, Yang, Hua, Alvarez, Claudia, Sood, Amika, Gibson, James, Woods, Robert J., Wang, Chunyu, Liu, Jian, Zhang, Fuming, Brett, Tom J., and Wang, Lianchun
- Published
- 2024
- Full Text
- View/download PDF
5. Inhibition of iduronic acid biosynthesis by ebselen reduces glycosaminoglycan accumulation in mucopolysaccharidosis type I fibroblasts.
- Author
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Maccarana M, Tykesson E, Pera EM, Gouignard N, Fang J, Malmström A, Ghiselli G, and Li JP
- Subjects
- Dose-Response Relationship, Drug, Fibroblasts metabolism, Fibroblasts pathology, Glycosaminoglycans metabolism, HEK293 Cells, Humans, Iduronic Acid metabolism, Isoindoles chemistry, Molecular Structure, Mucopolysaccharidosis I metabolism, Mucopolysaccharidosis I pathology, Organoselenium Compounds chemistry, Structure-Activity Relationship, Fibroblasts drug effects, Glycosaminoglycans antagonists & inhibitors, Iduronic Acid antagonists & inhibitors, Isoindoles pharmacology, Mucopolysaccharidosis I drug therapy, Organoselenium Compounds pharmacology
- Abstract
Mucopolysaccharidosis type I (MPS-I) is a rare lysosomal storage disorder caused by deficiency of the enzyme alpha-L-iduronidase, which removes iduronic acid in both chondroitin/dermatan sulfate (CS/DS) and heparan sulfate (HS) and thereby contributes to the catabolism of glycosaminoglycans (GAGs). To ameliorate this genetic defect, the patients are currently treated by enzyme replacement and bone marrow transplantation, which have a number of drawbacks. This study was designed to develop an alternative treatment by inhibition of iduronic acid formation. By screening the Prestwick drug library, we identified ebselen as a potent inhibitor of enzymes that produce iduronic acid in CS/DS and HS. Ebselen efficiently inhibited iduronic acid formation during CS/DS synthesis in cultured fibroblasts. Treatment of MPS-I fibroblasts with ebselen not only reduced accumulation of CS/DS but also promoted GAG degradation. In early Xenopus embryos, this drug phenocopied the effect of downregulation of DS-epimerase 1, the main enzyme responsible for iduronic production in CS/DS, suggesting that ebselen inhibits iduronic acid production in vivo. However, ebselen failed to ameliorate the CS/DS and GAG burden in MPS-I mice. Nevertheless, the results propose a potential of iduronic acid substrate reduction therapy for MPS-I patients., (© The Author(s) 2021. Published by Oxford University Press.)
- Published
- 2021
- Full Text
- View/download PDF
6. d-Idose, d-Iduronic Acid, and d-Idonic Acid from d-Glucose via Seven-Carbon Sugars.
- Author
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Liu Z, Jenkinson SF, Yoshihara A, Wormald MR, Izumori K, and Fleet GWJ
- Subjects
- Carbohydrate Conformation, Glucose chemistry, Heptoses chemistry, Hexoses chemistry, Iduronic Acid chemistry, Molecular Structure, Sugar Acids chemistry, Hexoses chemical synthesis, Iduronic Acid chemical synthesis, Sugar Acids chemical synthesis
- Abstract
A practical synthesis of the very rare sugar d-idose and the stable building blocks for d-idose, d-iduronic, and d-idonic acids from ido -heptonic acid requires only isopropylidene protection, Shing silica gel-supported periodate cleavage of the C6-C7 bond of the heptonic acid, and selective reduction of C1 and/or C6. d-Idose is the most unstable of all the aldohexoses and a stable precursor which be stored and then converted under very mild conditions into d-idose is easily prepared.
- Published
- 2019
- Full Text
- View/download PDF
7. Sulfation Code and Conformational Plasticity of l-Iduronic Acid Homo-Oligosaccharides Mimic the Biological Functions of Heparan Sulfate.
- Author
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Shanthamurthy CD, Gimeno A, Leviatan Ben-Arye S, Kumar NV, Jain P, Padler-Karavani V, Jiménez-Barbero J, and Kikkeri R
- Subjects
- Magnetic Resonance Spectroscopy methods, Structure-Activity Relationship, Heparitin Sulfate chemistry, Iduronic Acid chemistry, Molecular Mimicry, Oligosaccharides chemistry, Sulfates chemistry
- Abstract
Recently, the activity of heparan sulfate (HS) has led to the discovery of many drug candidates that have the potential to impact both medical science and human health. However, structural diversity and synthetic challenges impede the progress of HS research. Here, we report a library of novel l-iduronic acid (IdoA)-based HS mimics that are highly tunable in conformation plasticity and sulfation patterns to produce many of the functions of native HS oligosaccharides. The NMR analysis of HS mimics confirmed that 4- O -sulfation enhances the population of the
1 C4 geometry. Interestingly, the1 C4 conformer becomes exclusive upon additional 2- O -sulfation. HS mimic microarray binding studies with different growth factors showed that selectivity and avidity are greatly modulated by the oligosaccharide length, sulfation code, and IdoA conformation. Particularly, we have identified 4- O -sulfated IdoA disaccharide ( I-21 ) as a potential ligand for vascular endothelial growth factor (VEGF165 ), which in a multivalent display modulated endothelial cell proliferation, migration, and angiogenesis. Overall, these results encourage the consideration of HS mimics for therapeutic applications.- Published
- 2021
- Full Text
- View/download PDF
8. Synthesis of a Heparinoid Pentasaccharide Containing <scp>l</scp>-Guluronic Acid Instead of <scp>l</scp>-Iduronic Acid with Preserved Anticoagulant Activity
- Author
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Mihály Herczeg, Fruzsina Demeter, Erika Lisztes, Márk Racskó, Balázs István Tóth, István Timári, Zsuzsanna Bereczky, Katalin E. Kövér, and Anikó Borbás
- Subjects
Heparinoids ,Iduronic Acid ,Organic Chemistry ,Oligosaccharides ,Anticoagulants ,Mannose - Abstract
l-Iduronic acid is a key constituent of heparin and heparan sulfate polysaccharides due to its unique conformational plasticity, which facilitates the binding of polysaccharides to proteins. At the same time, this is the synthetically most challenging unit of heparinoid oligosaccharides; therefore, there is a high demand for its replacement with a more easily accessible sugar unit. In the case of idraparinux, an excellent anticoagulant heparinoid pentasaccharide, we demonstrated that l-iduronic acid can be replaced by an easier-to-produce l-sugar while maintaining its essential biological activity. From the inexpensive d-mannose, through a highly functionalized phenylthio mannoside, the l-gulose donor was prepared by C-5 epimerization in 10 steps with excellent yield. This unit was incorporated into the pentasaccharide by α-selective glycosylation and oxidized to l-guluronic acid. The complete synthesis required only 36 steps, with 21 steps for the longest linear route. The guluronate containing pentasaccharide inhibited coagulation factor Xa by 50% relative to the parent compound, representing an excellent anticoagulant activity. To the best of our knowledge, this is the first biologically active heparinoid anticoagulant which contains a different sugar unit instead of l-iduronic acid.
- Published
- 2022
9. Protein interactome analysis of iduronic acid-containing glycosaminoglycans reveals a novel flagellar invasion factor MbhA
- Author
-
Hsiao, Felix Shih-Hsiang, Yang, Shyi-Kuen, Lin, Jun-Mu, Chen, Yi-Wen, and Chen, Chien-Sheng
- Published
- 2019
- Full Text
- View/download PDF
10. A combinatorial approach towards the synthesis of non-hydrolysable triazole-iduronic acid hybrid inhibitors of human α-l-iduronidase: discovery of enzyme stabilizers for the potential treatment of MPSI.
- Author
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Cheng WC, Lin CK, Li HY, Chang YC, Lu SJ, Chen YS, and Chang SY
- Subjects
- Click Chemistry, Enzyme Stability drug effects, Humans, Iduronic Acid chemistry, Iduronidase metabolism, Molecular Structure, Mucopolysaccharidosis I metabolism, Small Molecule Libraries chemistry, Triazoles chemistry, Drug Discovery, Iduronic Acid pharmacology, Iduronidase antagonists & inhibitors, Mucopolysaccharidosis I drug therapy, Small Molecule Libraries chemical synthesis, Small Molecule Libraries pharmacology, Triazoles pharmacology
- Abstract
Preparation of substituent-diverse, triazole-iduronic acid hybrid molecules by click reaction of an azido iduronic acid derivative with randomly chosen alkynes is described. Library members were screened for their ability to inhibit α-l-iduronidase, and hit molecules and analogues were then investigated for their ability to stabilize rh-α-IDUA in a thermal denaturation study. This work resulted in the discovery of the first small molecules that can be used to stabilize exogenous rh-α-IDUA protein in vitro.
- Published
- 2018
- Full Text
- View/download PDF
11. Inhibition of iduronic acid biosynthesis by ebselen reduces glycosaminoglycan accumulation in mucopolysaccharidosis type I fibroblasts
- Abstract
Mucopolysaccharidosis type I (MPS-I) is a rare lysosomal storage disorder caused by deficiency of the enzyme alpha-L-iduronidase, which removes iduronic acid in both chondroitin/dermatan sulfate (CS/DS) and heparan sulfate (HS) and thereby contributes to the catabolism of glycosaminoglycans (GAGs). To ameliorate this genetic defect, the patients are currently treated by enzyme replacement and bone marrow transplantation, which have a number of drawbacks. This study was designed to develop an alternative treatment by inhibition of iduronic acid formation. By screening the Prestwick drug library, we identified ebselen as a potent inhibitor of enzymes that produce iduronic acid in CS/DS and HS. Ebselen efficiently inhibited iduronic acid formation during CS/DS synthesis in cultured fibroblasts. Treatment of MPS-I fibroblasts with ebselen not only reduced accumulation of CS/DS but also promoted GAG degradation. In early Xenopus embryos, this drug phenocopied the effect of downregulation of DS-epimerase 1, the main enzyme responsible for iduronic production in CS/DS, suggesting that ebselen inhibits iduronic acid production in vivo. However, ebselen failed to ameliorate the CS/DS and GAG burden in MPS-I mice. Nevertheless, the results propose a potential of iduronic acid substrate reduction therapy for MPS-I patients.
- Published
- 2021
- Full Text
- View/download PDF
12. Conformational Modulation of Iduronic Acid-Containing Sulfated Glycosaminoglycans by a Polynuclear Platinum Compound and Implications for Development of Antimetastatic Platinum Drugs.
- Author
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Gorle AK, Haselhorst T, Katner SJ, Everest-Dass AV, Hampton JD, Peterson EJ, Koblinski JE, Katsuta E, Takabe K, von Itzstein M, Berners-Price SJ, and Farrell NP
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Cell Line, Tumor, Cell Movement drug effects, Density Functional Theory, Heparitin Sulfate chemistry, Humans, Magnetic Resonance Spectroscopy, Molecular Conformation, Organoplatinum Compounds chemical synthesis, Organoplatinum Compounds pharmacology, Antineoplastic Agents chemistry, Glycosaminoglycans chemistry, Iduronic Acid chemistry, Organoplatinum Compounds chemistry, Platinum chemistry
- Abstract
1 H NMR spectroscopic studies on the 1:1 adduct of the pentasaccharide Fondaparinux (FPX) and the substitution-inert polynuclear platinum complex TriplatinNC show significant modulation of geometry around the glycosidic linkages of the FPX constituent monosaccharides. FPX is a valid model for the highly sulfated cell signalling molecule heparan sulfate (HS). The conformational ratio of the1 C4 :2 S0 forms of the FPX residue IdoA(2S) is altered from ca. 35:65 (free FPX) to ca. 75:25 in the adduct; the first demonstration of a small molecule affecting conformational changes on a HS oligosaccharide. Functional consequences of such binding are suggested to be inhibition of HS cleavage in MDA-MB-231 triple-negative breast cancer (TNBC) cells. We further describe inhibition of metastasis by TriplatinNC in the TNBC 4T1 syngeneic tumour model. Our work provides insight into a novel approach for design of platinum drugs (and coordination compounds in general) with intrinsic anti-metastatic potential., (© 2020 Wiley-VCH GmbH.)- Published
- 2021
- Full Text
- View/download PDF
13. Synthetic di-sulfated iduronic acid attenuates asthmatic response by blocking T-cell recruitment to inflammatory sites
- Author
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Nonaka, Motohiro, Bao, Xingfeng, Matsumura, Fumiko, Götze, Sebastian, Kandasamy, Jeyakumar, Kononov, Andrew, Broide, David H., Nakayama, Jun, Seeberger, Peter H., and Fukuda, Minoru
- Published
- 2014
14. Degeneracy of the Antithrombin Binding Sequence in Heparin: 2-O-Sulfated Iduronic Acid Can Replace the Critical Glucuronic Acid.
- Author
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Elli S, Stancanelli E, Wang Z, Petitou M, Liu J, and Guerrini M
- Subjects
- Anticoagulants pharmacology, Antithrombins metabolism, Magnetic Resonance Spectroscopy, Molecular Conformation, Sulfates chemistry, Anticoagulants chemistry, Antithrombins chemistry, Glucuronic Acid chemistry, Heparin chemistry, Iduronic Acid chemistry, Oligosaccharides chemistry, Polysaccharides chemistry
- Abstract
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
1 C4 -2 S0 equilibrium in the unbound saccharide, shift to full2 S0 and full1 C4 upon binding to antithrombin, providing the best illustration of the critical role of iduronic acid conformational flexibility in biological systems., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)- Published
- 2020
- Full Text
- View/download PDF
15. A method for measuring disease-specific iduronic acid from the non-reducing end of glycosaminoglycan in mucopolysaccharidosis type II mice.
- Author
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Shimada Y, Wakabayashi T, Akiyama K, Hoshina H, Higuchi T, Kobayashi H, Eto Y, Ida H, and Ohashi T
- Subjects
- Animals, Biomarkers metabolism, Cerebrum metabolism, Enzyme Replacement Therapy, Female, Humans, Iduronate Sulfatase chemistry, Iduronate Sulfatase therapeutic use, Iduronic Acid chemistry, Iduronidase chemistry, Iduronidase therapeutic use, Liver metabolism, Mice, Inbred C57BL, Mucopolysaccharidosis II drug therapy, Mucopolysaccharidosis II metabolism, Glycosaminoglycans metabolism, Iduronic Acid metabolism, Mucopolysaccharidosis II diagnosis
- Abstract
Mucopolysaccharidosis type II (MPS II) is an X-linked lysosomal storage disorder arising from deficiency of iduronate-2-sulfatase (IDS), which results in progressive accumulation of glycosaminoglycans (GAGs) in multiple tissues. Accumulated GAGs are generally measured as the amount of total GAGs. However, we recently demonstrated that GAG accumulation in the brain of MPS II model mice cannot be reliably detected by conventional dye-binding assay measuring total GAGs. Here we developed a novel quantitative method for measurement of disease-specific GAGs based on the analysis of 2-sulfoiduronic acid levels derived from the non-reducing terminal end of the polysaccharides by using recombinant human IDS (rhIDS) and recombinant human iduronidase (rhIDUA). This method was evaluated on GAGs obtained from the liver and brain of MPS II mice. The GAGs were purified from tissue homogenates and then digested with rhIDS and rhIDUA to generate a desulfated iduronic acid from their non-reducing terminal end. HPLC analysis revealed that the generated iduronic acid levels were markedly increased in the liver and cerebrum of the MPS II mice, whereas the uronic acid was not detected in wild-type mice. These results indicate that this assay clearly detects the disease-specific GAGs in tissues from MPS II mice., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
16. Interacting polymer-modification enzymes in heparan sulfate biosynthesis.
- Author
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Zhang T, Yu M, Li H, Maccarana M, Zhang W, Shi D, Kan Y, Zhang X, Chi L, Lindahl U, Li H, Li JP, and Tan T
- Subjects
- Glucuronic Acid, Polymers, Protons, Racemases and Epimerases, Sulfotransferases, Heparitin Sulfate, Multienzyme Complexes, Iduronic Acid
- Abstract
Glucuronyl 5-epimerase (Hsepi) converts D-glucuronic acid (GlcA) into L-iduronic acid (IdoA) units, through a mechanism involving reversible abstraction of a proton at C5 of hexuronic acid residues. Incubations of a [4GlcAβ1-4GlcNSO
3 α1-]n precursor substrate with recombinant enzymes in a D2 O/H2 O medium enabled an isotope exchange approach to the assessment of functional interactions of Hsepi with hexuronyl 2-O-sulfotransferase (Hs2st) and glucosaminyl 6-O-sulfotransferase (Hs6st), both involved in the final polymer-modification steps. Enzyme complexes were supported by computational modeling and homogeneous time resolved fluorescence. GlcA and IdoA D/H ratios related to product composition revealed kinetic isotope effects that were interpreted in terms of efficiency of the coupled epimerase and sulfotransferase reactions. Evidence for a functional Hsepi/Hs6st complex was provided by selective incorporation of D atoms into GlcA units adjacent to 6-O-sulfated glucosamine residues. The inability to achieve simultaneous 2-O- and 6-O-sulfation in vitro supported topologically separated reactions in the cell. These findings provide novel insight into the roles of enzyme interactions in heparan sulfate biosynthesis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Ltd.)- Published
- 2023
- Full Text
- View/download PDF
17. Inhibition of iduronic acid biosynthesis by ebselen reduces glycosaminoglycan accumulation in mucopolysaccharidosis type I fibroblasts
- Author
-
Marco Maccarana, Jianping Fang, Edgar M. Pera, Emil Tykesson, Anders Malmström, Giancarlo Ghiselli, Jin-Ping Li, and Nadège Gouignard
- Subjects
Iduronic Acid ,AcademicSubjects/SCI01000 ,Mucopolysaccharidosis I ,Iduronic acid ,Isoindoles ,Biochemistry ,Dermatan sulfate ,Glycosaminoglycan ,Mucopolysaccharidosis type I ,chemistry.chemical_compound ,Structure-Activity Relationship ,chondroitin dermatan sulfate ,Organoselenium Compounds ,Humans ,Glycosaminoglycans ,chemistry.chemical_classification ,Genetic Disorders of Glycosylation ,Dose-Response Relationship, Drug ,Molecular Structure ,Ebselen ,Catabolism ,mucopolysaccharidosis type I ,Heparan sulfate ,Fibroblasts ,Molecular biology ,substrate reduction therapy ,Enzyme ,HEK293 Cells ,chemistry ,epimerases ,ebselen - Abstract
Mucopolysaccharidosis type I (MPS-I) is a rare lysosomal storage disorder caused by deficiency of the enzyme alpha-L-iduronidase, which removes iduronic acid in both chondroitin/dermatan sulfate (CS/DS) and heparan sulfate (HS) and thereby contributes to the catabolism of glycosaminoglycans (GAGs). To ameliorate this genetic defect, the patients are currently treated by enzyme replacement and bone marrow transplantation, which have a number of drawbacks. This study was designed to develop an alternative treatment by inhibition of iduronic acid formation. By screening the Prestwick drug library, we identified ebselen as a potent inhibitor of enzymes that produce iduronic acid in CS/DS and HS. Ebselen efficiently inhibited iduronic acid formation during CS/DS synthesis in cultured fibroblasts. Treatment of MPS-I fibroblasts with ebselen not only reduced accumulation of CS/DS but also promoted GAG degradation. In early Xenopus embryos, this drug phenocopied the effect of downregulation of DS-epimerase 1, the main enzyme responsible for iduronic production in CS/DS, suggesting that ebselen inhibits iduronic acid production in vivo. However, ebselen failed to ameliorate the CS/DS and GAG burden in MPS-I mice. Nevertheless, the results propose a potential of iduronic acid substrate reduction therapy for MPS-I patients.
- Published
- 2021
18. d-Idose, d-Iduronic Acid, and d-Idonic Acid from d-Glucose via Seven-Carbon Sugars
- Author
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Zilei Liu, Sarah F. Jenkinson, Akihide Yoshihara, Mark R. Wormald, Ken Izumori, and George W. J. Fleet
- Subjects
rare sugar ,d-idose ,d-iduronic acid ,d-idonic acid ,monosaccharide ,Organic chemistry ,QD241-441 - Abstract
A practical synthesis of the very rare sugar d-idose and the stable building blocks for d-idose, d-iduronic, and d-idonic acids from ido-heptonic acid requires only isopropylidene protection, Shing silica gel-supported periodate cleavage of the C6-C7 bond of the heptonic acid, and selective reduction of C1 and/or C6. d-Idose is the most unstable of all the aldohexoses and a stable precursor which be stored and then converted under very mild conditions into d-idose is easily prepared.
- Published
- 2019
- Full Text
- View/download PDF
19. Synthetic Approaches to L-Iduronic Acid and L-Idose: Key Building Blocks for the Preparation of Glycosaminoglycan Oligosaccharides.
- Author
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Mohamed S and Ferro V
- Subjects
- Carbohydrate Conformation, Glycosaminoglycans chemistry, Hexoses chemistry, Iduronic Acid chemistry, Oligosaccharides chemistry, Stereoisomerism, Glycosaminoglycans chemical synthesis, Hexoses chemical synthesis, Iduronic Acid chemical synthesis, Oligosaccharides chemical synthesis
- Abstract
L-Iduronic acid (IdoA) is an important monosaccharide component of glycosaminoglycans (GAGs) such as heparin, heparan sulfate and dermatan sulfate. GAGs are complex, highly sulfated polysaccharides that mediate a multitude of physiological and pathological processes via their interactions with a range of diverse proteins. The main challenge in the synthesis of GAG oligosaccharides is the efficient gram-scale preparation of IdoA building blocks since neither IdoA nor L-idose is commercially available or readily accessible from natural sources. In this review, the different synthetic approaches for the preparation of IdoA and its derivatives, including L-idose, are presented and discussed. Derivatives of the latter are often used in GAG synthesis and are elaborated to IdoA via selective oxidation at C-6 after incorporation into a GAG chain. Particular focus will be given to the preparation of IdoA synthons most commonly used for GAG oligosaccharide synthesis, and on the progress made since the last systematic review in this area., (© 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
20. Synthesis of L-iduronic acid derivatives via [3.2.1] and [2.2.2] L-iduronic lactones from bulk glucose-derived cyanohydrin hydrolysis: a reversible conformationally switched superdisarmed/rearmed lactone route to heparin disaccharides.
- Author
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Hansen SU, Dalton CE, Baráth M, Kwan G, Raftery J, Jayson GC, Miller GJ, and Gardiner JM
- Subjects
- Hydrolysis, Iduronic Acid chemistry, Lactones, Magnetic Resonance Spectroscopy, Molecular Conformation, Heparin analogs & derivatives, Heparin chemistry, Iduronic Acid chemical synthesis, Nitriles chemistry, Oligosaccharides chemistry
- Abstract
L-Idofuranoside cyanohydrin 1 is converted on large scale into a mixture of L-IdoA methyl pyranosides and furanosides, which is converged to provide short 2-step routes to bicyclic [3.2.1] or [2.2.2] L-iduronate lactones. The former is obtained via a 100 g scale synthesis of 3-OBn L-IdoA. A two-step conversion of this mixture provides either pure anomer of the novel [2.2.2] l-iduronate thioglycoside lactones. Both [3.2.1] and [2.2.2] lactones are converted into GlcN-IdoA heparin precursor disaccharides. The [2.2.2] lactone enables a scalable 3-step route from 1 to a new type of highly disarmed O-4 iduronate thioglycoside, which is an effective acceptor with glucoazide thioglycoside donors. The resulting new iduronic [2.2.2] lactone disaccharides are readily rearmed by mild methanolysis to provide GlcN-IdoA thiophenyl disaccharide donors, intercepting their established utility for the assembly of both heparin- and heparan sulfate-like oligosaccharides. The [2.2.2] lactonization acts as a conformational switch to superdisarm iduronate components, reversible by lactone ring opening. In addition, the separated 2,4-diacetates also provide short access to all four anomeric and ring size isomers of l-iduronic acid methyl glycosides, including the first syntheses of the parent idofuranosides. X-ray structures are reported for a [2.2.2] iduronate lactone and examples of both methyl L-idopyranoside and novel methyl-L-idofuranoside systems.
- Published
- 2015
- Full Text
- View/download PDF
21. An N-linked tetrasaccharide from Halobacterium salinarum presents a novel modification, sulfation of iduronic acid at the O-3 position
- Author
-
Anna Notaro, Zlata Vershinin, Ziqiang Guan, Jerry Eichler, Cristina De Castro, Notaro, A., Vershinin, Z., Guan, Z., Eichler, J., and De Castro, C.
- Subjects
Halobacterium salinarum ,Glycosylation ,Polysaccharides ,Iduronic Acid ,Organic Chemistry ,Oligosaccharides ,General Medicine ,Glycoprotein ,Polysaccharide ,Biochemistry ,Analytical Chemistry ,Glycoproteins ,Oligosaccharide - Abstract
Halobacterium salinarum, a halophilic archaeon that grows at near-saturating salt concentrations, provided the first example of N-glycosylation outside Eukarya. Yet, almost 50 years later, numerous aspects of such post-translational protein processing in this microorganism remain to be determined, including the architecture of glycoprotein-bound glycans. In the present report, nuclear magnetic resonance spectroscopy was used to define a tetrasaccharide N-linked to both archaellins, building blocks of the archaeal swimming device (the archaellum), and the S-layer glycoprotein that comprises the protein shell surrounding the Hbt. salinarum cell as β-GlcA(2S)-(1 → 4)-α-IdoA(3S)-(1 → 4)-β-GlcA-(1 → 4)-β-Glc-Asn. The structure of this tetrasaccharide fills gaps remaining from previous studies, including confirmation of the first known inclusion of iduronic acid in an archaeal N-linked glycan. At the same time, the sulfation of this iduronic acid at the O-3 position has not, to the best of our knowledge, been previously seen. As such, this may represent yet another unique facet of N-glycosylation in Archaea.
- Published
- 2022
22. Degeneracy of the Antithrombin Binding Sequence in Heparin: 2‐O‐Sulfated Iduronic Acid Can Replace the Critical Glucuronic Acid
- Author
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Marco Guerrini, Jian Liu, Zhangjie Wang, Maurice Petitou, Eduardo Stancanelli, and Stefano Elli
- Subjects
Magnetic Resonance Spectroscopy ,Iduronic Acid ,Stereochemistry ,Glycoconjugate ,Molecular Conformation ,Oligosaccharides ,Iduronic acid ,Plasma protein binding ,010402 general chemistry ,01 natural sciences ,Antithrombins ,Catalysis ,chemistry.chemical_compound ,Sulfation ,Molecular recognition ,Glucuronic Acid ,Polysaccharides ,medicine ,chemistry.chemical_classification ,Heparin ,Sulfates ,010405 organic chemistry ,Organic Chemistry ,Antithrombin ,Anticoagulants ,General Chemistry ,Glucuronic acid ,0104 chemical sciences ,chemistry ,medicine.drug - Abstract
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 1 C4 -2 S0 equilibrium in the unbound saccharide, shift to full 2 S0 and full 1 C4 upon binding to antithrombin, providing the best illustration of the critical role of iduronic acid conformational flexibility in biological systems.
- Published
- 2020
23. From d-glucuronic acid to l-iduronic acid derivatives via a radical tandem decarboxylation–cyclization
- Author
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Salamone, Stéphane, Boisbrun, Michel, Didierjean, Claude, and Chapleur, Yves
- Published
- 2014
- Full Text
- View/download PDF
24. Occurrence of L-iduronic acid and putative D-glucuronyl C5-epimerases in prokaryotes
- Author
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Raedts, John, Kengen, Servé W. M., and van der Oost, John
- Published
- 2011
- Full Text
- View/download PDF
25. Sulfation Code and Conformational Plasticity of l-Iduronic Acid Homo-Oligosaccharides Mimic the Biological Functions of Heparan Sulfate
- Author
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Jesús Jiménez-Barbero, Prashant Jain, Nanjundaswamy Vijendra Kumar, Ragahvendra Kikkeri, Ana Gimeno, Shani Leviatan Ben-Arye, Chethan D. Shanthamurthy, and Vered Padler-Karavani
- Subjects
chemistry.chemical_classification ,education.field_of_study ,Magnetic Resonance Spectroscopy ,Angiogenesis ,Iduronic Acid ,Sulfates ,Population ,Molecular Mimicry ,Disaccharide ,Oligosaccharides ,Iduronic acid ,General Medicine ,Heparan sulfate ,Oligosaccharide ,Ligand (biochemistry) ,Biochemistry ,chemistry.chemical_compound ,Structure-Activity Relationship ,Sulfation ,chemistry ,Molecular Medicine ,Heparitin Sulfate ,education - Abstract
Recently, the activity in heparan sulfate (HS) has led to the discovery of many drug molecules that have the potential to impact both medical science and human health. However, structural diversity and synthetic challenges impede the progress of HS research. Here we show that synthetic HS mimics can be engineered to produce many of the functions of native HS. HS mimics were synthesized from an L-Iduronic acid (IdoA) scaffold, which was homooligomerized by stereoselective α-1,4-glycosylation and regioselective sulfation. The exhaustive NMR analysis of these HS mimics, using both NOE and vicinal 3JH-H coupling constants, confirmed that sulfation at the O-4 enhances the 1C4 geometry population at the corresponding ring. Interestingly, the 1C4 conformer becomes almost exclusive upon additional sulfation at O-2. Microarray and SPR analysis of HS mimics with different growth factors established that oligosaccharide length, sulfation code, and exclusive IdoA conformation synergistically affect the specificity and activity of growth factors. Particularly, 4-O-sulfated IdoA disaccharide had a strong binding affinity to vascular endothelial growth factor (VEGF165) and therefore, modulated endothelial cell proliferation, migration, and angiogenesis. These results establish the potential of sulfated IdoA oligosaccharides to be used as structurally well-defined HS mimics as they provide several functions of native HS.
- Published
- 2021
26. Determination of iduronic acid and glucuronic acid in sulfated chondroitin/dermatan hybrid chains by 1H-nuclear magnetic resonance spectroscopy
- Author
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Li, Fuchuan, Yamada, Shuhei, Basappa, Shetty, Ajaya K., Sugiura, Makiko, and Sugahara, Kazuyuki
- Published
- 2008
- Full Text
- View/download PDF
27. The glycosaminoglycan interactome 2.0.
- Author
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Vallet SD, Berthollier C, and Ricard-Blum S
- Subjects
- Heparitin Sulfate metabolism, Hyaluronic Acid, Proteoglycans metabolism, Glycosaminoglycans chemistry, Glycosaminoglycans metabolism, Iduronic Acid
- Abstract
Glycosaminoglycans (GAGs) are complex linear polysaccharides, which are covalently attached to core proteins (except for hyaluronan) to form proteoglycans. They play key roles in the organization of the extracellular matrix, and at the cell surface where they contribute to the regulation of cell signaling and of cell adhesion. To explore the mechanisms and pathways underlying their functions, we have generated an expanded dataset of 4,290 interactions corresponding to 3,464 unique GAG-binding proteins, four times more than the first version of the GAG interactome (Vallet, Clerc, and Ricard-Blum. J Histochem Cytochem 69: 93-104, 2021). The increased size of the GAG network is mostly due to the addition of GAG-binding proteins captured from cell lysates and biological fluids by affinity chromatography and identified by mass spectrometry. We review here the interaction repertoire of natural GAGs and of synthetic sulfated hyaluronan, the specificity and molecular functions of GAG-binding proteins, and the biological processes and pathways they are involved in. This dataset is also used to investigate the differences between proteins binding to iduronic acid-containing GAGs (dermatan sulfate and heparin/heparan sulfate) and those interacting with GAGs lacking iduronic acid (chondroitin sulfate, hyaluronan, and keratan sulfate).
- Published
- 2022
- Full Text
- View/download PDF
28. Replacement of the L-iduronic acid unit of the anticoagulant pentasaccharide idraparinux by a 6-deoxy-L-talopyranose - Synthesis and conformational analysis.
- Author
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Demeter F, Gyöngyösi T, Bereczky Z, Kövér KE, Herczeg M, and Borbás A
- Subjects
- Anticoagulants therapeutic use, Deoxy Sugars chemical synthesis, Heparin chemistry, Hexoses chemical synthesis, Humans, Iduronic Acid chemistry, Magnetic Resonance Spectroscopy, Oligosaccharides therapeutic use, Sulfonic Acids chemistry, Anticoagulants chemistry, Deoxy Sugars chemistry, Hexoses chemistry, Molecular Conformation, Oligosaccharides chemistry
- Abstract
One critical part of the synthesis of heparinoid anticoagulants is the creation of the L-iduronic acid building block featured with unique conformational plasticity which is crucial for the anticoagulant activity. Herein, we studied whether a much more easily synthesizable sugar, the 6-deoxy-L-talose, built in a heparinoid oligosaccharide, could show a similar conformational plasticity, thereby can be a potential substituent of the L-idose. Three pentasaccharides related to the synthetic anticoagulant pentasaccharide idraparinux were prepared, in which the L-iduronate was replaced by a 6-deoxy-L-talopyranoside unit. The talo-configured building block was formed by C4 epimerisation of the commercially available L-rhamnose with high efficacy at both the monosaccharide and the disaccharide level. The detailed conformational analysis of these new derivatives, differing only in their methylation pattern, was performed and the conformationally relevant NMR parameters, such as proton-proton coupling constants and interproton distances were compared to the corresponding ones measured in idraparinux. The lack of anticoagulant activity of these novel heparin analogues could be explained by the biologically not favorable
1 C4 chair conformation of their 6-deoxy-L-talopyranoside residues.- Published
- 2018
- Full Text
- View/download PDF
29. Iduronic acid in chondroitin/dermatan sulfate affects directional migration of aortic smooth muscle cells.
- Author
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Bartolini B, Thelin MA, Svensson L, Ghiselli G, van Kuppevelt TH, Malmström A, and Maccarana M
- Subjects
- Animals, Aorta cytology, Carbohydrate Epimerases deficiency, Carbohydrate Epimerases metabolism, Cell Adhesion, Cell Movement, Focal Adhesion Kinase 1 genetics, Focal Adhesion Kinase 1 metabolism, Focal Adhesions, Gene Expression, Iduronic Acid metabolism, Mice, Mice, Knockout, Myocytes, Smooth Muscle cytology, Primary Cell Culture, Aorta metabolism, Carbohydrate Epimerases genetics, Chondroitin Sulfates chemistry, Dermatan Sulfate chemistry, Iduronic Acid chemistry, Myocytes, Smooth Muscle metabolism
- Abstract
Aortic smooth muscle cells produce chondroitin/dermatan sulfate (CS/DS) proteoglycans that regulate extracellular matrix organization and cell behavior in normal and pathological conditions. A unique feature of CS/DS proteoglycans is the presence of iduronic acid (IdoA), catalyzed by two DS epimerases. Functional ablation of DS-epi1, the main epimerase in these cells, resulted in a major reduction of IdoA both on cell surface and in secreted CS/DS proteoglycans. Downregulation of IdoA led to delayed ability to re-populate wounded areas due to loss of directional persistence of migration. DS-epi1-/- aortic smooth muscle cells, however, had not lost the general property of migration showing even increased speed of movement compared to wild type cells. Where the cell membrane adheres to the substratum, stress fibers were denser whereas focal adhesion sites were fewer. Total cellular expression of focal adhesion kinase (FAK) and phospho-FAK (pFAK) was decreased in mutant cells compared to control cells. As many pathological conditions are dependent on migration, modulation of IdoA content may point to therapeutic strategies for diseases such as cancer and atherosclerosis.
- Published
- 2013
- Full Text
- View/download PDF
30. Synthesis of a bicyclic analog of L-iduronic acid adopting the biologically relevant 2S0 conformation.
- Author
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Herrera AJ, Beneitez MT, Amorim L, Cañada FJ, Jiménez-Barbero J, Sinaÿ P, and Blériot Y
- Subjects
- Carbohydrate Conformation, Glycosaminoglycans chemistry, Heparin chemistry, Iduronic Acid chemical synthesis, Indicators and Reagents, Models, Molecular, Molecular Conformation, Oligosaccharides chemical synthesis, Bridged Bicyclo Compounds chemistry, Iduronic Acid analogs & derivatives, Iduronic Acid chemistry, Oligosaccharides chemistry
- Abstract
The synthesis of a bicyclic analogue of the naturally occurring alpha-L-iduronic acid locked in a biologically active (2)S0 skewboat conformation is disclosed. The desired (2)S0 conformation has been obtained by tethering the C-2 and C-5 carbon atoms of the sugar ring with a dimethyloxy bridge and confirmed by NMR and molecular modeling. The new mimic displays the exact hydroxyl pattern of alpha-L-iduronic acid, a major monosaccharide component of glycosaminoglycans and thus represents a closer mimic of the latter, compared to previously reported bicyclic analogs.
- Published
- 2007
- Full Text
- View/download PDF
31. Structure of the O-polysaccharide of Escherichia coli O112ab containing L-iduronic acid.
- Author
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Perepelov AV, Liu B, Senchenkova SN, Shashkov AS, Feng L, Knirel YA, and Wang L
- Subjects
- Carbohydrate Conformation, Carbohydrate Sequence, Magnetic Resonance Spectroscopy, Molecular Sequence Data, O Antigens isolation & purification, Escherichia coli chemistry, Iduronic Acid, O Antigens chemistry
- Abstract
An acidic O-polysaccharide was isolated by mild acid degradation of the lipopolysaccharide of Escherichia coli O112ab and studied by sugar analysis along with (1)H and (13)C NMR spectroscopy. The O-polysaccharide was found to contain a rarely occurring sugar component, L-iduronic acid (L-IdoA), and the following structure of the branched pentasaccharide repeating unit was established: [structure: see text].
- Published
- 2008
- Full Text
- View/download PDF
32. Linear Synthesis of De novo Oligo-Iduronic Acid
- Author
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Raghavendra Kikkeri and Chethan D. Shanthamurthy
- Subjects
chemistry.chemical_compound ,Glycosylation ,Biochemistry ,chemistry ,Organic Chemistry ,medicine ,Iduronic acid ,Heparin ,Physical and Theoretical Chemistry ,medicine.drug - Published
- 2019
33. Conformational Modulation of Iduronic Acid-Containing Sulfated Glycosaminoglycans by a Polynuclear Platinum Compound and Implications for Development of Antimetastatic Platinum Drugs
- Author
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Erica J. Peterson, Arun V. Everest-Dass, Mark von Itzstein, Nicholas Farrell, Kazuaki Takabe, Susan J. Berners-Price, Eriko Katsuta, Thomas Haselhorst, James D. Hampton, Anil K. Gorle, Samantha J. Katner, and Jennifer E. Koblinski
- Subjects
Magnetic Resonance Spectroscopy ,Organoplatinum Compounds ,Stereochemistry ,Iduronic Acid ,Molecular Conformation ,Iduronic acid ,Antineoplastic Agents ,010402 general chemistry ,01 natural sciences ,Catalysis ,Article ,Adduct ,chemistry.chemical_compound ,Sulfation ,Cell Movement ,Cell Line, Tumor ,Humans ,Density Functional Theory ,Glycosaminoglycans ,Platinum ,chemistry.chemical_classification ,010405 organic chemistry ,Chemistry ,Glycosidic bond ,General Chemistry ,Nuclear magnetic resonance spectroscopy ,Heparan sulfate ,Small molecule ,0104 chemical sciences ,Platinum Compound ,Heparitin Sulfate - Abstract
(1)H NMR spectroscopic studies on the 1:1 adduct of the pentasaccharide Fondaparinux (FPX) and the substitution-inert polynuclear platinum complex TriplatinNC show significant modulation of geometry around the glycosidic linkages of the FPX constituent monosaccharides. FPX is a valid model for the highly sulfated cell signalling molecule heparan sulfate (HS). The conformational ratio of the (1)C(4):(2)S(0) forms of the FPX residue IdoA(2S) is altered from ≈ 35:65 (free FPX) to ≈ 75:25 in the adduct; the first demonstration of a small molecule affecting conformational changes on a HS oligosaccharide. Functional consequences of such binding are suggested to be inhibition of HS cleavage in MDA-MB-231 triple-negative breast cancer (TNBC) cells. We further describe inhibition of metastasis by TriplatinNC in the TNBC 4T1 syngeneic tumour model. Our work provides insight into a novel approach for design of platinum drugs (and coordination compounds in general) with intrinsic anti-metastatic potential.
- Published
- 2020
34. Molecular recognition and proteoglycan mimic arrangement: modulating cisplatin toxicity.
- Author
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Anand S, Mardhekar S, Bhoge PR, Mishra SK, and Kikkeri R
- Subjects
- Heparitin Sulfate chemistry, Glucuronic Acid metabolism, Iduronic Acid, Sulfates, Proteoglycans, Cisplatin
- Abstract
We have demonstrated that cisplatin (CP), an anticancer drug, showed a preference for binding the sulfated-L-iduronic acid (S-L-IdoA) unit over the sulfated-D-glucuronic acid unit of heparan sulfate. The multivalency of S-L-IdoA, such as in the proteoglycan mimic, resulted in distinct modes of cell-surface engineering in normal and cancer cells, with these disparities having a significant impact on CP-mediated toxicity.
- Published
- 2024
- Full Text
- View/download PDF
35. Lentiviral Gene Therapy for Mucopolysaccharidosis II with Tagged Iduronate 2-Sulfatase Prevents Life-Threatening Pathology in Peripheral Tissues But Fails to Correct Cartilage.
- Author
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Catalano F, Vlaar EC, Dammou Z, Katsavelis D, Huizer TF, Zundo G, Hoogeveen-Westerveld M, Oussoren E, van den Hout HJMP, Schaaf G, Pike-Overzet K, Staal FJT, van der Ploeg AT, and Pijnappel WWMP
- Subjects
- Animals, Mice, Iduronic Acid metabolism, Lentivirus genetics, Lentivirus metabolism, Tissue Distribution, Genetic Therapy methods, Cartilage metabolism, Cartilage pathology, Mucopolysaccharidosis II genetics, Iduronate Sulfatase genetics
- Abstract
Deficiency of iduronate 2-sulfatase (IDS) causes Mucopolysaccharidosis type II (MPS II), a lysosomal storage disorder characterized by systemic accumulation of glycosaminoglycans (GAGs), leading to a devastating cognitive decline and life-threatening respiratory and cardiac complications. We previously found that hematopoietic stem and progenitor cell-mediated lentiviral gene therapy (HSPC-LVGT) employing tagged IDS with insulin-like growth factor 2 (IGF2) or ApoE2, but not receptor-associated protein minimal peptide (RAP12x2), efficiently prevented brain pathology in a murine model of MPS II. In this study, we report on the effects of HSPC-LVGT on peripheral pathology and we analyzed IDS biodistribution. We found that HSPC-LVGT with all vectors completely corrected GAG accumulation and lysosomal pathology in liver, spleen, kidney, tracheal mucosa, and heart valves. Full correction of tunica media of the great heart vessels was achieved only with IDS.IGF2co gene therapy, while the other vectors provided near complete ( IDS.ApoE2co ) or no ( IDSco and IDS.RAP12x2co ) correction. In contrast, tracheal, epiphyseal, and articular cartilage remained largely uncorrected by all vectors tested. These efficacies were closely matched by IDS protein levels following HSPC-LVGT. Our results demonstrate the capability of HSPC-LVGT to correct pathology in tissues of high clinical relevance, including those of the heart and respiratory system, while challenges remain for the correction of cartilage pathology.
- Published
- 2024
- Full Text
- View/download PDF
36. Fusion of Rabies Virus Glycoprotein or gh625 to Iduronate-2-Sulfatase for the Treatment of Mucopolysaccharidosis Type II.
- Author
-
Wood SR, Chaudrhy A, Ellison S, Searle R, Burgod C, Tehseen G, Forte G, O'Leary C, Gleitz H, Liao A, Cook J, Holley R, and Bigger BW
- Subjects
- Mice, Animals, Iduronic Acid, Glycoproteins genetics, Peptides, Mucopolysaccharidosis II genetics, Mucopolysaccharidosis II therapy, Rabies virus, Iduronate Sulfatase genetics, Nervous System Diseases
- Abstract
Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disease caused by a mutation in the IDS gene, resulting in deficiency of the enzyme iduronate-2-sulfatase (IDS) causing heparan sulfate (HS) and dermatan sulfate (DS) accumulation in all cells. This leads to skeletal and cardiorespiratory disease with severe neurodegeneration in two thirds of sufferers. Enzyme replacement therapy is ineffective at treating neurological disease, as intravenously delivered IDS is unable to cross the blood-brain barrier (BBB). Hematopoietic stem cell transplant is also unsuccessful, presumably due to insufficient IDS enzyme production from transplanted cells engrafting in the brain. We used two different peptide sequences (rabies virus glycoprotein [RVG] and gh625), both previously published as BBB-crossing peptides, fused to IDS and delivered via hematopoietic stem cell gene therapy (HSCGT). HSCGT with LV.IDS.RVG and LV.IDS.gh625 was compared with LV.IDS.ApoEII and LV.IDS in MPS II mice at 6 months post-transplant. Levels of IDS enzyme activity in the brain and peripheral tissues were lower in LV.IDS.RVG- and LV.IDS.gh625-treated mice than in LV.IDS.ApoEII- and LV.IDS-treated mice, despite comparable vector copy numbers. Microgliosis, astrocytosis, and lysosomal swelling were partially normalized in MPS II mice treated with LV.IDS.RVG and LV.IDS.gh625. Skeletal thickening was normalized by both treatments to wild-type levels. Although reductions in skeletal abnormalities and neuropathology are encouraging, given the low levels of enzyme activity compared with control tissue from LV.IDS- and LV.IDS.ApoEII-transplanted mice, the RVG and gh625 peptides are unlikely to be ideal candidates for HSCGT in MPS II and are inferior to the ApoEII peptide that we have previously demonstrated to be more effective at correcting MPS II disease than IDS alone.
- Published
- 2024
- Full Text
- View/download PDF
37. Synthesis and conformational analysis of carbasugar bioisosteres of α- l-iduronic acid and its methyl glycoside
- Author
-
Säwén, Elin, Roslund, Mattias U., Cumpstey, Ian, and Widmalm, Göran
- Published
- 2010
- Full Text
- View/download PDF
38. Can current force fields reproduce ring puckering in 2- O-sulfo-α- l-iduronic acid? A molecular dynamics simulation study
- Author
-
Gandhi, Neha S. and Mancera, Ricardo L.
- Published
- 2010
- Full Text
- View/download PDF
39. Glycosylations of Simple Acceptors with 2‐ O ‐Acyl <scp>l</scp> ‐Idose or <scp>l</scp> ‐Iduronic Acid Donors Reveal Only a Minor Role for Neighbouring‐Group Participation
- Author
-
Qi Qi He, Vito Ferro, Elizabeth H. Krenske, Romain J. Lepage, and Shifaza Mohamed
- Subjects
chemistry.chemical_classification ,Glycosylation ,010405 organic chemistry ,Stereochemistry ,Organic Chemistry ,Oxocarbenium ,Glycosidic bond ,Iduronic acid ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,carbohydrates (lipids) ,chemistry.chemical_compound ,Stereospecificity ,chemistry ,Neighbouring group participation ,Idose ,lipids (amino acids, peptides, and proteins) ,Glycosyl ,Physical and Theoretical Chemistry - Abstract
Several l-idose and l-iduronic acid glycosyl donors (mostly thioglycosides but also halides and trichloroacetimidates) with acyl protecting groups at the C-2 position were prepared and evaluated in glycosylation reactions with simple acceptors. In glycosaminoglycan oligosaccharide syntheses in the literature, the presence of C-2 acyl protecting groups in l-ido-configured glycosyl donors generally results in exclusive formation of 1,2-trans glycosidic linkages, a finding that has typically been attributed to neighbouring-group participation. However, glycosylations of simple alcohols with l-ido-configured donors (particularly thioglycosides), reported here, generally displayed incomplete stereocontrol and gave mixtures of the 1,2-trans and 1,2-cis products, suggesting that neighbouring-group participation has lesser importance in these reactions. Glycosyl donors and reaction conditions were identified that gave improved, but not exclusive, selectivity for the desired α-l-anomer (1,2-trans) as the major product. Interestingly, glycosylations under the same reaction conditions with more complex monosaccharide acceptors gave exclusively the expected 1,2-trans products. The role of neighbouring-group participation in these glycosylations was explored with density functional theory (DFT) calculations, which revealed that the non-stereoselective addition of the acceptor alcohol to the intermediate oxocarbenium ion is competitive with the stereospecific addition of the acceptor to the acyloxonium ion intermediate.
- Published
- 2018
40. Synthesis and antimetastatic activity of L-iduronic acid-type 1-N-iminosugars.
- Author
-
Nishimura Y, Satoh T, Adachi H, Kondo S, Takeuchi T, Azetaka M, Fukuyasu H, and Iizuka Y
- Subjects
- Animals, Antineoplastic Agents pharmacology, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Iduronic Acid pharmacology, Lung Neoplasms secondary, Mice, Models, Chemical, Neoplasm Metastasis prevention & control, Piperidines chemistry, Piperidines pharmacology, Structure-Activity Relationship, Tumor Cells, Cultured, Antineoplastic Agents chemical synthesis, Iduronic Acid analogs & derivatives
- Abstract
L-Iduronic acid-type 1-N-iminosugars, (3R,4S,5R,6R)- and (3R,4S,5S,6R)-6-acetamido-4-amino-5-hydroxypiperidine-3-carboxylic acid (6 and 7, respectively), (3R,4S,5R,6R)-6-acetamido-4- guanidino-5-hydroxypiperidine-3-carboxylic acid (8), and (3R,4S,5R,6R)-4-amino- and -guanidino-5-hydroxy-6-(trifluoroacetamido) piperidine-3-carboxylic acid (9 and 10, respectively), were synthesized from siastatin B (1), isolated from Streptomyces culture, by the intramolecular Michael addition of O-imidate to its alpha,beta-unsaturated ester through cis oxiamination as a key step. Preincubation of B16 BL6 cells with these compounds inhibited invasion of the cells through reconstituted basement membranes. Pulmonary metastasis of B16 BL6 cells in mice was remarkably inhibited by pretreatment of the cells with these compounds in culture.
- Published
- 1997
- Full Text
- View/download PDF
41. Combined NMR and molecular modeling study of an iduronic acid-containing trisaccharide related to antithrombotic heparin fragments.
- Author
-
Cros S, Petitou M, Sizun P, Pérez S, and Imberty A
- Subjects
- Angiotensin III chemistry, Angiotensin III metabolism, Binding Sites, Carbohydrate Conformation, Carbohydrate Sequence, Chemical Phenomena, Chemistry, Physical, Fibrinolytic Agents metabolism, Heparin metabolism, Iduronic Acid metabolism, Magnetic Resonance Spectroscopy methods, Molecular Sequence Data, Sulfates chemistry, Sulfates metabolism, Thermodynamics, Trisaccharides metabolism, Fibrinolytic Agents chemistry, Heparin chemistry, Iduronic Acid chemistry, Models, Molecular, Trisaccharides chemistry
- Abstract
An iduronic acid-containing trisaccharide, methyl-O-(4-O-methyl-2,3,6-tri-O-sulfo-alpha-D-glucopyranosyl-(1-->4)-O- (2-O-sulfo-alpha-L-idopyranosyluronic acid)-(1-->4)-O-2,6-di-O-sulfo-alpha-D-glucopyranoside, related to antithrombotic heparin fragments has been subjected to a combined NMR and molecular modeling investigation. The conformational behavior of the two constituting disaccharide segments was investigated using a systematic grid search approach with the MM3 force field along with the proper parameters for the sulfate ester group. The exploration of the potential energy surfaces of the trisaccharide was performed through the use of the CICADA methods interfaced with the MM3 force field. In all cases, the 2-O-sulfo-alpha-L-iduronate moiety was given the three favored ring conformations (1)C4, (4)C1, and (2)S0. Conformations were clustered into families, four of which are likely to exhibit significant occupancy in solution. The different low-energy conformational families display different orientations at the glycosidic linkages and/or different ring shapes for the iduronate ring. The (2)S0 conformation is the major one for the 2-O-sulfo-alpha-L-iduronate but is still in equilibrium with the (1)C4 ring shape. The occurrence of such a conformational equilibrium in solution was probed via high-resolution NMR spectroscopy through measurements of coupling constants and NOE build-up. These results are in keeping with the observation that 2-O-sulfated pentasaccharides display a similar affinity for antithrombin III as their 2-N-sulfated counterparts.
- Published
- 1997
- Full Text
- View/download PDF
42. L-iduronic acid derivatives as glycosyl donors.
- Author
-
Tabeur C, Machetto F, Mallet JM, Duchaussoy P, Petitou M, and Sinaÿ P
- Subjects
- Carbohydrate Sequence, Fluorides chemistry, Glycosylation, Iduronic Acid chemistry, Molecular Sequence Data, Iduronic Acid analogs & derivatives
- Abstract
O-[Methyl (2-O-acetyl-3-O-benzyl-4-O-levulinyl-alpha, and beta-L-idopyranosid)uronate] trichloroacetimidate and the corresponding n-pentenyl glycosides are efficient L-iduronic acid glycosyl donors. Both have been used for the high-yielding synthesis of basic disaccharide blocks which are useful for the subsequent synthesis of complex oligosaccharides related to heparin/heparan sulfate, and dermatan sulfate. In contrast, the corresponding thioethyl glycosides, thiophenyl glycosides, and fluoride, did not yield the expected disaccharides.
- Published
- 1996
- Full Text
- View/download PDF
43. Iduronic acid-rich proteoglycans (PGIdoA) and human post-burn scar maturation: isolation and characterization.
- Author
-
Garg HG, Siebert JW, Garg A, and Neame PJ
- Subjects
- Amino Acid Sequence, Burns metabolism, Chromatography, Gel, Cicatrix metabolism, Cicatrix, Hypertrophic metabolism, Cicatrix, Hypertrophic pathology, Electrophoresis, Cellulose Acetate, Electrophoresis, Polyacrylamide Gel, Humans, Iduronic Acid chemistry, Molecular Sequence Data, Molecular Weight, Proteoglycans chemistry, Burns pathology, Cicatrix pathology, Iduronic Acid isolation & purification, Proteoglycans isolation & purification
- Abstract
Proteoglycans (PGs) were extracted from human hypertrophic and normal scar tissues from two different stages of maturation after burn injury, under dissociative conditions (4 M guanidinium chloride containing proteinase inhibitors). The extracts were fractionated by ion-exchange chromatography, followed by ethanol precipitation, to give PG-containing iduronic acid (PGIdoA). The size of the PGIdoA decreased with the maturation of scars. Glycosaminoglycan (GAG) chains from PGIdoA were released by alkaline borohydride treatment, and their M(r) values were evaluated by polyacrylamide gel electrophoresis. The M(r) values for PGIdoA protein cores of the hypertrophic scars (5+ years and 2-5 years) and normal scar (5+ years and 2-5 years) were 22.6, 25, 19 and 21 kDa, respectively. The iduronic acid content of PGIdoA from both types of scar increased in their maturation phase. The M(r) values of PGIdoA decreased with maturation. PGIdoA carried the sulfate group mainly attached at C-4 of the 2-amino-2-deoxy-D-galactose residue. The NH2-terminal amino acid sequences of all the PGIdoA were similar to those of normal human skin or bone PG II (decorin) (i.e., Asp-Glu-Ala-B-Gly-Ile-Gly-Pro-Glu-Val-Pro-Asp-Asp-Arg).
- Published
- 1995
- Full Text
- View/download PDF
44. New Antimetastatic Study Findings Have Been Reported from Griffith University (Conformational Modulation of Iduronic Acid-containing Sulfated Glycosaminoglycans By a Polynuclear Platinum Compound and Implications for Development of ...)
- Subjects
Sulfates ,Glycosaminoglycans ,Physical fitness ,Fondaparinux ,Health ,Griffith University - Abstract
2021 JAN 30 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Current study results on Drugs and Therapies - Antimetastatic have been published. [...]
- Published
- 2021
45. Uncovering the Relationship between Sulphation Patterns and Conformation of Iduronic Acid in Heparan Sulphate.
- Author
-
Hsieh PH, Thieker DF, Guerrini M, Woods RJ, and Liu J
- Subjects
- Molecular Conformation, Molecular Dynamics Simulation, Heparitin Sulfate chemistry, Iduronic Acid chemistry, Sulfates chemistry
- Abstract
The L-iduronic acid (IdoA) residue is a critically important structural component in heparan sulphate polysaccharide for the biological functions. The pyranose ring of IdoA is present in (1)C4-chair, (2)SO-skew boat, and less frequently, in (4)C1-chair conformations. Here, we analyzed the conformation of IdoA residue in eight hexasaccharides by NMR. The data demonstrate a correlation between the conformation of IdoA and sulphations in the surrounding saccharide residues. For the 2-O-sulpho IdoA residue, a high degree of sulphation on neighboring residues drives ring dynamics towards the (2)SO-skew boat conformer. In contrast, the nonsulphated IdoA residue is pushed towards the (1)C4-chair conformer when the neighboring residues are highly sulphated. Our data suggest that the conformation of IdoA is regulated by the sulphation pattern of nearby saccharides that is genetically controlled by the heparan sulphate biosynthetic pathway.
- Published
- 2016
- Full Text
- View/download PDF
46. Significance of the 2- O-sulfo group of l-iduronic acid residues in heparin on the growth inhibition of bovine pulmonary artery smooth muscle cells
- Author
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Garg, Hari G., Mrabat, Hicham, Yu, Lunyin, Freeman, Craig, Li, Boyangzi, Zhang, Fuming, Linhardt, Robert J., and Hales, Charles A.
- Published
- 2008
- Full Text
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47. Depiction of the forces participating in the 2- O-sulfo-α- l-iduronic acid conformational preference in heparin sequences in aqueous solutions
- Author
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Pol-Fachin, Laercio and Verli, Hugo
- Published
- 2008
- Full Text
- View/download PDF
48. An efficient synthesis of l-idose and l-iduronic acid thioglycosides and their use for the synthesis of heparin oligosaccharides
- Author
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Tatai, János, Osztrovszky, Györgyi, Kajtár-Peredy, Mária, and Fügedi, Péter
- Published
- 2008
- Full Text
- View/download PDF
49. Protein interactome analysis of iduronic acid-containing glycosaminoglycans reveals a novel flagellar invasion factor MbhA
- Author
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Jun Mu Lin, Yi Wen Chen, Felix Shih-Hsiang Hsiao, Chien Sheng Chen, and Shyi Kuen Yang
- Subjects
0301 basic medicine ,Proteomics ,Iduronic Acid ,Biophysics ,Chondroitin sulfate B ,Iduronic acid ,Biochemistry ,Interactome ,Bacterial Adhesion ,Conserved sequence ,Cell Line ,03 medical and health sciences ,chemistry.chemical_compound ,Gentamicin protection assay ,Escherichia coli ,Humans ,Protein Interaction Maps ,Escherichia coli Infections ,Glycosaminoglycans ,Host cell surface ,030102 biochemistry & molecular biology ,Chemistry ,Escherichia coli Proteins ,030104 developmental biology ,Proteome ,Bacterial outer membrane - Abstract
Pathogens are able to exploit specific glycosaminoglycans (GAGs), especially iduronic acid (IdoA)-containing GAGs, to invade the host. By analyzing Escherichia coli proteome chip data, we identified the interactomes of three IdoA-containing GAGs: heparin, heparin sulfate (HS), and chondroitin sulfate B (CSB). Using non-IdoA-containing GAG, chondroitin sulfate C, as a negative control, 157 proteins specifically binding with IdoA-containing GAGs were revealed in the present study. These proteins showed functional enrichment in protein synthesis and metabolism. Fifteen proteins which commonly interacts with three IdoA-containing GAGs were further examined. The regular expression for motif showed these common IdoA interactome shared a conserved sequence. Among them, we identified a second flagellar system outer membrane protein, MbhA. The MbhA has Kd values of 8.9 × 10−8 M, 5.3 × 10−7 M, and 1.79 × 10−7 M to interact with heparin, HS, and CSB, respectively. Using flow cytometry, we confirmed that the MbhA protein can bind to human epithelial cells HCT-8. Overexpression of mbhA increased the percentage of invasion in E. coli which lacks a second flagellar system. Moreover, pre-blocking of HCT-8 cells with MbhA inhibited the bacterial invasion, implying the importance of the direct interaction of MbhA and the host cell surface on bacterial invasion. Significance We analyzed the Escherichia coli proteomic data to elucidate the interactomes of three different IdoA-containing GAGs (heparin, HS, and CSB) because these IdoA-containing GAGs can mediate bacterial invasion to the host. Through proteomic and systematic analysis, a second flagellar system outer membrane protein, MbhA, was also identified in the present study. Affinity assay confirmed that MbhA can bind to three IdoA-containing GAGs heparin, HS, and CSB. The result of flow cytometry also showed MbhA can interact with human epithelial cells HCT-8. Results of bacteria invasion assay showed overexpression of mbhA promoted the bacterial invasion. Moreover, pre-blocking of HCT-8 cells with MbhA also reduced the percentage of bacterial invasion. These findings correspond well that MbhA is one of invasion factors.
- Published
- 2019
50. Metal binding to heparin monosaccharides: D-glucosamine-6-sulphate, D-glucuronic acid, and L-iduronic acid.
- Author
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Whitfield DM and Sarkar B
- Subjects
- Cadmium metabolism, Calcium metabolism, Glucosamine analogs & derivatives, Glucuronic Acid, Hymecromone analogs & derivatives, Hymecromone metabolism, Iduronic Acid analogs & derivatives, Lead metabolism, Magnetic Resonance Spectroscopy, Molecular Conformation, Nickel metabolism, Zinc metabolism, Zinc pharmacology, Glucosamine metabolism, Glucuronates metabolism, Heparin metabolism, Iduronic Acid metabolism, Metals metabolism
- Abstract
In order to ascertain which residues in heparin may be responsible for its metal binding capacities we have investigated metal binding to some of its component monosaccharides by 1H and 13C NMR. The diamagnetic Zn ion and the paramagnetic Ni ion were used as probes. 4-Methylumbelliferyl-2-deoxy-2-acetamido-6-O-sulpho-D-glucosamine was used as a model for O-sulphates. Only weak interactions with the sulphate group were found. The 4C1 ring conformation of sodium methyl-beta-D-glucopyranosiduronate was not perturbed by binding to its carboxylate and little evidence exists for chelation. By contrast, the ring conformation of the sodium methyl-alpha-L-idopyranosiduronate is affected by the addition of Zn greater than Pb greater than Cd greater than Ca much greater than K ions. The sodium salt is suggested to be an equilibrium mixture of the 2SO and 1C4 ring conformations. Cation binding to the carboxylate group shifts this equilibrium towards the 1C4 conformation and suggests additional binding to O5 or, less likely, O4. This effect appears to be electrostatic in nature, as excess Na and protonation produce similar shifts. Lead complexation is different from the other ions and suggests some covalent character. The control of the ring conformation of iduronic acid by metal ions may have biological implications for the action of heparin and heparin-like compounds.
- Published
- 1991
- Full Text
- View/download PDF
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