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G J Davies - One of the best experts on this subject based on the ideXlab platform.
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divergence of catalytic mechanism within a Glycosidase family provides insight into evolution of carbohydrate metabolism by human gut flora
Chemistry & Biology, 2008Co-Authors: T M Gloster, Bernard Henrissat, J P Turkenburg, Jennifer R Potts, G J DaviesAbstract:Enzymatic cleavage of the glycosidic bond yields products in which the anomeric configuration is either retained or inverted. Each mechanism reflects the dispositions of the enzyme functional groups; a facet of which is essentially conserved in 113 glycoside hydrolase (GH) families. We show that family GH97 has diverged significantly, as it contains both inverting and retaining α-Glycosidases. This reflects evolution of the active center; a glutamate acts as a general base in inverting members, exemplified by Bacteroides thetaiotaomicron α-glucosidase BtGH97a, whereas an aspartate likely acts as a nucleophile in retaining members. The structure of BtGH97a and its complexes with inhibitors, coupled to kinetic analysis of active-site variants, reveals an unusual calcium ion dependence. 1H NMR analysis shows an inversion mechanism for BtGH97a, whereas another GH97 enzyme from B. thetaiotaomicron, BtGH97b, functions as a retaining α-galactosidase.
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Glycosidase inhibition an assessment of the binding of 18 putative transition state mimics
Journal of the American Chemical Society, 2007Co-Authors: T M Gloster, Peter J Meloncelli, Robert V Stick, David L Zechel, A Vasella, G J DaviesAbstract:The inhibition of glycoside hydrolases, through transition-state mimicry, is important both as a probe of enzyme mechanism and in the continuing quest for new drugs, notably in the treatment of cancer, HIV, influenza, and diabetes. The high affinity with which these enzymes are known to bind the transition state provides a framework upon which to design potent inhibitors. Recent work [for example, Bulow, A. et al. J. Am. Chem. Soc. 2000, 122, 8567−8568; Zechel, D. L. et al. J. Am. Chem. Soc. 2003, 125, 14313−14323] has revealed quite confusing and counter-intuitive patterns of inhibition for a number of Glycosidase inhibitors. Here we describe a synergistic approach for analysis of inhibitors with a single enzyme ‘model system', the Thermotoga maritima family 1 β-glucosidase, TmGH1. The pH dependence of enzyme activity and inhibition has been determined, structures of inhibitor complexes have been solved by X-ray crystallography, with data up to 1.65 A resolution, and isothermal titration calorimetry was ...
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an unusual mechanism of glycoside hydrolysis involving redox and elimination steps by a family 4 β Glycosidase from thermotoga maritima
Journal of the American Chemical Society, 2004Co-Authors: Annabelle Varrot, G J Davies, S S Rajan, X Yang, John F Thompson, W F Anderson, Stephen G. WithersAbstract:Among the numerous well-characterized families of Glycosidases, family 4 appears to be the anomaly, requiring both catalytic NAD+ and a divalent metal for activity. The unusual cofactor requirement prompted the proposal of a mechanism involving key NAD+-mediated redox steps as well as elimination of the glycosidic oxygen. Primary kinetic isotope effects for the 2- and 3-deutero substrate analogues, isotopic exchange with solvent, and structural analysis of a 6-phospho-β-glucosidase, BglT (E.C. 3.2.1.6), provided evidence in support of the proposed mechanism, which has striking resemblances to that of the sugar dehydratases. Furthermore, analysis of the stereochemical outcome indicated that family 4 enzymes are retaining Glycosidases.
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iminosugar Glycosidase inhibitors structural and thermodynamic dissection of the binding of isofagomine and 1 deoxynojirimycin to β glucosidases
Journal of the American Chemical Society, 2003Co-Authors: David L Zechel, T M Gloster, Robert V Stick, A B Boraston, Catherine M Boraston, James M Macdonald, Matthew D G Tilbrook, G J DaviesAbstract:The design and synthesis of transition-state mimics reflects the growing need both to understand enzymatic catalysis and to influence strategies for therapeutic intervention. Iminosugars are among the most potent inhibitors of Glycosidases. Here, the binding of 1-deoxynojirimycin and (+)-isofagomine to the “family GH-1” β-glucosidase of Thermotoga maritima is investigated by kinetic analysis, isothermal titration calorimetry, and X-ray crystallography. The binding of both of these iminosugar inhibitors is driven by a large and favorable enthalpy. The greater inhibitory power of isofagomine, relative to 1-deoxynojirimycin, however, resides in its significantly more favorable entropy; indeed the differing thermodynamic signatures of these inhibitors are further highlighted by the markedly different heat capacity values for binding. The pH dependence of catalysis and of inhibition suggests that the inhibitory species are protonated inhibitors bound to enzymes whose acid/base and nucleophile are ionized, whil...
Naoki Asano - One of the best experts on this subject based on the ideXlab platform.
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Glycosidase inhibitors update and perspectives on practical use
Glycobiology, 2003Co-Authors: Naoki AsanoAbstract:About 40 years have passed since the classical Glycosidase inhibitor nojirimycin was discovered from the cultured broth of the Streptomyces species. Since then, over 100 Glycosidase inhibitors have been isolated from plants and microorganisms. Modifying or blocking biological processes by specific Glycosidase inhibitors has revealed the vital functions of Glycosidases in living systems. Because enzyme-catalyzed carbohydrate hydrolysis is a biologically widespread process, Glycosidase inhibitors have many potential applications as agrochemicals and therapeutic agents. Glycosidases are involved in the biosynthesis of the oligosaccharide chains and quality control mechanisms in the endoplasmic reticulum of the N-linked glycoproteins. Inhibition of these Glycosidases can have profound effects on quality control, maturation, transport, and secretion of glycoproteins and can alter cell‐ cell or cell‐virus recognition processes. This principle is the basis for the potential use of Glycosidase inhibitors in viral infection, cancer, and genetic disorders. In this review, the past and current applications of Glycosidase inhibitors to agricultural and medical fields and the prospect for new therapeutic applications are reconsidered.
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n containing sugars from morus alba and their Glycosidase inhibitory activities
Carbohydrate Research, 1994Co-Authors: Naoki Asano, Kengo Oseki, Emiko Tomioka, Haruhisa Kizu, Katsuhiko MatsuiAbstract:Abstract The reexamination of N -containing sugars from the roots of Morus alba by improved purification procedures led to the isolation of eighteen N -containing sugars, including seven that were isolated from the leaves of Morus bombycis . These N -containing sugars are 1-deoxynojirimycin ( 1 ), N -methyl-1-deoxynojirimycin ( 2 ), fagomine ( 3 ), 3- epi -fagomine ( 4 ), 1,4-dideoxy-1,4-imino-pD-arabinitol ( 5 ), 1,4-dideoxy-1,4-imino-pD-ribitol ( 6 ), calystegin B 2 (1α,2β,3α,4β-tetrahydroxy- nor -tropane, 7 ), calystegin C 1 , (1α,2β,3α,6α-pentahydroxy- nor -tropane, 8 ), 1,4-dideoxy-1,4-imino-(2- O -β-pD-glucopyranosyl)- d -glucopyranosyl)- d -arabinitol ( 9 ), and nine glycosides of 1 . These glycosides consist of 2- O - and 6- O -α- d -galactopyranosyl-1-deoxynojirimycins ( 10 and 11 , respectively), 2- O -, 3- O - and 4- O -α- d -glucopyranosyl-1-deoxynojirimycins ( 12 , 13 , and 14 , respectively), and 2- O -, 3- O -, 4- O - and 6- O -β- D -glucopyranosyl-1-deoxynojirimycins ( 15 , 16 , 17 , and 18 , respectively). Compound 4 is a new member of polyhydroxylated piperidine alkaloids, and the isolation of 6 is the first report of its natural occurrence. It has recently been found that the polyhydroxy- nor -tropane alkaloids possess potent Glycosidase inhibitory activities. Calystegin A 3 is the trihydroxy- nor -tropane, and calystegins B 1 and B 2 are the tetrahydroxy- nor -tropane. Calystegin C 1 , a new member of calystegins, is the first naturally occurring pentahydroxy- nor -tropane alkaloid. The inhibitory activities of these compounds are investigated against rat digestive Glycosidases and various commercially available Glycosidases.
Philippe Compain - One of the best experts on this subject based on the ideXlab platform.
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Multivalent Effect in Glycosidase Inhibition: The End of the Beginning
Chemical Record, 2019Co-Authors: Philippe CompainAbstract:Glycosidases are ubiquitous enzymes involved in a diversity of key biological processes such as energy uptake or cell wall degradation. The design of specific Glycosidase inhibitors has been therefore the subject of intense research efforts in academia and pharmaceutical industry. However, until recently, the study of the impact of multivalency on Glycosidase inhibition was almost completely neglected. The following account will review our ten year journey on the design of multivalent glycomimetics within our research group, from the discovery of the first strong multivalent effect in Glycosidase inhibition to the high-resolution crystal structures of Jack bean α-mannosidase in complex with the multimeric inhibitor displaying the largest binding enhancements reported so far.
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the multivalent effect in Glycosidase inhibition probing the influence of architectural parameters with cyclodextrin based iminosugar click clusters
Chemistry: A European Journal, 2011Co-Authors: Camille Decroocq, David Rodriguezlucena, Virginie Russo, Teresa Mena Barragan, Carmen Ortiz Mellet, Philippe CompainAbstract:In contrast to most lectins, Glycosidases may appear to be unprom- ising targets for multivalent binding be- cause they display only a single active site. To explore the potential of multi- valency on Glycosidase inhibition, un- precedented cyclodextrin-based imino- sugar conjugates have been designed and prepared. The synthesis was per- formed by way of Cu I -catalyzed azide- alkyne cycloaddition reaction under microwave activation between propar- gylated multivalent b-cyclodextrins and an azide-armed N-alkyl 1-deoxynojiri- mycin derivative. Evaluation with a panel of Glycosidases of this new class of glycomimetic clusters revealed the strongest affinity enhancement ob- served to date for a multivalent glycosi- dase inhibitor, with binding enhance- ment up to four orders of magnitude over the corresponding monovalent ligand for a-mannosidase. These results demonstrate that the multivalency con- cept extends beyond carbohydrate- lectin recognition processes to glycomi- metic-enzyme inhibition.
Ki Hun Park - One of the best experts on this subject based on the ideXlab platform.
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Glycosidase inhibitory phenolic compounds from the seed of psoralea corylifolia
Food Chemistry, 2010Co-Authors: Kyeong Yeol Oh, Marcus J Curtislong, Ki Hun ParkAbstract:Abstract The seeds of Psoralea corylifolia were extracted into five different polar solvents: chloroform, 50% ethanol in water, ethanol, methanol and water. All extracts were evaluated for Glycosidase inhibitory activity. The chloroform extract (CE) showed the lowest IC 50 values against α-glucosidase (82.9 μg/ml) and α-mannosidase (132 μg/ml). Chromatography of CE yielded nine phenolic compounds which were identified as isovabachalcone ( 1 ), 4′- O -methylbavachalcone ( 2 ), isobavachromene ( 3 ), corylifolin ( 4 ), bavachinin ( 5 ), psoralidin ( 6 ), neobavaisoflavone ( 7 ), corylifol A ( 8 ), and bakuchiol ( 9 ). All isolated compounds, apart from compound 5 , possessed α-glucosidase inhibitory activities. Among them, compounds 6 – 8 exhibited potent inhibition with IC 50 s of 13.7, 27.7 and 11.3 μM, respectively. Furthermore, compounds 2 and 6 showed α-mannosidase inhibitory activity. Mechanistic analysis of their inhibition modes against α-glucosidase showed that compounds ( 6 and 7 ) were noncompetitive, whereas compound 8 was mixed. Furthermore, the most active Glycosidase inhibitors ( 2 , 6 – 8 ) were proven to be present in the native seed in high quantities by an HPLC chromatogram.
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Glycosidase inhibitory flavonoids from sophora flavescens
Biological & Pharmaceutical Bulletin, 2006Co-Authors: Nam Suk Kang, Illyun Jeong, Ki Hun ParkAbstract:The methanol extract of Sophora flavescens showed a potent Glycosidase inhibitory activity. Active components were identified as well-known flavonoid antioxidants: kushenol A (1), (-)-kurarinone (2), sophoraflavanone G (3), 2'-methoxykurarinone (4), kurarinol (5), 8-prenylkaempferol (6), isoxanthohumol (7), kuraridin (8) and maackian (9). All flavonoids were effective inhibitors of α-glucosidase and β-amylase. Interestingly, lavandulylated flavanones 1-5 had strong α-glucosidase inhibitory activities, with IC 50 values of 45 μM, 68 μM, 37 μM, 155 μM and 179 μM, respectively. Kushenol A (1) which does not bear a 4'-hydroxy group showed selective α-glucosidase inhibitory activity. Lavandulylated chalcone, kuraridine (8), exhibited IC 50 value of 57 μM against β-glucosidase, which is the first report of a chalcone displaying Glycosidase inhibition. Results showed that 8-lavandulyl group in B-ring was a key factor of the Glycosidase inhibitory activities. The inhibition pattern was noncompetitive for α-glucosidase, whereas mixed inhibition was observed for β-amylase.
Hironobu Hashimoto - One of the best experts on this subject based on the ideXlab platform.
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thiasugars potential Glycosidase inhibitors
Current Topics in Medicinal Chemistry, 2009Co-Authors: Hideya Yuasa, Masayuki Izumi, Hironobu HashimotoAbstract:The inhibitory activities against Glycosidases of synthetic thiasugars, the ring sulfur analogs of carbohydrate, were surveyed with a special emphasis on our own studies. 5-Thio-L-fucose, the ring sulfur analog of L-fucose, was the first thiopyran that shows a Ki value in the micromolar range against a Glycosidase. The structure-activity relationship studies for the fucosidase inhibition by 5-thio-L-fucose disclosed that a hydrophobic interaction between the ring sulfur atom and the enzyme is responsible for the strong binding. The syntheses and activities of di- and trisaccharide analogs incorporating thiasugars are also outlined. These oligosaccharide analogs are Glycosidase-resistant and some of them show strong binding to antibodies or lectins. We created a sulfylimine compound having a thiafuran structure as a transitionstate analog inhibitor of glucosidases and found that it has a weak inhibition against a glucosidase. The same thiafuran structure could be found in a natural product, salacinol, which was isolated and elucidated to be a strong glucosidase inhibitor by another group. A study of the structure-activity relationship using the synthetic analogs of salacinol indicated the relevance of both the sulfonium ion in the thiafuran ring and its intramolecular counter anion, sulfate, to the inhibition activity.
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Thiasugars as Potential Glycosidase Inhibitor
Journal of Synthetic Organic Chemistry Japan, 2002Co-Authors: Hideya Yuasa, Masayuki Izumi, Hironobu HashimotoAbstract:The potential of synthetic thiasugars, the ring sulfur analogs of carbohydrate, as Glycosidase inhibitor was discussed in terms of activity and specificity, based on our own studies. The syntheses of these analogs including di- and tri-saccharide derivatives were also outlined. 5-Thiofucose was the first thiapyran to show a Ki value of micromolar range against a Glycosidase. The structure-activity relationship studies indicated that its fucosidase inhibition was due in part to a hydrophobic interaction between the ring sulfur and the enzyme. A sulfylimine compound having a thiafuran structure was created as a transition-state analog inhibitor of glucosidases and found to have a weak activity. The same thiafuran structure was later found by another group in a natural product, salacinol, which is a sulfonium derivative and is a strong glucosidase inhibitor. The structure-activity relationship study with synthetic analogs of salacinol indicated importance of the sulfonium ion and its internal counter anion, sulfate, for the inhibition activity.
