Showing papers on "Pyranose published in 2016"

The Dependence of Carbohydrate–Aromatic Interaction Strengths on the Structure of the Carbohydrate

Abstract: Interactions between proteins and carbohydrates are ubiquitous in biology. Therefore, understanding the factors that determine their affinity and selectivity are correspondingly important. Herein, we have determined the relative strengths of intramolecular interactions between a series of monosaccharides and an aromatic ring close to the glycosylation site in an N-glycoprotein host. We employed the enhanced aromatic sequon, a structural motif found in the reverse turns of some N-glycoproteins, to facilitate face-to-face monosaccharide–aromatic interactions. A protein host was used because the dependence of the folding energetics on the identity of the monosaccharide can be accurately measured to assess the strength of the carbohydrate–aromatic interaction. Our data demonstrate that the carbohydrate–aromatic interaction strengths are moderately affected by changes in the stereochemistry and identity of the substituents on the pyranose rings of the sugars. Galactose seems to make the weakest and allose the ...

A β-Mannanase with a Lysozyme-like Fold and a Novel Molecular Catalytic Mechanism

Abstract: The enzymatic cleavage of β-1,4-mannans is achieved by endo-β-1,4-mannanases, enzymes involved in germination of seeds and microbial hemicellulose degradation, and which have increasing industrial and consumer product applications. β-Mannanases occur in a range of families of the CAZy sequence-based glycoside hydrolase (GH) classification scheme including families 5, 26, and 113. In this work we reveal that β-mannanases of the newly described GH family 134 differ from other mannanase families in both their mechanism and tertiary structure. A representative GH family 134 endo-β-1,4-mannanase from a Streptomyces sp. displays a fold closely related to that of hen egg white lysozyme but acts with inversion of stereochemistry. A Michaelis complex with mannopentaose, and a product complex with mannotriose, reveal ligands with pyranose rings distorted in an unusual inverted chair conformation. Ab initio quantum mechanics/molecular mechanics metadynamics quantified the energetically accessible ring conformations and provided evidence in support of a 1C4 → 3H4‡ → 3S1 conformational itinerary along the reaction coordinate. This work, in concert with that on GH family 124 cellulases, reveals how the lysozyme fold can be co-opted to catalyze the hydrolysis of different polysaccharides in a mechanistically distinct manner.

Synthesis of Unprecedented Sulfonylated Phosphono-exo-Glycals Designed as Inhibitors of the Three Mycobacterial Galactofuranose Processing Enzymes.

Abstract: This study reports a new methodology to synthesize exo-glycals bearing both a sulfone and a phosphonate. This synthetic strategy provides a way to generate exo-glycals displaying two electron-withdrawing groups and was applied to eight different carbohydrates from the furanose and pyranose series. The Z/E configurations of these tetrasubstituted enol ethers could be ascertained using NMR spectroscopic techniques. Deprotection of an exo-glycal followed by an UMP (uridine monophosphate) coupling generated two new UDP (uridine diphosphate)-galactofuranose analogues. These two Z/E isomers were evaluated as inhibitors of UGM, GlfT1, and GlfT2, the three mycobacterial galactofuranose processing enzymes. Molecule 46-(E) is the first characterized inhibitor of GlfT1 reported to date and was also found to efficiently inhibit UGM in a reversible manner. Interestingly, GlfT2 showed a better affinity for the (Z) isomer. The three enzymes studied in the present work are not only interesting because, mechanistically, they are still the topic of intense investigations, but also because they constitute very important targets for the development of novel antimycobacterial agents.

Alpha-d-galactoside inhibitors of galectins

Abstract: The present invention relates to a compound of the general formula (1). wherein the pyranose ring is a-D-galactopyranose, A is selected from The compound of formula (1) is suitable for use in a method for treating a disorder relating to the binding of a galectin, such as galectin-3 to a ligand in a mammal, such as a human. Furthermore the present invention concerns compounds for use in a method of treatment of a disorder relating to the binding of a galectin, such as galectin-3 to a ligand in a mammal, such as a human.

Acyclic forms of aldohexoses and ketohexoses in aqueous and DMSO solutions: conformational features studied using molecular dynamics simulations.

Abstract: The molecular properties of aldohexoses and ketohexoses are usually studied in the context of their cyclic, furanose or pyranose structures which is due to the abundance of related tautomeric forms in aqueous solution. We studied the conformational features of a complete series of D-aldohexoses (D-allose, D-altrose, D-glucose, D-mannose, D-gulose, d-idose, D-galactose and D-talose) and D-ketohexoses (D-psicose, D-fructose, D-sorbose and D-tagatose) as well as of L-psicose by using microsecond-timescale molecular dynamics in explicit water and DMSO with the use of enhanced sampling methods. In each of the studied cases the preferred conformation corresponded to an extended chain structure; the less populated conformers included the quasi-cyclic structures, close to furanose rings and common for both aldo- and ketohexoses. The orientational preferences of the aldehyde or ketone groups are correlated with the relative populations of anomers characteristic of cyclic aldo- and ketohexoses, respectively, thus indicating that basic features of anomeric equilibria are preserved even if hexose molecules are not in their cyclic forms. No analogous relationship is observed in the case of other structural characteristics, such as the preferences of acyclic molecules to form either the furanose-or pyranose-like structures or maintaining the chair-like geometry of pseudo-pyranose rings.

Characterization of a bacterial pyranose 2-oxidase from Arthrobacter siccitolerans

Abstract: In this study we provide the first biochemical characterization of a bacterial pyranose 2-oxidase (AsP2Ox) from Arthrobacter siccitolerans. The enzyme catalyzes the oxidation of several aldopyranoses at the C-2 position, coupling it to the reduction of dioxygen to hydrogen peroxide. Pyranose 2-oxidases belong to the glucose-methanol-choline oxidoreductase family. A structural model based on the known X-ray structure of P2Ox from Phanerochaete chrysosporium supports that AsP2Ox shares structural features with well-characterized fungal P2Oxs. The gene coding for AsP2Ox was cloned and heterologously expressed in Escherichia coli. The purified recombinant enzyme is a 64-kDa monomer containing a non-covalently bound flavin adenine dinucleotide (FAD) cofactor, distinct features as compared with fungal counterparts that are ∼ 270 kDa homotetramers with covalent-linked FAD. AsP2Ox exhibits a redox potential of −50 mV, an optimum temperature of 37 °C and an optimum pH at 6.5. AsP2Ox oxidizes d -glucose at the highest efficiency, using additionally d -galactose, d -xylose, l -arabinose and d -ribose as electron donors, coupling their oxidation to the reduction of both dioxygen and 1,4-benzoquinone. AsP2Ox shows a relatively low thermal stability with a melting temperature (Tm) of 43 °C and a half-life (t1/2) at 40 °C of 25 min. This work expands the repertoire of bacterial oxidoreductases with importance in biotechnological and diagnostic applications.

Enantioselective Synthesis of Dideoxy-tetrafluorinated Hexoses.

Abstract: Carbohydrates typically have low affinities to protein binding sites, and the development of carbohydrate mimetics with improved binding is therefore of interest. Tetrafluorination of monosaccharides is one of the strategies currently under investigation for that purpose. The synthesis of the required tetrafluorinated monosaccharides is achieved by a fluorinated building block approach. The enantioselective synthesis of tetrafluorinated hexose derivatives is described here, in both pyranose and furanose forms. In particular, the optimization of the enantioselective synthesis of the previously reported 2,3-dideoxy-2,2,3,3-tetrafluoro-d-threo-hexopyranose 3, 2,3-dideoxy-2,2,3,3-tetrafluoro-d-threo-hexofuranose 4, and 2,3-dideoxy-2,2,3,3-tetrafluoro-d-erythro-hexopyranose 5 is described as is the synthesis of two novel sugar derivatives, 3,4-dideoxy-3,3,4,4-tetrafluoro-d-threo-hexopyranose 6 and 3,4-dideoxy-3,3,4,4-tetrafluoro-d-erythro-hexopyranose 7. The key step of all syntheses is a perfluoroalkyl lithiu...

Evaluation of fluoropyruvate as nucleophile in reactions catalysed by N -acetyl neuraminic acid lyase variants: scope, limitations and stereoselectivity

Abstract: The catalysis of reactions involving fluoropyruvate as donor by N-acetyl neuraminic acid lyase (NAL) variants was investigated. Under kinetic control, the wild-type enzyme catalysed the reaction between fluoropyruvate and N-acetyl mannosamine to give a 90 : 10 ratio of the (3R,4R)- and (3S,4R)-configured products; after extended reaction times, equilibration occurred to give a 30 : 70 mixture of these products. The efficiency and stereoselectivity of reactions of a range of substrates catalysed by the E192N, E192N/T167V/S208V and E192N/T167G NAL variants were also studied. Using fluoropyruvate and (2R,3S)- or (2S,3R)-2,3-dihydroxy-4-oxo-N,N-dipropylbutanamide as substrates, it was possible to obtain three of the four possible diastereomeric products; for each product, the ratio of anomeric and pyranose/furanose forms was determined. The crystal structure of S. aureus NAL in complex with fluoropyruvate was determined, assisting rationalisation of the stereochemical outcome of C–C bond formation.

Structural basis for cellulose binding by the type A carbohydrate-binding module 64 of Spirochaeta thermophila.

Abstract: Spirochaeta thermophila secretes seven glycoside hydrolases for plant biomass degradation that carry a carbohydrate-binding module 64 (CBM64) appended at the C-terminus. CBM64 adsorbs to various β1-4-linked pyranose substrates and shows high affinity for cellulose. We present the first crystal structure of a CBM64 at 1.2 A resolution, which reveals a jelly-roll-like fold corresponding to a surface-binding type A CBM. Modeling of its interaction with cellulose indicates that CBM64 achieves association with the hydrophobic face of β-linked pyranose chains via a unique coplanar arrangement of four exposed tryptophan side chains. Proteins 2016; 84:855-858. © 2016 Wiley Periodicals, Inc.

Computational insights into octyl-D-xyloside isomers towards understanding the liquid crystalline structure: physico-chemical features

Abstract: We applied density functional theory to study octyl-D-xyloside isomers in order to explain the features responsible for the liquid crystal mesophases. Compared to a glucoside, the xylose headgroup has a proton instead of the hydroxymethyl group on C5. Thus, a xyloside has a reduced headgroup volume that renders it less hydrophilic. Our results have shown that the xylose headgroup may adopt stable pyranose and furanose conformations, which may lead to different effective headgroup hydrophilicities. These features are probably responsible for forming two non-equivalent inverse micelles, which are self-assembled into a cubic discontinuous phase with a space group of Fd3m commonly found for xylosides. While different factors are responsible for controlling the relative stability of each isomer, the role of intramolecular hydrogen bonding was highlighted for the investigated single molecule. The polarisable continuum model was used to take into account the solvent effect in order to understand the mole...

Conformational dynamics of the single lipopolysaccharide O‐antigen in solution

Abstract: The O-antigen is the most variable and highly immunogenic part of the lipopolysaccharide molecule that covers the surface of Gram-negative bacteria and makes up the first line of cellular defense. To provide insight into the details of the O-antigen arrangement on the membrane surface, we simulated its behavior in solution by molecular dynamics. We developed the energetically favorable O-antigen conformation by analyzing free-energy distributions for its disaccharide fragments. Starting from this conformation, we simulated the behavior of the O-antigen chain on long timescales. Depending on the force field and temperature, the single molecule can undergo reversible or irreversible coil-to-globule transitions. The mechanism of these transitions is related either to the rotation of the carbohydrate residues around O-glycosidic bonds or to flips of the pyranose rings. We found that the presence of rhamnose in the O-antigen chain crucially increases its conformational mobility.

Radical-mediated C–H functionalization: a strategy for access to modified cyclodextrins

Abstract: A simple and efficient radical C–H functionalization to access modified cyclodextrins (CDs) has been developed. The well-defined conformation of glycosidic and aglyconic bonds in α-, β-, and γ-CDs favors the intramolecular 1,8-hydrogen atom transfer (HAT) promoted by the 6I-O-yl radical, which abstracts regioselectively the hydrogen at C5II of the contiguous pyranose. The C5II-radical evolves by a polar crossover mechanism to a stable 1,3,5-trioxocane ring between two adjacent glucoses or alternatively triggers the inversion of one α-d-glucose into a 5-C-acetoxy-β-l-idose unit possessing a 1C4 conformation. The 6I,IV- and 6I,III-diols of α- and β-CDs behave similarly to the monoalcohols, forming mostly compounds originating from two 1,8-HAT consecutive processes. In the case of 6I,II-diols the proximity of the two 6-O-yl radicals in adjacent sugar units allows the formation of unique lactone rings within the CD framework via a 1,8-HAT−β-scission tandem mechanism. X-ray diffraction carried out on the cryst...

Synthesis of the C8’-epimeric thymine pyranosyl amino acid core of amipurimycin

Abstract: The C8’-epimeric pyranosyl amino acid core 2 of amipurimycin was synthesized from D-glucose derived alcohol 3 in 13 steps and 14% overall yield. Thus, the Sharpless asymmetric epoxidation of allyl alcohol 7 followed by trimethyl borate mediated regio-selective oxirane ring opening with azide, afforded azido diol 10. The acid-catalyzed 1,2-acetonide ring opening in 10 concomitantly led to the formation of the pyranose ring skeleton to give 2,7-dioxabicyclo[3.2.1]octane 12. Functional group manipulation in 12 gave 21 that on stereoselective β-glycosylation afforded the pyranosyl thymine nucleoside 2 – a core of amipurimycin.

Spirocyclic Orthoesters, Orthothioesters and Orthoaminals in the Synthesis and Structural Modification of Natural Products

Abstract: Spirocyclic scaffolds are embedded in several families of natural products. In the spirocyclic structure, the two rings constituting the spirane are linked through a common carbon atom. This review covers families of compounds that have three heteroatoms directly attached to the spirocarbon. Common heteroatoms are nitrogen, oxygen and sulfur, constituting spirocyclic orthoesters, ortholactones, orthothioesters and orthoaminals, or combinations thereof. Embedded spirocyclic scaffolds introduce steric restrictions and thereby influence bioactivity. In polymer chemistry, synthetic ortholactones may serve as monomers. Synthesis of anomeric spironucleosides will afford molecules where the basic unit is in a fixed conformation around the N-glycosidic bond. Synthesis of glycosidic and 2-deoxyglycosidic ortholactones in disaccharides and regioselective reductive cleavage of cyclic orthoesters result in stereoselective β-(1→4)-glycosidic bond formation. Pyranose and furanose free-radical chemistry via spirocyclic ­orthoesters can be applied in the generation of carbacyclic sugars and nucleosides. 1 Introduction 2 Heteraspiro[3.m]alkanes 3 Heteraspiro[4.m]alkanes 4 Heteraspiro[5.m]alkanes 5 Conclusion

Oxidation of Phe454 in the Gating Segment Inactivates Trametes multicolor Pyranose Oxidase during Substrate Turnover.

Abstract: The flavin-dependent enzyme pyranose oxidase catalyses the oxidation of several pyranose sugars at position C-2. In a second reaction step, oxygen is reduced to hydrogen peroxide. POx is of interest for biocatalytic carbohydrate oxidations, yet it was found that the enzyme is rapidly inactivated under turnover conditions. We studied pyranose oxidase from Trametes multicolor (TmPOx) inactivated either during glucose oxidation or by exogenous hydrogen peroxide using mass spectrometry. MALDI-MS experiments of proteolytic fragments of inactivated TmPOx showed several peptides with a mass increase of 16 or 32 Da indicating oxidation of certain amino acids. Most of these fragments contain at least one methionine residue, which most likely is oxidised by hydrogen peroxide. One peptide fragment that did not contain any amino acid residue that is likely to be oxidised by hydrogen peroxide (DAFSYGAVQQSIDSR) was studied in detail by LC-ESI-MS/MS, which showed a +16 Da mass increase for Phe454. We propose that oxidation of Phe454, which is located at the flexible active-site loop of TmPOx, is the first and main step in the inactivation of TmPOx by hydrogen peroxide. Oxidation of methionine residues might then further contribute to the complete inactivation of the enzyme.

Electrochemical characterization of the pyranose 2-oxidase variant N593C shows a complete loss of the oxidase function with full preservation of substrate (dehydrogenase) activity

Abstract: This study presents the first electrochemical characterization of the pyranose oxidase (POx) variant N593C (herein called POx-C), which is considered a promising candidate for future glucose-sensing applications The resulting cyclic voltammograms obtained in the presence of various concentrations of glucose and mediator (1,4-benzoquinone, BQ), as well as the control experiments by addition of catalase, support the conclusion of a complete suppression of the oxidase function and oxygen reactivity at POx-C Additionally, these electrochemical experiments demonstrate, contrary to previous biochemical studies, that POx-C has a fully retained enzymatic activity towards glucose POx-C was immobilized on a special screen-printed electrode (SPE) based on carbon ink and grafted with gold-nanoparticles (GNP) Suppression of the oxygen reactivity at N593C-POx variant is a prerequisite for utilizing POx in electrochemical applications for glucose sensing To our knowledge, this is the first report presented in the literature showing an absolute conversion of an oxidase into a fully active equivalent dehydrogenase via a single residue exchange

Glycosides, Synthesis and Characterization

Abstract: Monosaccharides are generally defined as aldoses and ketoses connected to a polyhydroxylated skeleton [1]. In an aqueous solution, monosaccharides are subject to internal nucleophilic addition to form cyclic hemiacetal structures. When addition occurs between -OH at C(4) or -OH at C(5), and the carbonyl group, a five- or a six-member ring is formed called a furanose or a pyranose respectively. It is also known that an equilibrium exists between the open and the cyclic form, being displaced to the latter by more than 90 %. Therefore, in aqueous solution, it is more accurate to consider that most sugars are present as cyclic molecules and behave chemically as hemiacetals.

Gel formulations for local drug release

Abstract: The present invention relates to a composition comprising non-water soluble carbohydrates, wherein at least 50% of the non-water soluble carbohydrates are carbohydrates selected from derivatives of lactose, maltose, trehalose, raffinose, glucosamine, galactosamine, lactosamine, or derivatives of disaccharides with at least two pyranose saccharide units, trisaccharides, tetrasaccharides, or mixtures thereof, and wherein the composition is a liquid before administration into the human or animal body and increases in viscosity by more than 1,000 centipoise (cP) after administration, for use as a medicament.

Macrolide derivatives and application thereof

Abstract: The invention provides macrolide derivatives and application thereof. The general molecular formula of the macrolide derivatives is as shown in the description, wherein R1 is selected from hydrogen or a hydroxyl group or a halogen or a C1-C6 alkyl group or a C1-C4 alkoxy group or a C1-C6 alkenyl group or (CH2)m(C6-C10 aryl group) or (CH2)m(C5-C10 ceteroary) or a C2-C10 alkynyl group, R2 and R3 are each selected from hydrogen or a hydroxyl group or a halogen or a C1-C6 alkyl group or a C1-C6 alkenyl group or (CH2)m(C6-C10 aryl group) or (CH2)m(C5-C10 ceteroary) or a C2-C10 alkynyl group or a C1-C4 alkoxy group or a pyranose group, the pyranose group is unsubstituted or substituted with one or more of the following groups of hydrogen, halogen, a C1-C6 alkyl group, a C1-C4 alkoxy group, a C1-C4 alkyl acyl group and a C1-C4 alkyl acyloxy group, and each m is an independent integer ranging from 0 to 4. The compounds can be used for preparing drugs which have the function of promoting alimentary motility and are low in antibiotic activity and small in side effect.