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PubMed2002

Disaccharide conformational maps: 3D contours or 2D plots?

The potential energy surfaces of several alpha-(1-->3)- and beta-(1-->4)-linked disaccharides were obtained and plotted in terms of energy versus psi glycosidic angle. These plots were compared to those obtained previously in the way of the usual 3D contour maps, which relate the energy with the two glycosidic angles (phi and psi). Given the usually small variations of the phi angle in the low-energy regions (at least using MM3), both kinds of graphs lead to similar conclusions concerning flexibility measurements by two different methods and assessment of the effects of sulfation and/or hydroxyl group orientation. Only second-order effects were found with some sulfated disaccharides, not changing the general conclusions. The computational efforts required to produce those plots are smaller, and the plots are easier to interpret. Besides, the conversion of a 3D map into a 2D plot leaves the possibility of constructing 3D maps of carbohydrates including a second variable different to phi, e.g., the second psi angle of a trisaccharide or the omega angle of a 6-linked disaccharide.

Carbohydrate Conformation↗
PubMed1998

Conversion of N-sulfated glucosamine to N-sulfated mannosamine in an unsaturated heparin disaccharide by non-enzymatic, base-catalyzed C-2 epimerization during enzymatic oligosaccharide preparation.

A novel disaccharide was isolated beside the predominant trisulfated disaccharide, delta HexA(2-O-sulfate)(alpha 1-4)GlcN(2-N-,6-O-disulfate) (delta HexA and GlcN represent 4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid and D-glucosamine, respectively) after treatment of porcine intestinal heparin with Flavobacterium heparinase. It accounted for 18% of total disaccharides. The structure was characterized by secondary ion mass spectrometry, enzymatic digestions, amino sugar analysis, and 500 MHz one- and two-dimensional 1H NMR spectroscopy as delta HexA(2-O-sulfate) (alpha 1-4)ManN(2-N-,6-O-disulfate), where ManN represents D-mannosamine. The C-2 epimerization from delta HexA(2-O-sulfate) (alpha 1-4)GlcN(2-N-,6-O-disulfate) to delta HexA(2-O-sulfate) (alpha 1-4)ManN(2-N-,6-O-disulfate) was also demonstrated to take place in vitro under very mild alkaline conditions. Hence, the latter compound is not a biosynthetic product, but is most likely an artifact generated by non-enzymatic, base-catalyzed C-2 epimerization during enzymatic preparation of heparin oligosaccharides. The present results warn that the formation of the C-2 epimerized compound has to be circumvented in the structural analysis of heparin/heparan sulfate.

Catalysis↗
PubMed2000

Synthesis of ethyl 2-acetamido-6-S-(5-amino-5-deoxy-beta-D- arabinopyranosyl)-2-deoxy-1,6-dithio-beta-D-glucopyranoside: a sulfur-linked 5-amino-5-deoxyglycopyranosyl disaccharide.

A novel pseudo-disaccharide having an imino sugar residue at the non-reducing end, namely, a sulfur-linked 5-amino-5-deoxyglycopyranosyl disaccharide, which is a potential specific inhibitor for glycosidases that recognize not only the glycosidic linkage but also the aglycone moiety, was synthesized. Glycosidation of N-Boc-5-amino-5-deoxy-D-arabinose with ethyl 2-acetamido-3,4-di-O-acetyl-2-deoxy-1,6-dithio-beta-D- glucopyranoside in the presence of TsOH gave exclusively the corresponding 1,2-cis-linked thioglycoside. The interglycosidic linkage proved stable enough under conditions for the deprotection of the N-Boc group with TFA. This pseudodisaccharide was unstable at pH > 5, but stable at lower pH. The sulfur-linked 5-amino-5-deoxyglycopyranosyl disaccharide was shown to be formed from 5-amino-5-deoxy-D-arabinose and ethyl 2-acetamido-2-deoxy-1,6-dithio-beta-D-glucopyranoside in an acidic buffer solution.

Disaccharides↗
PubMed1999

Ultrasensitive capillary electrophoresis of sulfated disaccharides in chondroitin/dermatan sulfates by laser-induced fluorescence after derivatization with 2-aminoacridone.

An ultrasensitive capillary electrophoretic method for separating the variously sulfated chondroitin/dermatan sulfate-derived delta-disaccharides after digestion with chondro/dermatolyases and derivatization with the fluorophore 2-aminoacridone is described. All known mono-, di- and tri-sulfated delta-disaccharides were completely separated using 15 mM orthophosphate buffer (pH 3.0) at 20 kV without any interference of the excess derivatizing reagent. They were detected at the anode (reversed polarity) using either an Ar-ion laser-induced fluorescence (LIF) detector (excitation wavelength 488 nm) or a UV detector. The sensitivity obtained by LIF (0.51 pmol/l) was at least 100 and 10 times higher as compared to those obtained by UV detection at 232 nm of underivatized delta-disaccharides and at 254 nm of those derivatized with aminoacridone, respectively. The method has been easily applied to the analysis of chondroitin/dermatan sulfates from various tissues at the attogram level, including chondrotin/dermatan sulfates from normal and aneurysmal human abdominal aortas.

Aminoacridines↗
PubMed1999

Temporal changes in disaccharide composition of dermatan sulfate in the skin after epicutaneous application of hapten.

Glycosaminoglycans change their amount, structure and distribution with age, differentiation and pathologic conditions. In order to investigate temporal changes in dermatan sulfate in the skin during inflammation and subsequent healing, 2,4-dinitrofluorobenzene (DNFB) was applied once to the dorsal skin of female BALB/cA mice, and the disaccharide composition of dermatan sulfate was examined. Application of DNFB induced a transient increase in the thickness of the dermis, which reached a maximum on day 15 and decreased to the control level on day 35. The total amount of unsaturated disaccharides from dermatan sulfate per cm2 in the DNFB-treated skin showed a temporal pattern similar to that of the thickness of the dermis. Mol% of 4,5-unsaturated 2-sulfo-hexuronic acid-4-sulfated N-acetylgalactosamine (deltaDi-diSB), the second most abundant unsaturated disaccharide from dermatan sulfate, decreased rapidly on day 3 in the DNFB-treated skin, remained less than the control on days 7 and 15, and returned to the control level on day 35. These results suggest that a single application of DNFB induces temporal changes not only in the amount but also in the structure of dermatan sulfate.

Administration, Cutaneous↗
PubMed2003

Incremented alkyl derivatives enhance collision induced glycosidic bond cleavage in mass spectrometry of disaccharides.

Electrospray ionization and collision induced dissociation on a triple quadrupole mass spectrometer were used to determine the effect of spatial crowding of incremented alkyl groups of two anomeric pairs of peralkylated (methyl to pentyl) disaccharides (maltose/cellobiose and isomaltose/gentiobiose). Protonated molecules were generated which underwent extensive fragmentation under low energy conditions. For both the 1 --> 4 and 1 --> 6 alpha and beta isomers, at comparable collision energies the methyl derivative exhibited the least fragmentation followed by ethyl, propyl, butyl, and pentyl. Collision energy is converted to rotational-vibrational modes in competition with bond cleavage, as represented by the slope of product/parent ion (D/P) ratio versus offset energy. Variable rotational freedom at the glycosidic linkage with incremented alkyl groups is hypothesized to be responsible for this effect. Discrimination of anomeric configuration was also assessed for these stereoiosmeric disaccharides. A systematic study showed that an increasing discrimination was attained for the 1 --> 4 isomeric pair as the size of the derivative increased from methyl to pentyl. No anomeric discrimination was attained for the 1 --> 6 isomeric pair. Parent and product ion scans confirmed the consistency of fragmentation pathways among derivatives. Chem-X and MM3 molecular modeling programs were used to obtain minimum energy structures and freedom of motion volumes for the permethylated disaccharides. The modeling results correlated with the fragmentation ratios obtained in the mass spectrometer giving strong indication that the collision induced spectra are dependent on the freedom of rotational motion around the glycosidic bond.

Algorithms↗
PubMed1999

Determining anomericity of the glycosidic bond in Zn(II)-diethylenetriamine-disaccharide complexes using MSn in a quadrupole ion trap.

Zinc-diethylenetriamine (Zn-dien) N-glycoside complexes of four 1,4 and four 1,6 linked disaccharides are prepared. Each reaction mixture is ionized by electrospray and the resulting species [Zn(dien)(disaccharide)-H]+ is allowed to undergo collision-induced dissociation in a quadrupole ion trap. An MS3 analysis is used to differentiate alpha versus beta anomericity of the glycosidic bond in the disaccharide moiety. In addition, the MS2 and MS3 spectra can be used together to determine the linkage position of this glycosidic bond.

Disaccharides↗
PubMed2000

Structural analysis of chromophore-labeled disaccharides by capillary electrophoresis tandem mass spectrometry using ion trap mass spectrometry.

Disaccharides tagged with p-aminobenzoic acid (ABA) were separated by capillary electrophoresis (CE) and analyzed on-line with negative ion electrospray ionization tandem mass spectrometry (ESI/MS/MS). The formation of glycosylamine instead of reductive amination was selected as the derivatization reaction. In negative ion ESI, the glycosylamine approach provides more information on linkage and anomeric configuration than reductive amination. In CE analysis of ABA-labeled disaccharides, alpha-cyclodextrin (CD) was found to play a crucial role in the separation of linkage isomers. Although ammonium acetate/alpha-CD provided the best resolution of linkage isomers, the borate buffer was superior to alpha-CD in the separation of disaccharides with the same linkage but different anomeric configuration and/or monosaccharide composition. Both alpha-CD and borate suppressed the ion signal in ESI, and operational conditions were successfully obtained using 10 mM alpha-CD or 10 mM borate.

Carbohydrate Sequence↗
PubMed2003

Determination of monosaccharides and disaccharides in mucopolysaccharidoses patients by electrospray ionisation mass spectrometry.

The mucopolysaccharidoses are a group of lysosomal storage disorders characterised by the storage of glycosaminoglycans. With the exception of Hunters syndrome (MPS II), which is X-linked, they are autosomal recessively inherited resulting in a defect in any one of 10 lysosomal enzymes needed to catabolise glycosaminoglycans. The type and size of the glycosaminoglycans stored in lysosomes are determined by the particular enzyme deficiency. These glycosaminoglycan elevations are subsequently observed in tissue, circulation, and urine. A method has been developed for the derivatisation and quantification of sulfated N-acetylhexosamine-containing mono- and disaccharides from patient samples by electrospray ionisation tandem mass spectrometry. Urine from most mucopolysaccharidoses types had significant increases in di- and monosulfated N-acetylhexosamines (GalNAc4,6S, GalNAc6S, GalNAc4S, or GlcNAc6S) and monosulfated N-acetylhexosamine-uronic acid disaccharides (GalNAc6S-UA, GalNAc4S-UA, or GlcNAc6S-UA). Analysis of plasma and dried blood spots on filter paper collected from mucopolysaccharidoses patients showed elevations of total monosulfated N-acetylhexosamines but less than that seen in urine. Urine samples from bone marrow transplant recipients, mucopolysaccharidosis IVA and mucopolysaccharidosis VI patients, showed decreases in HexNAcS, HexNAcS(2)/GalNAc4,6S, and HexNAcS-UA post-transplant. This decrease correlated with clinical improvement to levels comparable with those identified in patients with less severe phenotypes. These metabolic markers therefore have potential applications in diagnosis, phenotype prediction and monitoring of current and future therapies, particularly for the mucopolysaccharidosis IIID, IVA, VI, and multiple sulfatase deficiency. This paper reports a sensitive and simple method for the measurement of sulfated N-acetylhexosamines and sulfated disaccharides shown to be elevated in some mucopolysaccharidosis and multiple sulfatase deficient patients.

Adolescent↗
PubMed1998

Novel disaccharide inhibitors of human glioma cell division.

Several alpha-L-Fuc-(1-->3)-alpha-D-GlcNAcOC8H17 disaccharide derivatives bearing different hydroxylated alkyl chains, with or without sulfate groups at C-4 and/or C-6 positions of the GlcNAc unit, have been synthesized and tested as inhibitors of human astrocytoma lines U-373 and U-118. The antimitotic activity was dependent on the structure and position of the hydroxylated chain linked to the disaccharide. The compounds with a pentaerythritol or L-glyceryl chain at the C-6 position showed the best inhibitory properties, with an ID50 value of ca. 200 microM. On the contrary, sulfated disaccharide derivatives were inactive. The antimitotic activities of the compounds tested were essentially independent of the mitogen used to stimulate cell division.

Antineoplastic Agents↗
PubMed2000

An olefin metathesis route for the preparation of (1-->6)-linked C-disaccharide glycals. A convergent and flexible approach to C-saccharide synthesis.

A convergent route to a variety of C-1-disaccharide glycals based on the olefin metathesis reaction of enol ethers and alkenes is described. The DCC-mediated coupling reaction of a variety of pentose enitols (1a-c) with a number of C-5- and C-6-monosaccharide carboxylic acids (2a-e) gave the corresponding esters 3a-l in good yield. Methylenation of these compounds was followed by ring-closing metathesis, mediated by the Schrock molybdenum catalyst 8 in warm toluene, to provide the target C-disaccharide glycals 5a-l. The formed enol ether double bond in 5a was then transformed, via standard manipulations, into a variety of C-disaccharide derivatives 21-25.

Alkenes↗
PubMed2000

Anthracycline metabolism and toxicity in human myocardium: comparisons between doxorubicin, epirubicin, and a novel disaccharide analogue with a reduced level of formation and [4Fe-4S] reactivity of its secondary alcohol metabolite.

Secondary alcohol metabolites have been proposed to mediate chronic cardiotoxicity induced by doxorubicin (DOX) and other anticancer anthracyclines. In this study, NADPH-supplemented human cardiac cytosol was found to reduce the carbonyl group in the side chain of the tetracyclic ring of DOX, producing the secondary alcohol metabolite doxorubicinol (DOXol). A decrease in the level of alcohol metabolite formation was observed by replacing DOX with epirubicin (EPI), a less cardiotoxic analogue characterized by an axial-to-equatorial epimerization of the hydroxyl group at C-4 in the amino sugar bound to the tetracyclic ring (daunosamine). A similar decrease was observed by replacing DOX with MEN 10755, a novel anthracycline with preclinical evidence of reduced cardiotoxicity. MEN 10755 is characterized by the lack of a methoxy group at C-4 in the tetracyclic ring and by intercalation of 2, 6-dideoxy-L-fucose between daunosamine and the aglycone. Multiple comparisons with methoxy- or 4-demethoxyaglycones, and a number of mono- or disaccharide 4-demethoxyanthracyclines, showed that both the lack of the methoxy group and the presence of a disaccharide moiety limited alcohol metabolite formation by MEN 10755. Studies with enzymatically generated or purified anthracycline secondary alcohols also showed that the presence of a disaccharide moiety, but not the lack of a methoxy group, made the metabolite of MEN 10755 less reactive with the [4Fe-4S] cluster of cytoplasmic aconitase, as evidenced by its limited reoxidation to the parent carbonyl anthracycline and by a reduced level of delocalization of Fe(II) from the cluster. Collectively, these studies (i) characterize the different influence of methoxy and sugar substituents on the formation and [4Fe-4S] reactivity of anthracycline secondary alcohols, (ii) lend support to the role of alcohol metabolites in anthracycline-induced cardiotoxicity, as they demonstrate that the less cardiotoxic EPI and MEN 10755 share a reduction in the level of formation of such metabolites, and (iii) suggest that the cardiotoxicity of MEN 10755 might be further decreased by the reduced [4Fe-4S] reactivity of its alcohol metabolite.

Antibiotics, Antineoplastic↗
PubMed1998

Conformational analysis of a Chlamydia-specific disaccharide alpha-Kdo-(2-->8)-alpha-Kdo-(2-->O)-allyl in aqueous solution and bound to a monoclonal antibody: observation of intermolecular transfer NOEs.

The disaccharide alpha-Kdo-(2-->8)-alpha-Kdo (Kdo: 3-deoxy-D-manno-oct-2-ulosonic acid) represents a genus-specific epitope of the lipopolysaccharide of the obligate intracellular human pathogen Chlamydia. The conformation of the synthetically derived disaccharide alpha-Kdo-(2-->8)-alpha-Kdo-(2-->O)-allyl was studied in aqueous solution, and complexed to a monoclonal antibody S25-2. Various NMR experiments based on the detection of NOEs (or transfer NOEs) and ROEs (or transfer ROEs) were performed. A major problem was the extensive overlap of almost all 1H NMR signals of alpha-Kdo-(2-->8)-alpha-Kdo-(2-->O)-allyl. To overcome this difficulty, HMQC-NOESY and HMQC-trNOESY experiments were employed. Spin diffusion effects were identified using trROESY experiments, QUIET-trNOESY experiments and MINSY experiments. It was found that protein protons contribute to the observed spin diffusion effects. At 800 MHz, intermolecular trNOEs were observed between ligand protons and aromatic protons in the antibody binding site. From NMR experiments and Metropolis Monte Carlo simulations, it was concluded that alpha-Kdo-(2-->8)-alpha-Kdo-(2-->O)-allyl in aqueous solution exists as a complex conformational mixture. Upon binding to the monoclonal antibody S25-2, only a limited range of conformations is available to alpha-Kdo-(2-->8)-alpha-Kdo-(2-->O)-allyl. These possible bound conformations were derived from a distance geometry analysis using transfer NOEs as experimental constraints. It is clear that a conformation is selected which lies within a part of the conformational space that is highly populated in solution. This conformational space also includes the conformation found in the crystal structure. Our results provide a basis for modeling studies of the antibody-disaccharide complex.

Antibodies, Monoclonal↗
PubMed2003

Ab initio and NMR studies on the effect of hydration on the chemical shift of hydroxy protons in carbohydrates using disaccharides and water/methanol/ethers as model systems.

Density functional theory (DFT) and Hartree-Fock (HF) quantum mechanical calculations have been performed on the disaccharides, [small beta]-l-Fucp-(1[rightward arrow]4)-[small alpha]-d-Galp-OMe, [small beta]-l-Fucp-(1[rightward arrow]4)-[small alpha]-d-Glcp-OMe, and [small beta]-l-Fucp-(1[rightward arrow]3)-[small alpha]-d-Glcp-OMe. The [capital Delta][small delta]-values (difference between the chemical shift in the disaccharide and the corresponding monosaccharide methyl glycoside) for the exchangeable hydroxy protons have been calculated and compared to experimental values previously measured by NMR spectroscopy for samples in aqueous solutions. The calculations performed on molecules in vacuum showed that hydroxy protons hydrogen bonded to the neighboring ring oxygens have large positive [capital Delta][small delta]-values, indicating that they are deshielded relative to those in the corresponding methyl glycoside. The NMR experiments showed instead that these hydroxy protons close to the neighboring ring oxygens were shielded. This discrepancy between calculated and experimental data was attributed to solvent effects, and this hypothesis has been confirmed in this work by monitoring the chemical shift of the hydroxy proton of methanol in water, ethers and water/ether solutions. Shielding of the hydroxy proton of methanol is observed for increased ether concentrations, whereas deshielding is observed for increased concentration of water. The shielding observed for hydroxy protons in disaccharides is a consequence of reduced hydration due to intermolecular hydrogen bonding or steric effects. In strongly hydrated systems such as carbohydrates, the hydration state of a hydroxy proton is the key factor determining the value of the chemical shift of its NMR signal, and the [capital Delta][small delta] will be a direct measure of the change in hydration state.

Carbohydrate Conformation↗
PubMed2004

Synthesis of 6,6'-ether linked disaccharides from D-allose, D-galactose, D-glucose and D-mannose; evidence on the structure of coyolosa.

6,6'-Linked ethers derived from D-allose, D-galactose, D-glucose, and D-mannose have been prepared in order to allow comparisons with the reported 6,6'-linked hexopyranose coyolosa, an hypoglycemic compound which has been isolated by extraction of the root of the palm Acrocomia mexicana. Comparison of NMR data from the ethers and their derived peracetates with corresponding reported data from coyolosa and its peracetate indicate that coyolosa is not a 6,6'-linked disaccharide. The synthesised compounds are representatives of a novel class of disaccharide derivatives which are linked tail to tail in contrast to the more usual head to tail(e.g. maltose) or head to head(e.g. trehalose) disaccharides.

Disaccharides↗
PubMed1977

Specificity of flavobacterial glycuronidases acting on disaccharides derived from glycosaminoglycans.

The specificity of the unusual flavobacterial glycuronidases that act on disaccharides containing delta4,5-unsaturated uronic acids was reinvestigated. The results show that the enzyme that hydrolyses the uronidic bond in disaccharides from hyaluronic acid and the chondroitin sulphates appears to be mainly specific for beta-D-(1 leads to 3)-derived linkages. The enzyme that hydrolyses the uronidic bond in a variety of disaccharides obtained from heparan sulphate and heparin appears to be specific for beta-D-(1 leads to 4)- and alpha-L-(1 leads to 4)- derived linkages. Thus the glycuronidases seem to be specific for linkage position rather than anomeric configuration, as had been thought previously. In addition, the data confirm other evidence that the major glucuronidic linkages in heparan sulphate and heparin have the beta-D-configuration, and the iduronidic linkages the alpha-L-configuration.

Chondroitin Sulfates↗
PubMed1983

Changes in disaccharide composition of heparan sulphate fractions with increasing degrees of sulphation.

Heparan sulphate by-products from the commercial manufacture of pig mucosal heparin were freed of chondroitin sulphate and fractionated according to anionic density. The fractions were treated with HNO2 at pH 1.5, and the resulting mixtures of oligosaccharides were reduced with NaB3H4 and analysed for their disaccharide composition by paper chromatography and by high-pressure liquid chromatography. The results show that the molar ratio of 2-O-sulpho-alpha-L-iduronosylanhydromannose to 6-O-sulpho-(2-O-sulpho-alpha-L-iduronosyl)anhydromannose decreased from 2.5 to 0.04 as the degree of sulphation of the fractions increased. In contrast, the molar ratio of 6-O-sulpho-(beta-D-glucuronosyl)anhydromannose to 6-O-sulpho-(alpha-L-iduronosyl)anhydromannose was approx. 2.4 in all heparan sulphate fractions and decreased to only half of this value in the most highly sulphated heparin fractions. These results are consistent with biosynthetic studies, which have shown that the N-sulpho-(2-O-sulpho-alpha-L-iduronosyl)D-glucosamine disaccharide is the metabolic precursor of the NO-disulpho-(2-O-sulpho-alpha-L-iduronosyl)-D-glucosamine disaccharide in heparin biosynthesis. The high-pressure liquid chromatography of the heparan sulphate oligosaccharides also revealed a number of unidentified oligosaccharides in the deamination mixtures.

Blood Coagulation↗
PubMed2004

Conformational kinetics of disaccharides in aqueous solutions.

Between 100 kHz and 2 GHz ultrasonic attenuation spectra of disaccharides in water have been measured at 25 degrees C. Some additional measurements have been performed at different temperatures between 10 and 35 degrees C and as a function of saccharide concentration c (0.5 mol/l</=c</=1.8 mol/l). The analytical description of the spectra in terms of relaxation spectral functions revealed four relaxation regimes. Three relaxation regions correspond to such revealed by monosaccharides in solution. These relaxations reflect a pseudorotation, an exocyclic hydroxymethyl group rotation, and probably a saccharide-saccharide association. The relaxation term with relaxation time between 3.6 and 19 ns (25 degrees C) is characteristic for the disaccharide solutions. It has been assigned to a rotation of the disaccharide rings relative to one another.

Disaccharides↗