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PubMed1988

[Synthesis of determinant disaccharides of O-antigens of Salmonella of serological groups A, B and D1 in the form of glycosides suitable for conversion into artificial antigens via copolymerization].

The synthesis of 3-O-(alpha-paratosyl)-, 3-O-(alpha-abequosyl)-, and 3-O-(alpha-tyvelosyl)-alpha-D-mannopyranoses, group-specific disaccharides fragments of the Salmonella O-specific polysaccharides (serological groups A, B, and D1) is described. Disaccharides were prepared in the form of allyl and 2-acrylamidoethyl glycosides suitable for conversion into artificial antigens via copolymerisation.

Antigens, Bacterial↗
PubMed1989

Identification of a disaccharide (Xyl-Glc) and a trisaccharide (Xyl2-Glc) O-glycosidically linked to a serine residue in the first epidermal growth factor-like domain of human factors VII and IX and protein Z and bovine protein Z.

We have recently described a unique trisaccharide linked to a serine residue in the first epidermal growth factor-like domains of bovine blood coagulation factors VII (Ser-52) and IX (Ser-53) (Hase, S., Kawabata, S., Nishimura, H., Takeya, H., Sueyoshi, T., Miyata, T., Iwanaga, S., Takao, T., Shimonishi, Y., and Ikenaka, T. (1988) J. Biochem. (Tokyo) 104, 867-868). The sugar chain identified in these clotting factors consists of 1 mol of hexose (glucose (Glc] and 2 mol of pentose (xylose (Xyl]. We report here that human factors VII and IX and protein Z and bovine protein Z also contain such carbohydrate moieties linked to a serine residue at the same position found in bovine factors VII and IX. A glycopeptide derived from each of these proteins was subjected to amino acid sequence and component sugar analyses and fast atom bombardment mass spectrometric analysis. The results indicate that the glycopeptide derived from human factor IX contains 1 mol each of Glc and Xyl. The reducing end of this disaccharide was identified as Glc by analyzing the disaccharide generated by hydrazinolysis. In contrast, human factor VII and protein Z yielded two different glycopeptides which contained Glc and Xyl at molar ratios of 1:1 and 1:2, respectively, suggesting microheterogeneity of these O-linked sugar chains. Bovine protein Z glycopeptide contained 1 mol of Glc and 2 mol of Xyl. These sugar compositions were confirmed by analyses of the intact proteins. In relation to the trisaccharide sugar chain previously discovered in bovine factors VII and IX, these findings indicate the existence of a Xyl2-Glc-Ser and a Xyl-Glc-Ser structure in the first epidermal growth factor-like domains of human factors VII and IX and protein Z in addition to that of bovine protein Z. Whether these carbohydrate moieties contribute to the biological activities of these proteins is unknown.

Amino Acid Sequence↗
PubMed1988

[The nuclear Overhauser effect and structural factors determining the conformation of disaccharides].

Conformational analysis of 1.2-, 1.3- and 1.4-linked disaccharides built up of aldohexapyranose residues was performed on the basis of interresidue nuclear Overhauser effects in 1H-NMR spectra and theoretical calculation using atom-atom potential functions. It was shown that the preferred conformation of the disaccharides is determined by the following factors: absolute configurations of monosaccharide residues, configuration and position of the glycosidic linkage, orientation of protons at the aglycon carbon atom involved in the glycosidic linkage and at the adjacent carbons atoms.

Carbohydrate Conformation↗
PubMed1975

[Trehalose, the principle disaccharide of wine].

By gas chromatography of trimethylsilylated derivatives of sugars, trehalose has been shown to be the main disaccharide in wines; its amount can reach 600 mg/l. Other disaccharides identified (sucrose, isomaltose, lactose and turanose) are present in small amounts, seldom above 50 mg/l, sometimes below 5 mg/l. Traces of melibiose and gentiobiose are possible. Conditions of trehalose formation by yeast during fermentation are described. Also technological applications of these results are discussed.

Anion Exchange Resins↗
PubMed1993

Capillary electrophoresis to measure sulfoesterase activity on chondroitin sulfate and heparin derived disaccharides.

Capillary electrophoresis was used to assay sulfoesterase activity on sulfated disaccharides derived from chondroitin sulfate, dermatan sulfate and heparin. The three sulfoesterases studied were chondro-4-O-sulfatase (EC 3.1.6.9) and chondro-6-O-sulfatase (EC 3.1.6.10) from Proteus vulgaris and heparo-2-O-sulfatase from Flavobacterium heparinum. Capillary electrophoresis was used to analyse sulfated disaccharide before and after sulfoesterase treatment and a change in migration time was indicative of the presence of sulfoesterase activity. This assay was used both on purified sulfoesterases and on minor sulfoesterase contaminants present in other enzyme preparations. The high sensitivity of capillary electrophoresis permits the elimination of 35S-radiolabeled substrates normally required to assay sulfoesterases. The high resolution of capillary electrophoresis allows the use of this assay on impure enzyme preparations containing high protein concentrations.

Chondro-4-Sulfatase↗
PubMed1998

Improved efficacy and enlarged spectrum of activity of a novel anthracycline disaccharide analogue of doxorubicin against human tumor xenografts.

On the basis of a structure-activity study of a new series of anthracycline disaccharides, we recently identified a doxorubicin analogue (MEN 10755) with a promising antitumor activity. In the present study, to better support the pharmacological interest of MEN 10755, we extended the preclinical evaluation of antitumor efficacy to a large panel of 16 human tumor xenografts, which originated from different clinicopathological types. Tumors with typical multidrug-resistant phenotype were excluded because MEN 10755 was found unable to overcome resistance mediated by transport systems. In the doxorubicin-responsive series, MEN 10755 exhibited a higher activity in three of five tumors, as documented by a more marked tumor growth inhibition and an increased value of log-cell kill. In the series of doxorubicin-resistant tumors, MEN 10755 was found effective in 6 of 11 tumors (1 breast, 3 lung, and 2 prostate carcinomas). The overall response rates were 31% and 69% for doxorubicin and MEN 10755, respectively. The improvement in drug efficacy was also supported by a substantial increase in the long-term survivor rate of animals implanted with responsive tumors. Most of the tumors refractory to doxorubicin and responsive to MEN 10755 were characterized by overexpression of the antiapoptotic protein Bcl-2. In one of these tumors (MX-1 breast carcinoma), we examined the ability of MEN 10755 to induce phosphorylation of Bcl-2 after a single treatment with therapeutic doses. The results indicated that, unlike doxorubicin, MEN 10755 induced protein phosphorylation. A similar modification was produced by Taxol, which is known to be very effective against the tumor. The correlation between drug efficacy and Bcl-2 phosphorylation may underly a peculiar feature related to improvement of efficacy of the disaccharide analogue. In conclusion, the present study supports some favorable features of the novel doxorubicin analogue in terms of both efficacy and tolerability with comparison to doxorubicin, although the improvement is somewhat tumor- and schedule-dependent.

Animals↗
PubMed2005

Molecular dynamics and conformational kinetics of mono- and disaccharides in aqueous solution.

Acoustical attenuation spectra between 10 kHz and 2 GHz, complex dielectric spectra between 300 kHz and 40 GHz, and time-resolved non-equilibrium measurements are reported for aqueous solutions of various mono- and disaccharides with and without 2:1 valent salts. The spectra reveal a variety of relaxation regimes with relaxation times between 1 micros and 10 ps. In addition, the time-resolved observations enable the study of the mutarotation with relaxation times on the order of 10(3) s. Variation of the concentration and temperature as well as a careful choice of the saccharides allow a discussion of the relaxation processes in terms of a chair-chair ring inversion, two modes of pseudorotation, an exocyclic hydroxymethyl group rotation, a carbohydrate-carbohydrate association, and, in the disaccharide solutions, a rotation of the rings relative to another. Salt-containing solutions show also relaxation phenomena reflecting different steps cation-carbohydrate association and variations in the carbohydrate conformational isomerizations and associations due to interactions with cations.

Carbohydrate Conformation↗
PubMed1994

Microbial cometabolism of sucralose, a chlorinated disaccharide, in environmental samples.

During the rapid mineralization in soil of sucralose (4-chloro-4-deoxy-alpha, D-Galactopyranosyl-1,6-dichloro-1,6-dideoxy-beta, D-fructofuranoside), a metabolic product was formed that appears to be the corresponding unsaturated aldehyde. During the slow and incomplete mineralization of sucralose in lake water, which was not increased by the addition of nitrogen and phosphorus, the same compound was produced. That product was further metabolized by microorganisms in lake water and soil. Mineralization was also slow in sewage under aerobic conditions, but organic products were not detected. Little or no CO2 was formed from the disaccharide in flooded soil or anaerobic sewage. Bacteria in culture did not use sucralose as a carbon source but did convert it to the presumed unsaturated aldehyde, 1,6-dichloro-1,6-dideoxy-D-fructose and possibly the uronic acid of sucralose. Sucralose carbon was not incorporated into cells of two sucralose-metabolizing bacteria or the microbial biomass of sewage or lake water. The chlorinated disaccharide was slowly metabolized by a galactose oxidase preparation. It is concluded that the chlorinated sugar is acted on microbiologically by cometabolism.

Bacteria↗
PubMed1989

Intraischemic metabolic effects of different disaccharides on protected canine kidneys.

The addition of the disaccharides maltose (10, 20, 30 mM) and sucrose (30, 60 mM) to Bretschneider's organ protective HTK solution was evaluated to improve renal protection by an enhanced glycolytic energy supply. Canine kidneys were perfused for 8 min with either HTK solution or HTK solution containing additional disaccharides. After nephrectomy the kidneys were incubated at 25 degrees C and metabolic parameters were determined at regular intervals. Maltose and sucrose are slowly cleaved during renal ischemia but maltose distinctly faster than sucrose. Maltose increases intraischemic ATP supply. However, 30 mM maltose was no better than 10 mM. 60 mM sucrose was about as effective for glycolysis as 10 mM maltose. However, possibly due to fructose release there was an accelerated decrease of adenine nucleotides with sucrose. Although fructose enters glycolysis it seems to have negative side-effects. Hence, probably neither sucrose nor fructose are appropriate for renal substrate supply during ischemia.

Adenosine Triphosphate↗
PubMed1992

Molecular modelling of acarviosine, the pseudo-disaccharide moiety of acarbose, and other inhibitors of alpha-amylases.

Acarbose and its homologs inhibit alpha-D-glucosidases, particularly alpha-amylases. These homologs have the same core, the pseudo-disaccharide acarviosine, linked to various numbers of glucose residues. The conformations of (R)- and (S)-acarviosine have been analysed. The potential energy maps, obtained by molecular mechanics calculations, show that acarviosine is flexible and has several important minima. One low-energy form is close to the shape assumed by the acarviosine moiety when acarbose is adsorbed on the surface of glycogen phosphorylase. Another likely conformation is the same as that inferred from n.m.r. data and HSEA calculations. The results reconcile those conflicting reports. Molecular modelling of other inhibitors of alpha-amylases, such as 4-thiomaltose and moranoline, shows that these pseudo-disaccharides can fill similar volumes of conformational space.

1-Deoxynojirimycin↗
PubMed2005

Ramachandran free-energy surfaces for disaccharides: trehalose, a case study.

We present calculated potential of mean force surfaces for rotation about phi, psi dihedral angles of the alpha(1<-->1)alpha-glycosidic linkage in the disaccharide trehalose (alpha-D-Glc-(1<-->1)-alpha-D-Glc) in both vacuum and aqueous solution. The effects of aqueous solvation upon the alpha(1<-->1)alpha-glycosidic linkage are investigated through comparison of the vacuum and aqueous solution free-energy surfaces. These surfaces reveal that trehalose is restricted to a single minimum-energy conformation in both vacuum and solution. The exceptional rigidity of this disaccharide in solution may provide a molecular rationale for the antidesiccant properties of trehalose glasses.

Carbohydrate Conformation↗
PubMed2004

The X-ray structure of RANTES: heparin-derived disaccharides allows the rational design of chemokine inhibitors.

The biological activity of chemokines requires interactions with cell surface proteoglycans. We have determined the structure of the chemokine RANTES (regulated on activation normal T cell expressed) in the presence of heparin-derived disaccharide analogs by X-ray crystallography. These structures confirm the essential role of the BBXB motif in the interaction between the chemokine and the disaccharide. Unexpected interactions were observed in the 30s loop and at the amino terminus. Mutant RANTES molecules were designed to abrogate these interactions and their biological activity examined in vivo. The K45E mutant within the BBXB motif lost the capacity to bind heparin and the ability to elicit cellular recruitment. The Y3A mutant maintained its capacity to bind heparin but was unable to elicit cellular recruitment. Finally, a tetrasaccharide is the smallest oligosaccharide which effectively abolishes the ability of RANTES to recruit cells in vivo. These crystallographic structures provide a description of the molecular interaction of a chemokine with glycosaminoglycans.

Carbohydrate Sequence↗
PubMed1996

Association of lipid A disaccharide synthase with aerobic glycerol-3-phosphate dehydrogenase in extracts of Escherichia coli.

Variants of the Escherichia coli UDP-GlcNAc O-acyltransferase (LpxA) and of the lipid A disaccharide synthase (LpxB) containing affinity chromatography tags (C-terminal histidine 8 [H8] tails) were constructed in order to investigate whether or not these enzymes interact with other E. coli proteins. These variants (LpxA-H8 and LpxB-H8) had specific activities in vitro that were similar to wild-type enzymes. Crude extracts made from E. coli cells expressing LpxA-H8 or LpxB-H8 were chromatographed over Ni(2+)-NTA-Agarose, and proteins purifying with the tagged proteins were identified by SDS-PAGE, followed by blotting and N-terminal microsequencing. At high levels of LpxB-H8 expression, two heat-shock proteins (DnaK and GroEL) were associated with the disaccharide synthase, but not with the acyltransferase. Another major protein recovered with LpxB-H8 (both at low and high levels of expression) was the aerobic glycerol-3-phosphate dehydrogenase (GlpD). The latter interaction was specific, since GlpD did not bind the affinity resin when the affinity tag was present on the UDP-GlcNAc O-acyltransferase (LpxA-H8). Velocity centrifugation experiments indicated that both wild-type LpxB and GlpD sedimented together under some conditions, but these aggregates were smaller than and distinct from inner membranes. Our findings suggest a possible new mechanism by which the biosynthetic pathways for lipid A and glycerophospholipids may be coordinated.

Acyltransferases↗
PubMed2003

Modulation of [3H] TBOB binding to the rodent GABAA receptor by simple disaccharides.

We have recently reported evidence that a simple beta-linked alkylated mannose reversibly increased the magnitude of GABA(A) receptor currents evoked in cultured rat pyramidal neurons whilst concomitantly reducing the incidence of spontaneous synaptic activity. In this present study, the effects of the simple beta-linked disaccharide, lactose was investigated using a [3H] TBOB (t-[3H] butylbicycloorthobenzoate) binding assay in adult rat forebrain and cerebellum membranes. Lactose elicited a significant potentiation of [3H] TBOB binding to well-washed forebrain and cerebellar membranes (mean E(max) values=367 and 287%; mean EC(50) values=1.5 and 30 microM, respectively, N=4). The alpha-linked disaccharides, maltose and sucrose also potentiated [3H] TBOB binding, but with 100-600-fold higher EC(50) values than lactose. The lactose-mediated potentiation of [3H] TBOB in the forebrain and cerebellum was completely abolished in the presence of 0.3 microM GABA. Over the concentration range in which significant potentiation of [3H] TBOB binding was detected, lactose elicited no significant effect upon [3H] flunitrazepam binding. This study demonstrated that lactose can modulate the GABA(A) receptor channel, allosterically coupled to the agonist site, but independent of the benzodiazepine site. Furthermore, lactose displayed differential effects upon forebrain and cerebellar GABA(A) receptors indicating that it may be a novel subtype selective agent.

Animals↗
PubMed2001

Structures of heparin-derived disaccharide bound to cobra cardiotoxins: context-dependent conformational change of heparin upon binding to the rigid core of the three-fingered toxin.

Glycosaminoglycans (GAGs) have been suggested to be a potential target for cobra cardiotoxin (CTX) with high affinity and specificity via a cationic belt at the concave surface of the polypeptide. The interaction of GAGs, such as high-molecular weight heparin, with CTXs not only can induce aggregation of CTX molecules but also can enhance their penetration into membranes. The binding of short chain heparin, such as a heparin-derived disaccharide [DeltaUA2S(1-->4)-alpha-D-GlcNS6S], to CTX A3 from Taiwan cobra (Naja atra), however, will not induce aggregation and was, therefore, investigated by high-resolution (1)H NMR. A novel heparin binding site on the convex side of the CTX, near the rigid disulfide bond-tightened core region of Cys38, was identified due to the observation of intermolecular NOEs between the protein and carbohydrate. The derived carbohydrate conformation using complete relaxation and conformational exchange matrix analysis (CORCEMA) of NOEs indicated that the glycosidic linkage conformation and the ring conformation of the unsaturated uronic acid in the bound state depended significantly on the charge context of CTX molecules near the binding site. Specifically, comparative binding studies of several heparin disaccharide homologues with two CTX homologues (CTX Tgamma from Naja nigricollis and CTX A3) indicated that the electrostatic interaction of N-sulfate of glucosamine with NH(3)(+)zeta of Lys12 and of the 2-O-sulfate of the unsaturated uronic acid with NH(3)(+)zeta of Lys5 played an important role. These results also suggest a model on how the CTX-heparin interaction may regulate heparin-induced aggregation of the toxin via the second heparin binding site.

Animals↗
PubMed1998

Synthesis of 1,2- and 1,3-N-Linked Disaccharides of 5-Thio-alpha-D-mannopyranose as Potential Inhibitors of the Processing Mannosidase Class I and Mannosidase II Enzymes.

The syntheses of S/N acetal heteroatom analogues of 1,2- and 1,3-linked mannopyranose disaccharides are described. The compounds are analogues of the Man-alpha-(1-->2)-Man and Man-alpha-(1-->3)-Man disaccharide components of oligosaccharides found in N-glycoproteins that are cleaved by trimming mannosidases during glycoprotein processing. Glycosylamine formation, without the necessity of hydroxyl group protection, proceeded through acid-catalyzed condensation reactions of 5-thio-D-mannose with either methyl 2-amino-2-deoxy- or 3-amino-3-deoxy-alpha-D-mannopyranoside to give methyl 2-amino-2-deoxy-2-N-(5-thio-alpha/beta-D-mannopyranosyl)-alpha-D-mannopyranoside (2) or methyl 3-amino-3-deoxy-3-N-(5-thio-alpha/beta-D-mannopyranosyl)-alpha-D-mannopyranoside (3), respectively. The superiority of mercuric chloride over acetic acid as a catalyst for this reaction is reported. Acetylation of the anomeric mixtures gave the heptaacetates from which the major beta'-isomers could be separated by chromatography and/or crystallization.

Journal Article↗
PubMed1987

Reaction of unsaturated uronic acid residues with mercuric salts. Cleavage of the hyaluronic acid disaccharide 2-acetamido-2-deoxy-3-O-(beta-D-gluco-4-enepyranosyluronic acid)-D-glucose.

Degradation of connective-tissue polysaccharides with bacterial or fungal eliminases and subsequent characterization of the reaction products are now part of standard methodology for the analysis of these compounds. However, the scope of preparative and analytical work based on the use of eliminases has been limited by the lack of procedures for specific removal of the unsaturated uronic acid residues generated in the eliminase reactions. In the present investigation, we have shown that these residues are cleaved by mercuric salts under mild conditions that are not likely to affect other structures in an oligo- or poly-saccharide molecule. Thus the disaccharide generated from hyaluronic acid by digestion with chondroitinase AC or ABC was cleaved into a keto acid and free N-acetylglucosamine within 10 min at room temperature upon exposure to 14 mM-mercuric acetate at pH 5. The reaction of the disaccharide with mercuric salts was used for ready determination of the distribution of radioactivity between the glucuronic acid and N-acetylglucosamine moieties in radioactive hyaluronic acid that had been synthesized by IMR-90 fibroblasts from 3H-labelled monosaccharides. When the precursor was [3H]galactose, over 95% of the incorporated radioactivity was found in the glucuronic acid moiety. In contrast, cells grown in the presence of [3H]glucosamine synthesized a polysaccharide in which almost all of the label was located in the N-acetylglucosamine units. It is apparent from these experiments that the reaction of unsaturated uronic acid residues with mercuric salts provides a new tool with potential for many applications in the study of the structure and metabolism of connective-tissue polysaccharides.

Cell Line↗
PubMed2000

The conformation of the T-antigen disaccharide bound to Maclura pomifera agglutinin in aqueous solution.

The complex of Maclura pomifera agglutinin with the T-antigen disaccharide (beta-d-Gal-(1-->3)-alpha-d-GalNAc-(1-->O)-Me) was investigated by NMR spectroscopy in aqueous solution. Intramolecular transferred nuclear Overhauser enhancement (NOE) effects between the monosaccharide moieties were used to derive the ligand conformation in the lectin-bound state. Ligand protons in contact with the protein were identified by saturation transfer difference experiments and intermolecular transferred NOE effects. It is demonstrated that structural differences exist for the ligand-lectin complex in aqueous solution as compared with the previously published crystal structure (Lee, X., Thompson, A., Zhiming, Z., Ton-that, H., Biesterfeldt, J., Ogata, C., Xu, L., Johnston, R. A. Z. , and Young, N. M. (1998) J. Biol. Chem. 273, 6312-6318). In order to accommodate the O-methyl group of the disaccharide, the amino acid side chain of Tyr-122 has to rotate from its position in the crystal. The NMR data are in accord with two conformational families at the beta-(1-->3)glycosidic linkage in the solution complex with interglycosidic angles phi/psi = 45/-65 degrees and -65/-18 degrees. These differ from the bound conformation of the ligand in the crystal (phi/psi = 39/-8 degrees ) and are not highly populated by the ligand in the free state. The reason for the structural differences at the beta-(1-->3)glycosidic linkage are hydrogen bonds that stabilize the relative orientation of the monosaccharide units in the crystal. Our results demonstrate that the crystallization of a protein-carbohydrate complex can interfere with the delicate process of carbohydrate recognition in solution.

Antigens, Neoplasm↗