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PubMed1996

Unexpected carbohydrate cross-binding by Escherichia coli heat-labile enterotoxin. Recognition of human and rabbit target cell glycoconjugates in comparison with cholera toxin.

The bacterial protein enterotoxins, cholera toxin (CT) of Vibrio cholerae and heat-labile toxin (LT) of Escherichia coli, induce diarrhea by enhancing the secretory activity of the small intestine of man and rabbit (animal model). This physiological effect is mediated by toxin binding to a glycolipid receptor, the ganglioside GM1, Gal beta 3GalNAc beta 4(NeuAc alpha 3)GAl beta 4Glc beta 1Cer. However, LT, but not CT, was recently shown by us to bind also to paragloboside, Gal beta 4GlcNAc beta 3Gal beta 4Glc beta 1Cer, identified in the target cells. By molecular modeling of this tetrasaccharide in the known binding site of LT, the saccharide-peptide interaction was shown to be limited to the terminal disaccharide (N-acetyllactosamine). This sequence is expressed in many glycoconjugates, and we have therefore assayed glycolipids and glycoproteins prepared from the target tissues. In addition to paragloboside, receptor activity for LT was detected in glycoproteins of human origin and in polyglycosylceramides of rabbit. However, CT bound only to GM1. Two variants of LT with slightly different sequences, human (hLT) and porcine (pLT), were identical in their binding to target glycoproteins and polyglycosylceramides, but different regarding paragloboside, which was positive for pLT but negative for hLT. This difference is discussed on basis of modeling, taking in view the difference at position 13, with Arg in pLT and His in hLT. Although N-acetyllactosamine is differently recognized in form of paragloboside by the two toxin variants, we speculate that this sequence in human glycoproteins and rabbit polyglycosylceramides is the basis for the common binding. Much work remains, however, to clear up up this unexpected sophistication in target recognition.

Animals↗

PubMed1999

Helicobacter pylori attaches to NeuAc alpha 2,3Gal beta 1,4 glycoconjugates produced in the stomach of transgenic mice lacking parietal cells.

Helicobacter pylori infection of the human stomach is associated with altered acid secretion, loss of acid-producing parietal cells, and, in some hosts, adenocarcinoma. We have used a transgenic mouse model to study the effects of parietal cell ablation on H. pylori pathogenesis. Ablation results in amplification of the presumptive gastric epithelial stem cell and its immediate committed daughters. The amplified cells produce sialylated oncofetal carbohydrate antigens that function as receptors for H. pylori adhesins. Attachment results in enhanced cellular and humoral immune responses. NeuAc alpha 2,3Gal beta 1,4 glycoconjugates may not only facilitate persistent H. pylori infection in a changing gastric ecosystem, but by promoting interactions with lineage progenitors and/or initiated cells contribute to tumorigenesis in patients with chronic atrophic gastritis.

Animals↗

PubMed2001

Molecular diversity in the biosynthesis of GI tract glycoconjugates. A blood-group-related chart of microorganism receptors.

This paper examines the potential of carbohydrate blood-group antigens present on mucosal surfaces in acting as receptors for microorganisms. Mucosal surfaces express significant amounts of carbohydrate blood-group antigens under the control of the Secretor, Lewis and ABO systems. The exact glycoconjugate profile an individual presents to the lumen is complex, and can only be correctly determined by a combination of serology and genotyping. We have isolated and structurally resolved the glycolipids expressed in the small intestine of group O individuals having various common or rare phenotypes. Using this information, we have been able to construct a biosynthetic pathway and propose that the type, size and glycotopes expressed, are controlled to a major extent by blood-group-related glycosyltransferases. Many of these glycotopes are potential receptors for microorganisms; some resemble tumour antigens, while others resemble the lipopolysaccharides of some pathogens. Although the origins of the blood-group glycosyltransferases remain uncertain, it is evident that they significantly diversify the mucosal glycotopes exposed to microbes; and therein may be found a potential explanation for their existence.

ABO Blood-Group System↗

PubMed1997

Immunohistological analysis of antibodies against ABH and other glycoconjugates in normal human pyloric and duodenal mucosae.

Eighty-eight monoclonal antibodies were tested by immunohistochemistry on human gastro-duodenal mucosae of known ABO, Lewis and Secretor phenotypes. Antibodies were classified among anti-A, anti-B, anti-AB, anti-H and other anti-glycoconjugates (I, i, T, Tn, Lewis, P1, Tk). Anti-A, B and AB antibodies were subdivided into subgroups with "broad" or "restricted" reactivity according to the extent of epithelial cell labeling. Anti-H antibodies were classified in accordance to their degree of sensitivity to the secretor phenotype. Among anti-T and anti-I antibodies, only one of each showed positive staining of epithelial cells. All anti-Lewis antibodies had distinct reactivities, although, they were clearly anti-Lewis reagents. Some anti-P1 antibodies labeled epithelial cells, irrespective of the ABO, Lewis and secretor phenotypes. One anti-Tk stained the Golgi apparatus of most epithelial cells, irrespective of the individual's phenotype. In conclusion, some of the antibodies tested were defined as very useful reagents for immunohistochemistry showing both specificity and sensitivity.

ABO Blood-Group System↗

PubMed2002

Inmunoferon, a glycoconjugate of natural origin, regulates the liver response to inflammation and inhibits TNF-alpha production by an HPA axis-dependent mechanism.

In this report, we have examined the mechanism of action of Inmunoferon, a patented glycoconjugate (GC) of natural origin with immunomodulatory properties, in the regulation of TNF-alpha expression induced by LPS challenge in a rodent model. GC was found to be dependent on a normal HPA response to exert its regulatory effect on TNF-alpha expression. Adrenalectomized mice were unresponsive to the drug in terms of TNF-alpha levels after LPS challenge, whereas control mice showed lower serum TNF-alpha levels when treated with GC than vehicle-treated animals. GC treatment also induced the expression of acute phase proteins but it did not alter the normal metabolism or viability of hepatic cells. These data suggested the employment of GC as a novel adjuvant during antibacterial treatment without disadvantages such as side effects in the metabolism of the liver, thus, acting as an enhancer of the host response against infection.

Animals↗

PubMed1994

Glycoconjugate vaccines. What next?

The principle that infants can be protected from invasive diseases caused by encapsulated organisms has been proved with the introduction of Haemophilus influenzae type b conjugate vaccines. The use of glycoconjugates to implement some of the goals of the Children's Vaccine Initiative requires a clear delineation of the chemical and immunological specifications for optimal vaccines.

Antigen Presentation↗

PubMedDate not supplied

Strategies for the synthesis and screening of glycoconjugates. 2. Covalent immobilization for flow cytometry.

Glycosylamines are readily available carbohydrate derivatives that undergo acylation reactions with homobifunctional N-hydroxysuccinimidyl esters. The product glycosylamides carry a spacer group equipped with one active ester functionality. This route provides well-defined glycoconjugates, which may be cross-linked to various amino-functionalized resins. Carbohydrate recognition of the resulting sugar-bead conjugates is probed by lectin immunostaining or flow cytometry using a fluorescently labeled lectin.

Carbohydrate Sequence↗

PubMedDate not supplied

Solid-phase synthesis of multivalent glycoconjugates on a DNA synthesizer.

Carbohydrate-oligonucleotide conjugates and glycodendrimers were synthesized utilizing a DNA synthesizer. The synthesis of multivalent glycoconjugates on solid-phase allows custom tailoring of their structure to the requirements of biological assays within hours, as opposed to traditional approaches that require weeks or months of work in the laboratory. Therefore it will become much easier to investigate carbohydrate-protein interactions and optimize for objectives such as the receptor-mediated targeting of antisense oligonucleotides.

Amides↗

PubMedDate not supplied

A single-step method for the production of sugar hydrazides: intermediates for the chemoselective preparation of glycoconjugates.

The ability to selectively conjugate carbohydrate molecules to a protein is a key step in the preparation of conjugate vaccines, while facile methods for linking carbohydrates to polymers or solid surfaces to produce diagnostic probes and functional microarrays are also sought. Here, we describe a simple, single-step method of producing glycosylhydrazides from unprotected sugars, which were then linked in a controlled manner to a desired carrier, through an appropriate linker. The method was chemoselective and did not require coupling reagents, and the native pyranose form of the reducing end residue was retained. Initially, mono- and disaccharide hydrazides were produced from the corresponding reducing sugars and linked to BSA through a bifunctional linker. Final exemplification of the procedure was demonstrated by the preparation of a LewisY tetrasaccharide protein conjugate, which was recognized by a LewisY monoclonal antibody indicating the preservation of the natural conformation of the tetrasaccharide in the final construct. It is envisaged that this method will have general applicability to a variety of functionally diverse reducing sugars and provide a route to highly defined glycoconjugates, without the need for elaborate synthetic strategies.

Carrier Proteins↗

PubMedDate not supplied

Improving the antigenicity of sTn antigen by modification of its sialic acid residue for development of glycoconjugate cancer vaccines.

Sialyl Tn (sTn) antigen is a sialylated disaccharide abundantly expressed by many tumors. To search for effective cancer immunotherapies based on sTn antigen, we designed and synthesized a series of unnatural N-acyl derivatives of sTn and studied their immunological properties. For this purpose, an efficient method was developed to synthesize the natural and unnatural forms of sTn antigen and their protein conjugates. The resultant glycoconjugates were used to immunize C57BL/6 mice, and the immune response was assessed by enzyme-linked immunosorbent assay (ELISA). Whereas the keyhole limpet hemocyanin (KLH) conjugate of sTn elicited low levels of IgM antibodies, the KLH conjugates of N-iso-butanoyl sTn and N-phenylacetyl sTn, especially the latter, induced high titers of antigen-specific IgG antibodies, showing a T-cell-dependent response that is critical for the antitumor activity. The results suggest that the modified forms of sTn, especially N-phenylacetyl sTn, have improved antigenicity and promising immunological properties for use as cancer vaccines.

Animals↗

PubMedDate not supplied

Novel glycosynthons for glycoconjugate preparation: oligosaccharylpyroglutamylanilide derivatives.

The reducing sugar of an oligosaccharide reacting with the alpha-amino group of an amino acid is converted to an N-oligosaccharylamino acid which can then be stabilized by N-acylation. Oligosaccharides in solution in N,N-dimethylformamide reacted with alpha-glutamyl-p-nitroanilide at 50 degrees C for a few hours, leading to an N-oligosaccharylglutamyl-p-nitroanilide. Then, the gamma-carboxylic group of the glutamyl moiety, activated by adding (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), reacted with the substituted alpha-amino group of the glutamyl residue, leading to an N-oligosaccharylpyroglutamyl-p-nitroanilide within 0.5 h. Such a one-pot two-step reaction was shown to be very efficient in the case of a disaccharide such as lactose, or pentasaccharides such as lacto-N-fucopentaoses, Lewis(a) or Lewis(x). The glycosynthons were characterized by chromatography (HPAEC and HPLC); their molecular mass was determined by electrospray ionization mass spectrometry, and the glycosylamides were shown to have a beta-anomeric configuration on the basis of their proton NMR. The N-oligosaccharylpyroglutamyl-p-nitroanilides are quite stable at room temperature over a large pH range. They are easily converted to N-oligosaccharylpyroglutamyl-p-isothiocyanatoanilides which can be used to prepare glycoconjugates such as cationic glycosylated polylysines suitable for specifically delivering genes or oligonucleotides in a sugar-dependent manner.

Aminocaproic Acid↗

PubMed1993

L-29, an endogenous lectin, binds to glycoconjugate ligands with positive cooperativity.

The soluble mammalian lactose-binding lectins L-14-I and L-29 are both secreted and bind to oligosaccharides on laminin, a large extracellular matrix glycoprotein containing polylactosamine chains. Because of the potential functional significance of these lectin-laminin interactions, we compared quantitative aspects of L-14-I and L-29 binding to immobilized laminin using recombinant lectins labeled with 125I. We report that the concentration-dependent binding of L-29 exhibits positive cooperativity whereas binding of L-14-I does not. Cooperative binding of L-29 can also occur on glycoconjugate substrates other than laminin and is not dependent on cystine bond formation or aggregation in solution. L-29 contains repetitive sequences within the N-terminal domain not present in L-14-I. This domain is not required for binding activity, but is required for positive cooperativity. Though the precise mechanism of interaction of L-29 with laminin remains to be determined, it apparently results in assembly of a lectin aggregate on the substrate surface, which could have important functional consequences.

Animals↗

PubMed1991

A specific cell surface glycoconjugate controlling cell motility: evidence by functional monoclonal antibodies that inhibit cell motility and tumor cell metastasis.

The biochemical basis of cell motility has been viewed as a complex process involving cell surface membrane proteins, integrin receptors, growth factors and their receptors, and cytoskeletal components [Rosen & Goldberg (1989) In Vitro 25, 1079]. The possible involvement of glycoconjugates at the cell surface in controlling cell motility has not been systematically investigated. We addressed this question using functional monoclonal antibodies (MAbs), which inhibit cell motility and the metastatic potential of tumor cells, as probes. Two such MAbs, derived from two independent processes of immunization and selection, were found to directed to a common specific carbohydrate structure, Fuc alpha 1----2Gal beta 1----R. MAb MIA-15-5 was established after immunization of mice with small cell lung carcinoma line PC7 and selected on the basis of inhibition of U937 and HEL cell migration. MAb MIA-22-20 was established after immunization with lung adenocarcinoma line MAC-10 and selected on the basis of inhibition of MAC-10 cell migration. These two MAbs were both IgM and were consistently reactive with the Fuc alpha 1----2Gal beta 1----R structure, regardless of the identity of the R group. Various other anti-H MAbs, specific to carrier isotype, did not affect cell motility. MAb MIA-15-5 reacted with 30-40% of high-metastatic variant BL6 of mouse melanoma B16 line but with only less than 5% of low-metastatic variant F1. Metastatic deposition to lung after injection of BL6 cells was inhibited if MAb MIA-15-5 was injected within 3 h but was not inhibited by injection of other anti-H antibodies under the same conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2002

Characterization of a novel endo-beta-galactosidase specific for releasing the disaccharide GlcNAc alpha 1-->4Gal from glycoconjugates.

In contrast to the beta-linked GlcNAc, the alpha-linked GlcNAc has not been commonly found in glycoconjugates. We have recently revealed the presence of an unusual endo-beta-galactosidase (Endo-beta-Gal(GnGa)) in Clostridium perfringens capable of releasing GlcNAcalpha1-->4Gal from glycans expressed in the gastric mucous cell-type mucin [Ashida, H., Anderson, K., Nakayama, J., Maskos, K., Chou, C.-W., Cole, R. B., Li, S.-C., and Li, Y.-T. (2001) J. Biol. Chem. 276, 28226-28232]. To characterize Endo-beta-Gal(GnGa), we have cloned its gene, gngC, from the genomic DNA library prepared from C. perfringens ATCC10543. The gene encodes 420 amino acid residues including a 17-residue signal peptide at the N-terminus. Using pUC18, we were able to prepare 25 mg of the fully active and pure recombinant Endo-beta-Gal(GnGa) from 1 L of Escherichia coli DH5alpha culture, which was 170 times higher than that produced by the original clostridial strain. Endo-beta-Gal(GnGa) shares a low but significant sequence similarity with two other endo-beta-galactosidases (16-21% amino acid identity). It also shows some similarity with bacterial 1,3-1,4-beta-glucan 4-glucanohydrolases of the glycoside hydrolase family 16. Endo-beta-Gal(GnGa) was found to contain the EXDX(X)E sequence (Glu-168 to Glu-173), that has been identified as the catalytic motif of families 16 and 7 retaining glycoside hydrolases. We have used site-directed mutagenesis to show that Glu-168 and Glu-173 were essential for the Endo-beta-Gal(GnGa) activity. By NMR spectroscopy, Endo-beta-Gal(GnGa) was found to act as a retaining enzyme.

Amino Acid Sequence↗

PubMed1997

Gossypol modification of Ala-1 of secreted phospholipase A2: a probe for the kinetic effects of sulfate glycoconjugates.

Gossypol is shown to covalently modify secreted phospholipase A2 (PLA2) in the aqueous phase, but not at the interface. A rapid initial noncovalent binding of gossypol is followed by a slow covalent modification of the alpha-amino group of Ala-1 by stoichiometric amounts of gossypol. The rate of modification increases in the presence of calcium, but occupancy of the substrate binding site does not alter the rate. Pancreatic PLA2 is modified at the alpha-amino group of the N terminus to form a Schiff base, which can be stabilized by reduction with borohydride. Residual activity of the gossypol-modified PLA2 from several different sources is about 10%, indicative of impaired catalytic turnover. The half-time for the inactivation is about 10 min, and it is more than 100-fold longer for PLA2 at the interface. Gossypol promotes binding of PLA2 to the interface, and the binding of PLA2 to the interface promotes only the noncovalent binding of gossypol, but not the covalent modification. Gossypol, in conjunction with spectroscopic and kinetic protocols, is used to characterize the kinetic effects of sulfated glycoconjugates, heparin and artery wall proteoglycans, with human inflammatory and pancreatic PLA2.1 The conjugates do not interfere with the binding of PLA2 to the interface or with the catalytic cycle at the interface. The conjugates do not influence the kinetics of modification of PLA2 by gossypol in the aqueous phase, and the enzyme at the interface is not modified in the presence of the conjugates. The conjugates bind to PLA2 at the interface with only a modest effect on the interfacial catalytic turnover without dislodging the bound enzyme. Complex kinetic effects induced by the conjugates are shown to be due to sequestration of PLA2 in the aqueous phase as a high-molecular mass complex, which dissociates with added NaCl.

Alanine↗

PubMedDate not supplied

Synthesis, characterization, and preliminary biological study of glycoconjugates of poly(styrene-co-maleic acid).

Three derivatives of the biocompatible polymer poly(styrene-co-maleic anhydride) (SMA) were obtained with 1-amino-1-deoxy-beta-D-galactose, 1-amino-1-deoxy-beta-D-glucose, and 1-amino-1-deoxy-beta-D-lactose, respectively. The amino sugars were chemically conjugated via formation of an amide bond between the anomeric amino group of the sugar residue and the anhydride of the copolymer, giving the corresponding glycoconjugate derivatives. Colorimetric assay of the unreacted amino groups and elemental analysis were used to determine the degree of substitution. About 56%, 54%, and 94% of the available anhydride groups reacted to give galactosyl-amide (SMA-Gal), glucosyl-amide (SMA-Gluc), and lactosyl-amide (SMA-Lac) branched polymers, respectively. The synthesized glycopolymers were characterized by Fourier transform infrared spectroscopy, gel permeation chromatography, circular dichroism, and UV and fluorescence spectroscopy. The release of glucosylamine from the glucosyl-amide branched polymer, by basic hydrolysis, was monitored by high-performance anion-exchange chromatography and by capillary electrophoresis, providing for an additional check of the degree of substitution of this specific polymer derivative. Biological activity tests showed that both SMA-Gal and SMA-Lac allow adhesion of HepG2 hepatic cells about five times larger than that of hydrolyzed, underivatized SMA.

Amino Sugars↗

PubMedDate not supplied

Micropatterned carbohydrate displays by self-assembly of glycoconjugate polymers on hydrophobic templates on silicon.

We report a novel strategy for micropatterned carbohydrate displays on Si substrates. This method exploited the hydrophobic-hydrophilic microfabrication by photolithography of ODS-SAM on Si substrates and the subsequent selective self-assembly of glycoconjugate polymers onto the hydrophobic regions. Protein micropatterning by molecular recognition on the carbohydrate substrates was also successful.

Glycoconjugates↗

PubMed2001

Volatile compounds released by enzymatic hydrolysis of glycoconjugates of leaves and grape berries from Vitis vinifera Muscat of Alexandria and Shiraz cultivars.

Glycoconjugates from Muscat of Alexandria and Shiraz leaves and grape berries were isolated by adsorption on Amberlite XAD-2 resin, and enzymatically released aglycons were analyzed by GC-FID and GC-MS. About 120 aglycons were fully or tentatively identified. Compositional differences were observed between leaves and berries of the two varieties in five aglycon chemical groups: C6 alcohols, aliphatic alcohols, monoterpenes, shikimates, and C(13)-norisoprenoids, which were much more abundant in the leaves than in the berries. The differences observed for C(13)-norisoprenoids were in agreement with their hypothetical independent biosynthesis in leaves and berries. Thus, 3-hydroxy-beta-damascone, an important norisoprenoid aglycon of grape berries, was not detected in leaves, whereas its oxidized derivative, 3-oxo-alpha-damascone, was absent in berries. Compositional differences were also observed between Muscat and Shiraz leaves. 3-Oxo-alpha-ionol was not detected in Shiraz leaves, and its retro derivatives were less abundant than in Muscat of Alexandria leaves. Conversely, in Shiraz leaves the levels of 7,8-dihydroionone derivatives, such as megastigman-3,9-diol and 3-oxo-7,8-dihydro-alpha-ionol, were higher than in Muscat of Alexandria leaves.

Fruit↗