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PubMed1982

A comparative study on the specificity of Androctonus australis (Saharan scorpion) and Limulus polyphemus (horseshoe crab) agglutinins.

The specificities of Limulus polyphemus and Androctonus australis sera were compared by agglutination and agglutination-inhibition micromethods with human untreated and enzyme-treated peripheral blood cells (erythrocytes, normal lymphocytes and chronic lymphocytic leukemia lymphocytes). Androctonus sera give higher titers than Limulus sera with erythrocytes and lymphocytes. Both sera show more avidity for leukemic than for normal lymphocytes. Limulus sera fail to agglutinate neuraminidase-treated cells but Androctonus sera react with untreated and neuraminidase-treated erythrocytes at the same degree. Sialyl-lactose is the best inhibitor for Androctonus sera, followed by N-acetylneuraminic and N-glycolylneuraminic acids, glucuronic and galacturonic acids, N-acetyl-D-glucosamine and N-acetyl-D-galactosamine. The amounts of inhibitor required depend upon the particular cell and enzyme treatment: agglutination of neuraminidase-treated erythrocytes by Androctonus is inhibited by lower concentrations of the same compounds that inhibit untreated erythrocytes agglutination. Results suggest that although Limulus and Androctonus have specificity for sialic acid containing compounds, on the cell surface, the Limulus receptors might be different from Androctonus receptors.

Agglutination↗
PubMed2006

Functional expression of the P2Y14 receptor in human neutrophils.

Previous studies using quantitative reverse transcriptase polymerase chain reaction (RT-PCR) analysis have shown that the P2Y(14) receptor is expressed at high levels in human neutrophils. Therefore the primary aim of this study was to determine whether the P2Y(14) receptor is functionally expressed in human neutrophils. In agreement with previous studies RT-PCR analysis detected the expression of P2Y(14) receptor mRNA in human neutrophils. UDP-glucose (IC(50)=1 microM) induced a small but significant inhibition (circa 30%) of forskolin-stimulated cAMP accumulation suggesting functional coupling of endogenously expressed P2Y(14) receptors to the inhibition of adenylyl cyclase activity in human neutrophils. In contrast, the other putative P2Y(14) receptor agonists UDP-galactose and UDP-glucuronic acid (at concentrations up to 100 microM) had no significant effect, whereas 100 microM UDP-N-acetylglucosamine-induced a small but significant inhibition of forskolin-stimulated cAMP accumulation (20% inhibition). UDP-galactose, UDP-glucuronic acid and UDP-N-acetylglucosamine behaved as partial agonists by blocking UDP-glucose mediated inhibition of forskolin-induced cAMP accumulation. Treatment of neutrophils with pertussis toxin (G(i/o) blocker) abolished the inhibitory effects of UDP-glucose on forskolin-stimulated cAMP accumulation. UDP-glucose (100 microM) also induced a modest increase in extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, whereas the other sugar nucleotides had no effect on ERK1/2 activation. Finally, UDP-glucose and related sugar nucleotides had no significant effect on N-formyl-methionyl-leucyl-phenylalanine-induced elastase release from neutrophils. In summary, although we have shown that the P2Y(14) receptor is functionally expressed in human neutrophils (coupling to inhibition of forskolin-induced cAMP and ERK1/2 activation) it does not modulate neutrophil degranulation (assessed by monitoring elastase release). Clearly further studies are required in order to establish the functional role of the P2Y(14) receptor expressed in human neutrophils.

Cells, Cultured↗
PubMedDate not supplied

Glucuronidation of labetalol at the two hydroxy positions by bovine liver microsomes. Isolation, purification, and structure elucidation of the glucuronides of labetalol.

Glucuronidation is known to be a major metabolic pathway for labetalol. As the drug contains a phenolic and an alcoholic hydroxy group, in principle two regio isomeric glucuronides can be formed. By incubating the substrate labetalol with bovine liver microsomes, in the presence of the co-substrate UDP-glucuronic acid, both hydroxy positions were glucuronidated. The different glucuronides were isolated from the incubation mixture using Bond-Elut extraction cartridges and separated by means of high performance liquid chromatography. The formation of glucuronides was confirmed by performing reference incubations using radiolabeled UDP-glucuronic acid. Structure elucidation of the various glucuronides was done by nuclear magnetic resonance, ultraviolet spectroscopy, and mass spectrometry.

Animals↗
PubMed1979

Correlation between structure and function of heparin.

We have fractionated crude porcine heparin to obtain highly active as well as relatively inactive species of molecular weight approximately 7000 with specific anticoagulant activities of 360 and 12 units/mg, respectively. Nitrous acid degradation of both of these polymers yielded a tetrasaccharide fraction, 1beta, that contained equimolar amounts of iduronic and glucuronic acids, possessed an internal N-acetylated glucosamine, and carried anhydromannitol at the reducing end position. The 1beta tetrasaccharide derived from the highly active heparin, 1betaa, was recovered in a yield of 1.1 mol/7000 daltons. Our analyses indicate that at least 95% of the 1betaa is a single structure that consists of the following unique monosaccharide sequence: L-iduronic acid --> N-acetylated D-glucosamine-6-sulfate --> D-glucuronic acid --> N-sulfate D-glucosamine-6-sulfate. The 1beta tetrasaccharide fraction from relatively inactive mucopolysaccharide, 1betai, was recovered in a yield of 0.3 mol/7000 daltons and was a mixture of several components. Only 8.5% of the 1betai tetrasaccharide fraction exhibited the same uronic acid placement and sulfate group position found in 1betaa. Thus, 2.6% of relatively inactive mucopolysaccharide molecules contain the unique tetrasaccharide sequence found within each molecule of highly active heparin. Given the correlation between abundance of this unique 1betaa tetrasaccharide sequence and biologic potency, we suggest that this structure represents the critical site responsible for anticoagulant activity.

Animals↗
PubMed1988

Glycyrrhizin stimulates growth of Eubacterium sp. strain GLH, a human intestinal anaerobe.

Eubacterium sp. strain GLH was isolated from human feces and produced two kinds of beta-D-glucuronidase (EC 3.2.1.31), one new enzyme specific for glycyrrhizin (GL) and the other for phenyl beta-D-glucuronides. GL or p-nitrophenyl-mono-beta-D-glucuronide (pNPG) stimulated the production of GL or pNPG beta-glucuronidases and the growth of strain GLH in a basal medium lacking carbohydrate. D-Glucuronic acid also stimulated the growth of the bacterium, but glycyrrhetic acid did not. The increase of GL beta-glucuronidase paralleled the growth of the Eubacterium strain in pure culture. These results suggest that glucuronides such as GL and pNPG stimulate the growth of the Eubacterium strain in a nutrient-poor medium by providing D-glucuronic acid through the activity of beta-glucuronidases. The increase in GL beta-glucuronidase activity in the presence of GL was observed during the cultivation of human intestinal flora in a general anaerobic medium. During mixed cultivation of the Eubacterium strain with Streptococcus faecalis, which does not produce GL beta-glucuronidase, GL beta-glucuronidase was also increased by GL or pNPG, but not by glycyrrhetic acid and p-nitrophenol. It is suggested that GL stimulates the growth of strain GLH even in the mixed culture.

Anti-Bacterial Agents↗
PubMed1976

Structural studies on the extracellular polysaccharide of the red alga, Porhyridium.

Partial acid hydrolyzates of the extracellular polysaccharide from Porphyridium cruentum yield three disaccharides and two uronic acids. These constitute all of the uronic acid in the polymer. The novel disaccharides are 3-O(alpha-D-glucopyranosyluronic acid)-L-galactose, 3-O-(2-O-methyl-alpha-D-glucopyranosyluronic acid)-D-galactose, and 3-O-(2-O-methly-alpha-D-glucopyranosyluronic acid)-D-glucose. The polyanion of high molecular weight contains D- and L-galactose, xylose, D-glucose, D-glucuronic acid and 2-O-methyl-D-glucuronic acid, and sulfate in molar ratio (relative to D-glucose) of 2.12:2.42:1.00:1.22:2.61. Preliminary periodate-oxidation studies suggest that the hexose and uronic acids are joined to other residues by (1 leads to 3) glycosidic linkages. About one-half of the xylose residues are (1 leads to 3)-linked.

Animals↗
PubMedDate not supplied

Studies of intramolecular rearrangements of acyl-linked glucuronides using salicylic acid, flufenamic acid, and (S)- and (R)-benoxaprofen and confirmation of isomerization in acyl-linked delta 9-11-carboxytetrahydrocannabinol glucuronide.

NMR and HPLC have been used to investigate the rearrangements of 1-O-acylglucuronides in vitro and the occurrence of rearranged isomers in urine. Glucuronides of flufenamic acid, (S)- and (R)-benoxaprofen, salicylic acid, and delta 9-11-carboxytetrahydrocannabinol were synthesized, by use of immobilized enzymes, or purified from urine. Ester-linked isomers of these gluruconides were characterized, and isomers derived from flufenamic acid, (S)-benoxaprofen, and salicylic acid were purified for further study by NMR and HPLC. The positions of the new ester linkages could be identified by two-dimensional NMR. Shifts not only in the resonance of the proton adjacent to the esterified hydroxyl group but also in the resonance of the anomeric proton on carbon 1 of the glucuronic acid moiety could be correlated with the position of each isomeric ester bond. HPLC elution times also correlated with ester position in this small set of samples. The sequences of isomer formation were studied in situ by NMR and also at pH 8 by HPLC. These studies indicate that, for the three cases examined, the C-2 ester is formed first, followed by formation of C-3 and C-4 esters. The purified isomeric esters were found not to re-form the high-energy 1-O-acyl bond. All other rearrangement steps are reversible. In contrast to other glycosides and glycerol esters, no evidence could be found for rearrangements beyond nearest-neighbor hydroxyl groups in glucuronic acid. The sequence of formation and reversibility is consistent with an ortho ester intermediate, as has been proposed for rearrangements of other glycosides.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

A novel heparan sulphate with high degree of N-sulphation and high heparin cofactor-II activity from the brine shrimp Artemia franciscana.

With the aid of heparinase and heparitinases from Flavobacterium heparinum and 13C and IH NMR spectroscopy it was shown that the heparan sulphate isolated from the brine shrimp Artemia franciscana exhibits structural features intermediate between those of mammalian heparins and heparan sulphates. These include an unusually high degree of N-sulphation (with corresponding very low degree of N-acetylation), a relatively high content of iduronic acid residues (both unsulphated and 2-O-sulphated) and a relatively low degree of 6-O-sulphation of the glucosamine residues. The major sequences (glucuronic acid-->N-sulphated glucosamine and glucuronic acid-->N, 6-disulphated glucosamine) are most probably arranged in blocks. Although exhibiting negligible anticlotting activity in the APTT and anti-factor Xa assays the A. franciscana heparan sulphate has a high heparin cofactor-II activity (about 1/3 that of heparin).

Animals↗
PubMed1986

The isolation of anti-gum arabic antibodies by affinity chromatography.

Antibodies directed at gum arabic have been induced in rabbits immunized with gum arabic in Freund's complete adjuvant. These antibodies have been isolated in pure form by affinity chromatography on AH-Sepharose 4B containing gum arabic ligands. Oxidation of the susceptable carbohydrate residues of gum arabic with periodate or reduction of the glucuronic acid moieties with carbodiimide and borohydride converted the polysaccharide to products which no longer yielded precipitin reactions with the antibodies. The antibodies are therefore anti-carbohydrate antibodies with specificity for certain carbohydrate units of the gum arabic. Results of chemical modification and inhibition experiments indicate that 4-alpha-L-arabinofuranosyl-D-glucuronic acid units of the polysaccharide are the major immunodeterminant groups.

Antibodies↗
PubMed1989

Degradation of larchwood xylan by enzymes of a thermophilic fungus, Thermoascus aurantiacus.

Proteins from the culture filtrates of Thermoascus aurantiacus grown on paper were found to hydrolyze larchwood xylan completely to form xylose and 4-O-methyl-alpha-D-glucuronic acid. Partial hydrolysis of xylan by a xylanase purified from the culture filtrates resulted in the formation of neutral xylooligosaccharides of dp from 2 to 6 and acidic xylooligosaccharides of dp from 5 to 8. Each of these acidic sugars contained a single molecule of 4-O-methyl-alpha-D-glucuronic acid as a branch. Extensive hydrolysis of these oligosaccharides or xylan by xylanase led to the isolation of xylose, xylobiose, and an aldotetrauronic acid as terminal products. The structure of the aldotetrauronic acid was established by NMR as (2(2)-O-alpha-D,4-O-methyl-alpha-D-glucurono)-xylotriose. A beta-glucosidase, also purified from the culture filtrates, hydrolyzed xylan and the neutral or the acidic xylooligosaccharides from the nonreducing end to release only xylose. Neither xylanase nor beta-glucosidase hydrolyzed the beta-(1----4) linkage between the xylose carrying the branch and the adjacent xylose residue on each side.

Ascomycota↗
PubMed1999

Structural study of fucoidan from Cladosiphon okamuranus TOKIDA.

A structural study was carried out on a fucoidan isolated from the brown seaweed Cladosiphon okamuranus. The polysaccharide contained fucose, glucuronic acid and sulfate in a molar ratio of about 6.1 : 1.0 : 2.9. The results of Smith degradation showed that this polysaccharide has a linear backbone of 1-->3-linked alpha-fucopyranose with a half sulfate substitution at the 4-positions, and a portion of the fucose residues was O-acetylated. The data obtained from partial acid hydrolysis, a methylation analysis and NMR spectra indicated that the alpha-glucuronic acid residue is linked to the 2-positions of the fucose residues, which were not substituted by a sulfate group. These results indicated that the average structure of this fucoidan is as follows: -[(-->3Fuc-4(+/-OSO3-)alpha1-)5-->3[GlcA alpha1-->2]Fuc alpha1-]n-. (Half of each fucose residue was sulfated. One O-acetyl ester was present in every 6 fucose residues.)

Molecular Structure↗
PubMed2005

The lysine-rich arabinogalactan-protein subfamily in Arabidopsis: gene expression, glycoprotein purification and biochemical characterization.

AtAGP17, AtAGP18 and AtAGP19 are homologous genes encoding three putative glycosylphosphatidylinositol (GPI)-anchored classical arabinogalactan-proteins (AGPs) in Arabidopsis. They are distinguished from other AGPs by a short, C-terminal lysine-rich region. Organ-specific expression of these genes was revealed by Northern blot analysis. AtAGP17 was strongly expressed in leaves and stems, and weakly expressed in flowers and roots; AtAGP18 was strongly expressed in flowers, and moderately expressed in roots, stems and young leaves; and AtAGP19 was strongly expressed in stems, moderately expressed in flowers and roots, and weakly expressed in young leaves. One of these genes, AtAGP17, was expressed and purified as a green fluorescent protein (GFP) fusion protein in transgenic tobacco cells using hydrophobic interaction chromatography, size exclusion chromatography and reverse phase high-performance liquid chromatography. The fusion (glyco)protein produced a characteristic AGP 'smear' with a molecular mass of 80-150 kDa when detected by Western blot analysis. Glycosyl composition and linkage analyses of purified GFP-AtAGP17 showed that carbohydrate accounted for approximately 86% of the molecule, with arabinose and galactose as major, and rhamnose and glucuronic acid as minor glycosyl residues and with 1,3,6-galactose, 1,4-glucuronic acid, 1,3-galactose and terminal arabinose as major linkages. GFP-AtAGP17 was also precipitated by beta-Yariv reagent, further confirming that AtAGP17 is a bona fide AGP. Confocal fluorescence microscopy of plasmolysed, transformed cells indicated that AtAGP17 is localized on the plasma membrane and in Hechtian strands. Hydroxyproline (Hyp) glycoside profiles of GFP-AtAGP17 in conjunction with the deduced protein sequence also served to corroborate the Hyp contiguity hypothesis, which predicts contiguous Hyp residues as attachment sites for arabinosides and clustered, non-contiguous Hyp residues as attachment sites for arabinogalactan polysaccharides.

Amino Acid Sequence↗
PubMed1996

Cloning of an enzyme that synthesizes a key nucleotide-sugar precursor of hemicellulose biosynthesis from soybean: UDP-glucose dehydrogenase.

Hemicellulose is a major component of primary plant cell walls. Many of the glycosyl residues found in hemicellulose are derived from the sugar precursor UDP-glucuronic acid, which can be converted into UDP-arabinose, UDP-apiose, UDP-galacturonic acid, and UDP-xylose. The enzyme controlling the biosynthesis of UDP-glucuronic acid, UDP-glucose dehydrogenase (EC 1.1.1.22), was cloned from soybean (Glycine max [L.] Merr.) by an antibody screening procedure. This enzyme is surprisingly homologous to the bovine sequence, which is the only other eukaryotic UDP-glucose dehydrogenase sequence known. The characteristic motifs of the enzyme, the catalytic center, a NAD-binding site, and two proline residues for main chain bends, are conserved within the prokaryotic and eukaryotic sequences. The soybean full-length cDNA clone encodes a protein of 480 amino acids with a predicted size of 52.9 kD. The enzyme is highly expressed in young roots, but lower expression levels were observed in expanding tissues of the epicotyl and in young leaves. The expression pattern of the enzyme in different developmental stages strengthens the argument that UDP-glucose dehydrogenase is a key regulator for the availability of hemicellulose precursors.

Amino Acid Sequence↗
PubMed2000

Phosphorylation of D-glucose derivatives with inorganic cyclo-triphosphate: substituent effect at the 5-CH2OH or 2-OH group.

The phosphorylation of several D-glucose derivatives has been achieved using inorganic sodium cyclo-triphosphate hexahydrate (P3m), Na3P3O9 x 6H2O, in aqueous solution. In the phosphorylation of D-glucuronic acid, 6-phosphoryl-D-glucose and D-xylose, beta-D-glucuronic acid 1-triphosphate, 6-phosphoryl-beta-D-glucose 1-triphosphate and beta-D-xylose 1-triphosphate were synthesized stereoselectively with maximum yields of 43.5, 32.8 and 41.9%, respectively. In the case of D-glucosamine and 2-deoxy-D-glucose, the main phosphorylated products were assigned to beta-D-glucosamine 1-triphosphate and 2-deoxy-beta-D-glucose 1-triphosphate by 1H-, 13C- and 31P-NMR, and the yields were 13.9 and 13.4%, respectively.

Carbohydrate Conformation↗
PubMed1984

Glucuronide conjugation reduces the cytotoxicity but not the mutagenicity of benzo(a)pyrene in the CHO/HGPRT assay.

Benzo(a)pyrene (B[a]P) is biotransformed by the mixed-function oxidase (MFO) system to numerous metabolites some of which are cytotoxic and/or mutagenic to mammalian cells. However, conjugation of B(a)P metabolites with glucuronic acid in vivo is a major pathway of detoxication and elimination. The effects of glucuronide conjugation on B(a)P-induced cytotoxicity and mutagenicity were studied using the CHO/HGPRT assay with a rat liver homogenate preparation containing MFO system cofactors (S9 mix) and uridine diphosphate alpha-D-glucuronic acid (UDPGA). B(a)P metabolites proximate to the biologically active B(a)P quinones (B[a]P 6-OH) and to the B(a)P 7,8-diol-9,10 epoxide isomers (B[a]P 7,8-diol), were also assayed with S9 mix in the absence and presence of UDPGA. The addition of UDPGA to S9 mix reduced B(a)P-induced cytotoxicity but did not affect mutagenicity. B(a)P 6-OH-mediated cytotoxicity was also reduced in the presence of UDPGA. UDPGA had no effect on B(a)P 7,8-diol-induced cytotoxicity or mutagenicity. B(a)P phenols have been shown to be the preferred B(a)P-metabolite substrates for UDP-glucuronyltransferase enzymes. Thus, the reduction of B(a)P and B(a)P 6-OH-induced cytotoxicity by glucuronide conjugation is likely due to the elimination of cytotoxic phenols and quinones. Since B(a)P 7,8-diol is a poor substrate for UDP-glucuronyltransferase enzymes, no effects on B(a)P-induced mutagenicity or B(a)P 7,8-diol-induced cytotoxicity and mutagenicity were observed.

Animals↗
PubMed2006

Oligomerization of the UDP-glucuronosyltransferase 1A proteins: homo- and heterodimerization analysis by fluorescence resonance energy transfer and co-immunoprecipitation.

UDP-glucuronosyltransferases (UGTs) are membrane-bound proteins localized to the endoplasmic reticulum and catalyze the formation of beta-d-glucopyranosiduronic acids (glucuronides) using UDP-glucuronic acid and acceptor substrates such as drugs, steroids, bile acids, xenobiotics, and dietary nutrients. Recent biochemical evidence indicates that the UGT proteins may oligomerize in the membrane, but conclusive evidence is still lacking. In the present study, we have used fluorescence resonance energy transfer (FRET) to study UGT1A oligomerization in live cells. This technique demonstrated that UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9, and UGT1A10 self-oligomerize (homodimerize). Heterodimer interactions were also explored, and it was determined that UGT1A1 was capable of binding with UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9, and UGT1A10. In addition to the in vivo FRET analysis, UGT1A protein-protein interactions were demonstrated through co-immunoprecipitation experiments. Co-expression of hemagglutinin-tagged and cyan fluorescent protein-tagged UGT1A proteins, followed by immunoprecipitation with anti-hemagglutinin beads, illustrated the potential of each UGT1A protein to homodimerize. Co-immunoprecipitation results also confirmed that UGT1A1 was capable of forming heterodimer complexes with all of the UGT1A proteins, corroborating the FRET results in live cells. These preliminary studies suggest that the UGT1A family of proteins form oligomerized complexes in the membrane, a property that may influence function and substrate selectivity.

Animals↗
PubMed1992

Role of N-glucuronidation in benzidine-induced bladder cancer in dog.

The mechanism by which benzidine induces bladder cancer in dog was evaluated by assessing metabolism of [3H]benzidine by dog liver slices and microsomes. Slices incubated with 0.05 mM [3H]benzidine exhibited a 32.5 min incubated with 0.05 mM [3H]benzidine exhibited a 32.5 min peak, which was also produced when microsomal incubations were supplemented with UDP-glucuronic acid. In contrast to microsomes, very little of the 32.5 min peak was produced with the 100,000 g supernatant fraction. Microsomal metabolism was increased 5-fold by pretreatment with Triton X-100. Very little activity was observed with rat microsomes in either the presence or absence of Triton X-100. This metabolite was also generated by incubating benzidine with glucuronic acid at 4 degrees C for 3 days. Thermospray MS identified this metabolite as benzidine N-glucuronide. At 37 degrees C, the t1/2 stability of purified N-glucuronide was 99, 25 and 3 min in dog urine adjusted to pH 7.3, 6.3 and 5.3 respectively. The N-glucuronide was quite stable at pH 9.3, in dog plasma, and in aprotic solvents for 4 h at 37 degrees C. Relative to benzidine, its N-glucuronide is weakly bound to plasma proteins but not more reactive with DNA. Thus, detoxification by liver provides a mechanism for accumulation of benzidine in acidic urine, uptake of benzidine into bladder epithelium, and activation of benzidine in bladder. The liver and N-glucuronidation play a potentially important role in the species specificity of benzidine carcinogenesis.

Animals↗