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At least 1,243 records · Page 69Linked to original sources
PubMed2005

A formyltransferase required for polymyxin resistance in Escherichia coli and the modification of lipid A with 4-Amino-4-deoxy-L-arabinose. Identification and function oF UDP-4-deoxy-4-formamido-L-arabinose.

Modification of the phosphate groups of lipid A with 4-amino-4-deoxy-L-arabinose (L-Ara4N) is required for resistance to polymyxin and cationic antimicrobial peptides in Escherichia coli and Salmonella typhimurium. We previously demonstrated that the enzyme ArnA catalyzes the NAD+-dependent oxidative decarboxylation of UDP-glucuronic acid to yield the UDP-4''-ketopentose, uridine 5'-diphospho-beta-(L-threo-pentapyranosyl-4''-ulose), which is converted by ArnB to UDP-beta-(L-Ara4N). E. coli ArnA is a bi-functional enzyme with a molecular mass of approximately 74 kDa. The oxidative decarboxylation of UDP-glucuronic acid is catalyzed by the 345-residue C-terminal domain of ArnA. The latter shows sequence similarity to enzymes that oxidize the C-4'' position of sugar nucleotides, like UDP-galactose epimerase, dTDP-glucose-4,6-dehydratase, and UDP-xylose synthase. We now show that the 304-residue N-terminal domain catalyzes the N-10-formyltetrahydrofolate-dependent formylation of the 4''-amine of UDP-L-Ara4N, generating the novel sugar nucleotide, uridine 5'-diphospho-beta-(4-deoxy-4-formamido-L-arabinose). The N-terminal domain is highly homologous to methionyl-tRNA(f)Met formyltransferase. The structure of the formylated sugar nucleotide generated in vitro by ArnA was validated by 1H and 13C NMR spectroscopy. The two domains of ArnA were expressed independently as active proteins in E. coli. Both were required for maintenance of polymyxin resistance and L-Ara4N modification of lipid A. We conclude that N-formylation of UDP-L-Ara4N is an obligatory step in the biosynthesis of L-Ara4N-modified lipid A in polymyxin-resistant mutants. We further demonstrate that only the formylated sugar nucleotide is converted in vitro to an undecaprenyl phosphate-linked form by the enzyme ArnC. Because the L-Ara4N unit attached to lipid A is not derivatized with a formyl group, we postulate the existence of a deformylase, acting later in the pathway.

Amino Sugars↗
PubMed2001

Identification of oligomeric domains within dermatan sulfate chains using differential enzymic treatments, derivatization with 2-aminoacridone and capillary electrophoresis.

Galactosaminoglycans, i.e. dermatan sulfate (DS) and chondroitin sulfate, are linear heteropolysaccharides consisting of repeating disaccharide units of L-iduronic acid (L-IdoA) or D-glucuronic acid (D-GlcA) residues linked to N-acetyl-galactosamine. High-performance capillary electrophoresis (HPCE or CE) has been successfully used for determining the disaccharide composition of glycosaminoglycans. However, only limited information is available on how to identify oligomeric domains rich in D-GlcA or L-IdoA. The aim of this study was therefore to develop a rapid and accurate CE procedure by which such oligosaccharides can be determined together with the variously sulfated disaccharides. Isolated dermatan sulfates of human origin were separately digested with chondroitinases ABC, AC and B and the enzymic products were derivatized with 2-aminoacridone. CE analysis of these products was performed using a phosphate buffer, pH 3.0, and reversed polarity at 30 kV. The derivatization enabled their detection with laser-induced fluorescence (LIF) and UV at 260 nm at much higher sensitivity than the detection of nonderivatized delta-saccharides at 232 nm and therefore components undetectable at 232 nm were nicely detected after derivatization. Except for delta-disaccharides, altogether five distinct oligosaccharides with differences in charge density were identified. Depending on the lyase that produced these oligomers, information on the presence of L-IdoA- or D-GlcA-containing domains within the DS chain and the sulfation pattern of these oligomeric domains was obtained. This CE method could also be useful in studying the functional oligomeric domains in galactosaminoglycan chains.

Aminoacridines↗
PubMed2002

Synthesis and biological activity of the prodrug of class I major histocompatibility peptide GILGFVFTL activated by beta-glucuronidase.

The first synthesis of a prodrug of HLA-A2.1 associated antigenic influenza peptide 2a was accomplished. Two methods for synthesis of prodrugs of antigenic peptides activated by beta-glucuronidase and comprising a self-immolative 3-nitrobenzyloxycarbonyl moiety were investigated. Reaction of beta-glucuronic acid glycoside of 4-hydroxy-3-nitrobenzyl alcohol (3) with N,N'-disuccinimidyl carbonate (DSC) followed by conjugation with AlaOMe, Gly, Thr, Phe-Leu, and Leu-Arg gave carbamates 4a-4f. Deacetylation of 4b and 4e with MeONa/MeOH gave beta-glucuronides 5b and 5e. Compound 5e was converted to beta-glucuronic acid conjugate 6e by the action of pig liver esterase (PLE). Compound 6e is a substrate for beta-glucuronidase. Method of a direct introduction of the prodrug residue into antigenic nonapeptide GILGFVFTL (2b) failed. Alternately, glycine conjugate 5b was activated to pentafluorophenyl ester 10. Model coupling of 10 with Phe-Leu gave tripeptide conjugate ester 11a which was hydrolyzed by PLE to uronic acid 12. Condensation of 10 with octapeptide ILGFVFTL (9) gave prodrug precursor 11b. Octapeptide 9 was prepared by de novo synthesis using a racemization-free fragment coupling method. Ester hydrolysis with Ba(OH)(2)/MeOH gave the target prodrug 2a which is a substrate for beta-glucuronidase. Prodrug 2a does not bind to HLA-A2.1 of T2 human cells defective in major histocompatibility complex I (MHC I)-associated peptide processing. Addition of beta-glucuronidase restored the binding to the level observed with parent nonapeptide 2b although higher concentrations of prodrug 2a and enzyme were necessary.

Glucuronidase↗
PubMed2005

Genes encoding enzymes responsible for biosynthesis of L-lyxose and attachment of eurekanate during avilamycin biosynthesis.

The oligosaccharide antibiotic avilamycin A is composed of a polyketide-derived dichloroisoeverninic acid moiety attached to a heptasaccharide chain consisting of six hexoses and one unusual pentose moiety. We describe the generation of mutant strains of the avilamycin producer defective in different sugar biosynthetic genes. Inactivation of two genes (aviD and aviE2) resulted in the breakdown of the avilamycin biosynthesis. In contrast, avilamycin production was not influenced in an aviP mutant. Inactivation of aviGT4 resulted in a mutant that accumulated a novel avilamycin derivative lacking the terminal eurekanate residue. Finally, AviE2 was expressed in Escherichia coli and the gene product was characterized biochemically. AviE2 was shown to convert UDP-D-glucuronic acid to UDP-D-xylose, indicating that the pentose residue of avilamycin A is derived from D-glucose and not from D-ribose. Here we report a UDP-D-glucuronic acid decarboxylase in actinomycetes.

Actinobacteria↗
PubMed1992

An acidic polysaccharide having immunological activities from the rhizome of Cnidium officinale.

An acidic polysaccharide, designated as cnidirhan AG, was isolated from the rhizomes of Cnidium officinale Makino. It was homogeneous on electrophoresis and gel chromatography, and its molecular mass was estimated to be 5.1 x 10(4). It showed pronounced reticuloendothelial system-potentiating activity in a carbon clearance test, and had a remarkable effect on both anti-complementary and alkaline phosphatase-inducing activities. It is composed of L-arabinose: D-galactose: D-glucuronic acid in the molar ratio of 2:6:1, in addition to small amounts of O-acetyl groups. Methylation analysis, carbon-13 nuclear magnetic resonance, controlled Smith degradation and limited acid hydrolysis indicated that the core structural features of cnidirhan AG include a backbone chain composed of beta-1,3-linked D-galactose residues. Some of the galactose units in the backbone carry beta-D-galactosyl side chains at position 6. Both alpha-L-arabinosyl arabinose side chains and terminal beta-D-glucuronic acid residues are linked to the core galactan units.

Alkaline Phosphatase↗
PubMed1979

Interference of UDP-glucuronyltransferase and beta-glucuronidase activity in rat liver microsomes at pH 7.5 with p-nitrophenol and p-nitrophenylglucuronide as substrates.

Microsomal fraction contains the whole of hepatic UDP-glucuronyltransferase as well as part of beta-glucuronidase. The activities of the two enzymes were assayed under identical conditions using untreated male rat liver microsomes at pH 7.5. In a 30-min incubation with p-nitrophenol and UPD-glucuronic acid, a net glucuronide formation of 0.010 mumol.min-1.g.liver-1 was measured. In the presence of saccharolactone at concentrations selectively blocking beta-glucuronidase, the glucuronidation rate was 0.015 mumol.min-1.g.liver-1. Using the kinetic parameters of beta-glucuronidase (Km = 0.06 mmol/l p-nitrophenylglucuronide, Vm = 0.075 mumol pNP formed.h-1.g.liver-1) determined in the absence of UDP-glucuronic acid, to correct for the beta-glucuronidase's interference on the glucuronidation process, a glucuronide formation of 0.011 mumol.min-1.g.liver-1 was calculated.

Animals↗
PubMed1992

Inhibition of alloxan-induced hyperglycaemia by compounds of similar molecular structure.

In this study we have shown that a range of compounds that are structurally similar to alloxan are able to protect mice against the diabetogenic effect of alloxan. The compounds include a group of five barbiturates, a group of five hydantoins, the methylxanthines caffeine and theophylline, the related compound uric acid, and ethosuximide. They were injected intraperitoneally prior to intravenous injection of alloxan, and blood glucose concentration was used as an index of alloxan toxicity. The salient structural feature possessed by all of these protective compounds is a pair of carbonyl oxygen atoms separated by a distance of 4.5 A and projecting from an approximately planar heterocyclic five- or six-membered ring; in all cases the carbonyl groups are separated by a ring nitrogen. We suggest that this feature is required for the protective effect of these compounds. In order to test further the requirement for two ring carbonyl groups, we also examined the effects of two compounds containing hydroxyl groups projecting from a six-membered ring, inositol and glucuronic acid. In agreement with previous studies on hexoses, we found that the effects of compounds such as these are unpredictable, with inositol protecting against alloxan toxicity but glucuronic acid not. We are unable to identify the critical difference in structure between these two compounds.

Allantoin↗
PubMedDate not supplied

Novel assay and pharmacokinetics of levamisole and p-hydroxylevamisole in human plasma and urine.

A new gas chromatographic method was developed for the quantification of levamisole in human plasma and urine, using a nitrogen-phosphorus flame ionization detector. The adsorption of the drug onto glass was prevented by treating the glassware with a siliconizing agent. The sensitivity of the assay was 10 ng ml-1 and as low as 2 ng ml-1 can be detected in plasma. The urinary metabolite p-hydroxylevamisole was analysed by high performance liquid chromatography with ultraviolet detection. The sensitivity of this assay was 0.50 micrograms ml-1. Plasma and urinary concentrations of levamisole were determined in 10 healthy volunteers including seven men and three women following the administration of a single 150 mg dose of levamisole. Levamisole was rapidly absorbed (tmax 1.5 h), giving a peak plasma concentration of 716.7 +/- 217.5 ng ml-1. The plasma elimination half-life of levamisole was 5.6 +/- 2.5 h. Only 3.2 +/- 2.9 per cent of the oral dose was recovered as unchanged drug in the urine, suggesting the importance of clearance of levamisole by routes other than the kidney, and most probably by hepatic metabolism. The urinary concentrations of p-hydroxylevamisole were determined before and after hydrolysis of the urine samples with beta-glucuronidase, and the level of conjugation of the metabolite with glucuronic acid was then estimated. Cumulative recovery of the metabolite accounted for 1.6 +/- 1.1 per cent and 12.4 +/- 5.5 per cent of the oral dose of levamisole before and after hydrolysis, respectively, indicating that p-hydroxylation is a relatively important route of metabolism of levamisole, and that the p-hydroxylated metabolite is excreted mainly in conjugation with glucuronic acid. Except for the absorption rate of levamisole which is approximately twice as rapid in women as in men, there is no marked difference in the pharmacokinetics of levamisole between healthy men and women.

Adult↗
PubMed1966

The capsular polysaccharide of pneumococcus type IX.

The capsular polysaccharide of Type IX pneumococcus contains D-glucose, N-acetyl-D-glucosamine, and D-glucuronic acid. Complete hydrolysis is difficult. All of the N-acetylglucosamine is resistant to oxidation by periodate, but the other two sugars are degraded in part. Chemical and quantitative serological data are consistent with the linkage of two D-glucose residues 1 --> 4, as in maltose; others may be linked 1 --> 3. Part, at least, of the glucuronic acid and N-acetylglucosamine is linked to glucose.

In Vitro Techniques↗
PubMed1988

Occurrence of a unique fucose-branched chondroitin sulfate in the body wall of a sea cucumber.

The sulfated polysaccharides in the body wall of the sea cucumber occur as three fractions that differ markedly in molecular mass and chemical composition. The fraction containing a high molecular mass component has a high proportion of fucose and small amounts of galactose and amino sugars, whereas another fraction contains primarily a sulfated fucan. The third fraction (F-2), which represents the major portion of the sea cucumber-sulfated polysaccharides, contains approximately equimolar quantities of glucuronic acid, N-acetyl galactosamine, and fucose, and has a sulfate content higher than that in the other two fractions. The structure of fraction F-2 was examined in detail. This polysaccharide has an unusual structure composed of a chondroitin sulfate-like core, containing side chain disaccharide units of sulfated fucopyranosyl linked to approximately half of the glucuronic acid moieties through the O-3 position of the acid. These unusual fucose branches obstruct the access of chondroitinases to the chondroitin sulfate core of F-2. However, after partial acid hydrolysis, which removes the sulfated fucose residues from the polymer, fraction F-2 is degraded by chondroitinases into 6-sulfated and nonsulfated disaccharides.

Animals↗
PubMed1976

Regulation of microsomal UDP-glucuronyltransferase by metal ions. Differential effects of Mn2+ on forward and reverse reactions.

Mn2+ activates UDP-glucuronyltransferase (assayed with p-nitrophenol as aglycone) in assays of the forward reaction. The kinetic mechanism of this activation is an increase in activity at V. The rate of the reverse reaction catalyzed by UDP-glucuronyltransferase (UDP-dependent hydrolysis of p-nitrophenylglucuronic acid) is inhibited by Mn2+. The basis for this inhibition is an increase in KUDP, and a small increase in KNphGlcUA. Mn2+ appears to have no effect of the activity of the reverse reaction of saturating concentrations of both substrates. The differential effects of divalent metal ions on rates of the forward and reverse reactions catalyzed by UDP-glucuronyltransferase are due in part to differences in the affinities of UDP-glucuronic acid and UDP for metals. Keq for the formation of UDP-Mn2+ is 8.6 X 10(3); Keq for the formation of UDP-glucuronic acid-Mn2+ is 4.8 X 10(2). High concentrations of UDP thus can compete for metal ions bound to UDP-glucuronyltransferase, but UDP-glucuronic acid is less likely to do so. This competition for metal ions between the enzyme and substrates accounts for the failure of Mn2+ to increase the activity at V of the reverse reaction. Mn2+-induced inhibition of the reverse reaction, due to an increase of KUDP, reflects that the affinity of the affinity of the enzyme for UDP is greater than that for UDP-Mn2+. On the other hand, formation of a complex between UDP-glucuronic and Mn2+ does not alter the affinity of UDP-glucuronyltransferase for this nucleotide derivative

Animals↗
PubMed1979

Metabolism of benzo[A]pyrene and the related enzyme activities in hamster embryo cells.

The rate of metabolism of benzo[a]pyrene (BP) and changes in related enzyme activities in cultured hamster embryo cells during successive subculture were studied. The activity of aryl hydrocarbon hydroxylase (AHH) was the highest when embryo cells were first dispersed in tissue culture flasks and decreased during subsequent passages. On the other hand, UDP-glucuronyl transferase activity increased gradually during successive subculture. Treatment of the cells with 13 nmol/ml of benz[a]anthracene (BA) for 24 h increased the activity of AHH but not that of UDP-glucuronyl transferase. The metabolism of BP was measured in cells of the passages 1, 3 and 7; metabolism of BP was most efficient in cells in passage 3 and their formation of glucuronic acid conjugates of BP, one of the major metabolites found in the medium, was 3- and 10-fold more than those of cells in passages 1 and 7, respectively. Analysis of BP-metabolites extracted from the medium with ethylacetate showed that the main metabolites were 9,10-diol and 7,8-diol. Phenols and quinones were released by treatment of the medium with beta- glucuronidase and their amounts were larger than those of diols at all passages. These results show that in hamster embryo cells in early passage, BP is metabolized to conjugates of phenols with glucuronic acid.

Animals↗
PubMed1999

Key fragments for identification of positional isomer pair in glucuronides from the hydroxylated metabolites of RT-3003 (Vintoperol) by liquid chromatography/electrospray ionization mass spectrometry.

The mass spectral properties of glucuronides of the 9- and 10-hydroxylated metabolites of RT-3003 (Vintoperol; (-)-1beta-ethyl-1alpha-hydroxymethyl-1,2,3,4,6,7, 12balpha-octahydroindolo[2,3-a]quinolizine), which were fractionated by high-performance liquid chromatography with fluorescence detection, were investigated using the positive ion electrospray ionization mode. These glucuronides showed predominantly the protonated molecular ion ([M + H](+) ion), and the [M + H](+) ion provided a characteristic product ion spectrum in which abundant ions were obtained at m/z 301, 160 and 142. The first ion, corresponding to the [aglycone + H](+) ion, was produced by neutral loss of the glucuronic acid moiety from the [M + H](+) ion. The product ion spectrum of the [M + H](+) ion of hydroxy-RT-3003 revealed a number of ions common to the glucuronide spectra, suggesting that other two ions observed most likely represent fragmentation of hydroxy-RT-3003. In turn, these glucuronides were positional isomers with respect to the binding site of glucuronic acid. The structures of the isomer pairs were discriminated by the presence of the ion of m/z 318 or 336 in the product ion spectrum. These ions were produced by fission of the C-ring, the same as for the formation of the ions of m/z 160 and 142, as were observed in the product ion spectrum from the [M + H](+) ion of hydroxy-RT-3003. For the formation of these ions, an unusual fragmentation process was proposed, and these ion structures were supported by evidence from the accurate mass measurement data. Additionally, in the sulfates of hydroxylated metabolites, a similar product ion corresponding to the ion of m/z 336 found in the phenolic glucuronides was observed, and was applied for identification of the sulfate metabolites.

Animals↗
PubMed1984

Secondary structure of hyaluronate in solution. A 1H-n.m.r. investigation at 300 and 500 MHz in [2H6]dimethyl sulphoxide solution.

The 1H-n.m.r. spectra of solutions in [2H6]dimethyl sulphoxide of the sodium salts of tetra-, hexa- and octa-saccharides prepared from hyaluronate by testicular-hyaluronidase digestion were examined at 300 and 500 MHz. The signals from hydroxy groups at positions 2 and 3 in the glucuronic acid moiety were assigned. Their chemical shifts and associated temperature-dependencies, as well as their coupling constants, depended on whether or not the uronic acid was at the non-reducing end. Deviations from the 'normal' pattern of hydroxy-group proton n.m.r. behaviour were attributable to participation in hydrogen bonds, either to the acetamido carbonyl oxygen atom or the pyranose ring oxygen atom of neighbouring N-acetylhexosamine moieties. A secondary structure, containing four different hydrogen bonds per trisaccharide unit of glucuronsyl-hexosaminyl-glucuronic acid, was demonstrated. This is the first complete and detailed secondary structure to be established for hyaluronate in any solvent. Hyaluronate is compared with chondroitin sulphate, dermatan sulphate, heparan sulphate and keratan sulphate in their potential to form secondary structures with features in common. The significance of the details of the structure to its overall stability, and the probability of their persistence into aqueous environments, are discussed. The presence of all or most of the secondary structure in glycosaminoglycuronans is correlated with a space-filling function in the tissue, and with a high carbohydrate content in the parent proteoglycan in the case of the chondroitin sulphates.

Carbohydrate Conformation↗
PubMed1982

Medium for selective isolation and presumptive identification of the Bacteroides fragilis group.

We developed and evaluated a new medium (FRAG agar) for the selective isolation and presumptive identification of the Bacteroides fragilis group. This medium contains 1% D-glucuronic acid as a fermentable carbon source, a reduced peptone content, gentamicin, and 20% bile. Presumptive identification of the B. fragilis group was based on growth, fermentation, and typical colony morphology. A total of 75 stock culture isolates of the B. fragilis group grew well on this medium, and 69 showed evidence of fermentation. Of 90 other anaerobes, none grew well or fermented glucuronic acid. In a clinical trial of 100 specimens sent for anaerobic culture, FRAG agar inhibited 71 of 71 anaerobes not belonging to the B. fragilis group, as well as 104 of 110 facultative organisms. A total of 33 isolates of the B. fragilis group were recovered on the selective medium, whereas only 23 were recovered by routine methods. Of 23 cultures positive for the B. fragilis group on routine plates, 22 were positive on FRAG agar.

Bacteriological Techniques↗
PubMedDate not supplied

Kidney and liver contributions to salicylate metabolism in rats.

The pharmacokinetics and metabolism of radiolabelled salicylate were studied in rats and compared with that of the isolated perfused rat liver and the perfused rat kidney. Both parent compound and salicylate metabolites (mainly conjugates with glycine and glucuronic acid) were eliminated mostly into urine. The comparison of a relative proportion of metabolites eliminated in whole rats with that of the isolated perfused rat liver and the perfused rat kidney showed that both kidney and liver contributed to the salicylate metabolism. The glycine conjugate of salicylate was formed predominantly in the kidney whereas both kidney and liver participated in the formation of glucuronic acid derivatives.

Animals↗
PubMed1984

Studies related to the metabolism of anabolic steroids in the horse: the phase I and phase II biotransformation of 19-nortestosterone in the equine castrate.

The metabolism of 19-nor[4-14C]testosterone has been studied in the equine castrate. Following XAD-2 extraction of aliquots of the 0-24 h urine samples, the glucuronic acid and sulphate conjugates were separated by Sephadex LH-20 column chromatography. After hydrolysis of the conjugates, the neutral phase I metabolites of 19-nortestosterone were extracted, purified and identified by g.l.c.-mass spectrometry. In phase I metabolism stereospecificity was observed in the reduction of the A-ring with the formation of the 5 alpha, 3 beta-isomers of estranediol. Epimerization at C-17 and hydroxylation at C-16 were the other major pathways. In phase II metabolism the C-17 alpha steroid epimers were predominantly conjugated with glucuronic acid and the C-17 beta epimers with sulphuric acid. One animal showed a slight variation in metabolism with a tendency towards the formation of polar metabolites.

Animals↗
PubMed1982

Quantitative determination of bile acid glucuronides in serum by mass fragmentography.

Individual non-glucuronidated . non-sulfated, glucuronidated and sulfated bile acids in serum were determined, i.e. lithocholic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, and cholic acid, by mass fragmentography. Glucuronic acid conjugates of lithocholic acid, deoxycholic acid, chenodeoxycholic acid, and cholic acid were synthesized via the Koenigs-Knorr condensation reaction. Deuterium labeled deoxycholic acid, lithocholic acid glucuronide, deoxycholic acid glucuronide, and deoxycholic acid sulfate were synthesized and used as internal standards. A serum sample of 1 ml including internal standards was purified with a Sep-Pak C18 cartridge. After the enzymatic cleavage of amino acid conjugates, bile acids were separated into three fractions, free, glucuronidated, and sulfated bile acids, using piperidinohydroxypropyl Sephadex LH-20 (Goto et al. (1978) Clin. Chim. Acta 87). Glucuronidated and sulfated bile acids were deconjugated by beta-glucuronidase treatment and solvolysis. Each fraction was converted to the hexafluoroisopropyl-trifluoroacetyl derivative and quantitated by mass fragmentography. The average concentrations of individual bile acid glucuronides from healthy fasting subjects (n = 9) were as follows; lithocholic acid 0.013 microgram/ml, deoxycholic acid 0.083 microgram/ml, chenodeoxycholic acid 0.078 microgram/ml, ursodeoxycholic acid 0.013 microgram/ml, and cholic acid 0.007 microgram/ml. Bile acid glucuronides occupied 7.8% of the total bile acids.

Bile Acids and Salts↗