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PubMed2002

Metabolomics of plant saponins: bioprospecting triterpene glycoside diversity with respect to mammalian cell targets.

One of the goals of cancer chemotherapy and prevention is the discovery of compounds that are relatively selective to tumor cells and, therefore, have reduced effects on normal cell growth. In previously published studies, it was shown that certain triterpene saponins (called avicins) from a desert tree, Acacia victoriae, are selectively toxic to tumor cells at very low doses (IC(50): 0.2 microg/mL for Jurkat cells). To extend this research to human clinical studies, we needed to find a reliable supply of avicins and have developed a transformed "hairy root" culture as a means of biomass production. Protocols were optimized for A. victoriae micropropagation; after a boiling water treatment, A. victoriae seeds were maintained under in vitro conditions on defined media. Embryo-axis explants from shoot tips were removed and infected with Agrobacterium rhizogenes Conn (R 1000) for hairy root induction. Plasmid integration was confirmed by PCR analysis with a primer set for a segment of the rol B gene. Culture conditions have been optimized for root biomass production, and various inducers have been investigated for enhancement of avicin production. Hairy root cultures were compared with intact pod tissue from field-grown sources for avicin content following partial purification of triterpene glycosides and HPLC separation of the secondary metabolites. From bioassays of the collected HPLC fractions, we have identified putative triterpene "metabolic clusters" with enhanced activity against tumor cells. This now provides a system for both production of clinical trial lots of active samples, but also a means to correlate structure of individual triterpene glycosides with specific cellular target activity in mammalian cells.

Acacia↗
PubMed1989

Reversed-phase chromatography of novel biologically effective aminoacridine-N-glycosides by OPLC.

The reversed-phase chromatographic behavior of novel biologically active aminoacridine-N-glycosides is studied. The chromatographic experiments are performed with overpressurized layer chromatography. Weak ion pairs are formed with methanesulfonic acid, but only at low concentrations of the ion-pairing reagent. The retention seems to involve a reversed-phase mechanism. The base compounds only slightly modify the retention, while the number and polarity of the substituents have larger effects. The pH dependence of the retention is very typical for the aminoacridine-N-glycosides, and it plays an important role in the separation. The monoglycosides are completely separated from the corresponding base compounds, as are the diglycosides from the monoglycosides, on RP-2, RP-8, and RP-18 layers with eluents containing 30 to 60% acetonitrile and at least 0.005 M ammonium carbonate at pH 4 to 6.

Acridines↗
PubMed1997

Influence of L-fucose attached alpha 1-->6 to the asparagine-linked N-acetylglucosamine on the hydrolysis of the N-glycosidic linkage by human glycosylasparaginase.

The sequence of hydrolytic reactions in the catabolism of the N-glycosidic oligosaccharide-to-protein region containing 6-linked fucose on the asparagine-linked N-acetylglucosamine may vary from species to species. When alpha-L-fucopyranosyl-(1-->6)-2-acetamido-1-N-(beta-L-aspartyl)-2-deoxy- beta -D-glucopyranosylamine (Fuc-GlcNAc-Asn) was incubated with recombinant human glycosylasparaginase, no hydrolysis of the N-glycosidic bond was detected. After removal of the alpha 1-->6-linked fucose from the compound by alpha-fucosidase, the residual GlcNAc-Asn was rapidly hydrolyzed by glycosylasparaginase. Enzymologically this demonstrates for the first time that the catabolism of Fuc-GlcNAc-Asn in humans occurs via consecutive action of alpha-fucosidase and glycosylasparaginase. The hydrolysis rate of GlcNAc-Asn by glycosylasparaginase remained unaffected in the presence of Fuc-GlcNAc-Asn or several different monosaccharides including fucose. This indicates that any fucose attached alpha 1-->6 to the asparagine-linked N-acetylglucosamine residue prevents the access of the L-asparagine residue of Fuc-GlcNAc-Asn into the deep, funnel-shaped active site of human glycosylasparaginase. These findings explain the accumulation of fucosylated and normal catabolism of nonfucosylated glycoasparagines in fucosidosis.

Acetylglucosamine↗
PubMed2005

Photoswitchable cluster glycosides as tools to probe carbohydrate-protein interactions: synthesis and lectin-binding studies of azobenzene containing multivalent sugar ligands.

Synthetic cluster glycosides have often been used to unravel mechanisms of carbohydrate-protein interactions. Although synthetic cluster glycosides are constituted on scaffolds to achieve high avidities in lectin binding, there have been no known attempts to modulate the orientations of the sugar clusters with the aid of a functional scaffold onto which the sugar units are linked. Herein, we describe synthesis, physical, and lectin-binding studies of a series of alpha-D-mannopyranoside and beta-D-galactopyranosyl-(1-->4)-beta-D-glucopyranoside glycoclusters that are attached to a photoswitchable azobenzenoid core. These glycoclusters were synthesized by the amidation of amine-tethered glycopyranosides with azobenzene carbonyl chlorides. From kinetic studies, the cis forms of the azobenzene-glycopyranoside derivative were found to be more stable in aqueous solutions than in organic solvents. Molecular modeling studies were performed to estimate the relative geometries of the photoswitchable glycoclusters in the trans- and cis-isomeric forms. Isothermal titration calorimetry (ITC) was employed to assess the binding of these glycoclusters to lectins peanut agglutinin (PNA) and concanavalin A (Con A). Although binding affinities were enhanced several orders higher as the valency of the sugar was increased, a biphasic-binding profile in ITC plots was observed during few glycoclusters lectin-binding processes. The biphasic-binding profile indicates a "cooperativity" in the binding process. An important outcome of this study is that in addition to inherent clustering of the sugar units as a molecular feature, an induced clustering emanates because of the isomerization of the trans form of the azobenzene scaffold to the cis-isomeric form.

Azo Compounds↗
PubMed2000

Structural features of normal and mutant human lysosomal glycoside hydrolases deduced from bioinformatics analysis.

Lysosomal storage diseases are due to inherited deficiencies in various enzymes involved in basic metabolic processes. As with other genetic diseases, accurate structure data for these enzymatic proteins should help in better understanding the molecular effects of mutations identified in patients with the corresponding lysosomal diseases; however, no such three-dimensional (3D) structure data are available for many lysosomal enzymes. Thus, we herein intend to illustrate for an audience of molecular geneticists how structure information can nonetheless be obtained via a bioinformatics approach in the case of five human lysosomal glycoside hydrolases. Indeed, using the two-dimensional hydrophobic cluster analysis method to decipher the sequence information available in data banks for the large group of glycoside hydrolases (clan GH-A) to which these human lysosomal enzymes belong, we could deduce structure predictions for their catalytic domains and propose explanations for the molecular effects of mutations described in patients. In addition, in the case of human beta-glucuronidase for which experimental 3D data have been reported, we also show here that bioinformatics methods relying on the available 3D structure information can be used to obtain further insights into the effects of various mutations described in patients with Sly disease. In a broader perspective, our work stresses that, in the context of a rapid increase in protein sequence information through genome sequencing, bioinformatics approaches might be highly useful for generating structure-function predictions based on sequence-structure interrelationships.

Crystallography, X-Ray↗
PubMed1984

Metabolism of orally administered alkyl beta-glycosides in the mouse.

The metabolism of octyl beta-D-[U-14C]glucoside, ]1-14C]dodecyl beta-D-maltoside and [1-14C]hexadecyl beta-D-glucoside was studied after oral administration to mice. The beta-glycosidic bond was rapidly hydrolyzed in intestine and liver. The cleavage products, sugars and long-chain alcohols, entered the pathways of lipid and carbohydrate metabolism. It appears that alkyl beta-glycosides are suitable as additives in food and feed.

Animals↗
PubMed1974

Nucleoside conformations. 15. Flexibility of natural pyrimidine nucleosides around the glycosidic bond.

The flexibility of pyrimidine nucleosides has been investigated by measuring their circular dichroism in hydroalcoholic solutions over a large temperature range (-100 degrees to +40 degrees C). It was observed that ss-Uridine (Urd) and ss-Cytidine (Cyd) showed a decrease of the main dichroic band of about 40 percent, while sterically hindered nucleosides (alphaUrd, ara-Uracile, 02-2' anhy-dro-Urd, 2'3'-0-isopropylidene-Urd) showed only small decreases. It is concluded that the flexibility of the glycosidic linkage in conjunction with the pseudo-rotation of the sugar residue is responsible for these changes; the thermodynamic values which can be deduced from these decreases are compatible with an oscillatory motion around the glycosidic bond, but exclude anti-syn transformations in pyrimidine nucleosides.

Circular Dichroism↗
PubMed2006

Dividing the large glycoside hydrolase family 13 into subfamilies: towards improved functional annotations of alpha-amylase-related proteins.

Family GH13, also known as the alpha-amylase family, is the largest sequence-based family of glycoside hydrolases and groups together a number of different enzyme activities and substrate specificities acting on alpha-glycosidic bonds. This polyspecificity results in the fact that the simple membership of this family cannot be used for the prediction of gene function based on sequence alone. In order to establish robust groups that show an improved correlation between sequence and enzymatic specificity, we have performed a large-scale analysis of 1691 family GH13 sequences by combining clustering, similarity search and phylogenetic methods. About 80% of the sequences could be reliably classified into 35 subfamilies. Most subfamilies appear monofunctional (i.e. contain enzymes with the same substrate and the same product). The close examination of the other, apparently polyspecific, subfamilies revealed that they actually group together enzymes with strongly related (or even sometimes virtually identical) activities. Overall our subfamily assignment allows to set the limits for genomic function prediction on this large family of biologically and industrially important enzymes.

Amino Acid Sequence↗
PubMed1990

Age-dependent change in myocardial cardiac glycoside receptor (Na,K-pump) concentration in children.

Myocardial Na,K-ATPase concentration was quantified in 18 0-8-year-old human subjects by vanadate-facilitated 3H-ouabain binding to intact samples of the left ventricle of the heart obtained at autopsy. Within the first 6 months of life, the Na,K-ATPase concentration showed a rapid decrease. The mean value in the age range from birth to 6 months was 1.6 times the mean value obtained in the age range 6 months to 8 years. The mean values +/- SEM were 1,076 +/- 57 (n = 10) and 671 +/- 28 (n = 8) (p less than 0.001) pmol/g wet weight, respectively. The highest value [1,433 +/- 56 pmol/g wet weight (n = 5)] was found in a 3-month-old child and the lowest value [545 +/- 22 pmol/g wet weight (n = 5)] in an 8-year-old. Evaluation of 3H-ouabain-binding kinetics showed no age-dependent variations. The total amount of Na,K-ATPase found in the heart was approximately 30 and 80 nmol within the first 3 years of life and at 8 years, respectively. The age-dependent change in myocardial Na,K-ATPase concentration can be ascribed to variation in the ratio between the amount of Na,K-ATPase and muscle mass during development. Since myocardial Na,K-ATPase is the receptor for cardiac glycosides, the present results may in part explain the clinical observation that cardiac glycoside sensitivity and toxicity change in young age.

Aging↗
PubMed1990

Effectiveness of cardiac glycosides in human myocardium with and without "downregulated" beta-adrenoceptors.

We investigated the "receptor-effector-coupling" in the beta-adrenoceptor- and the Na+, K(+)-ATPase-mediated systems in nonfailing hearts and terminally failing human myocardium from patients with cardiomyopathy. The density of beta-adrenoceptors in the failing human myocardium was significantly (p less than 0.01) lower as compared with nonfailing hearts, whereas the receptor density and affinity measured by [3H]ouabain binding (cardiac glycoside receptor) was not different in either group. The maximal inotropic response to isoprenaline was significantly reduced in papillary muscle strips from failing human hearts (2.1 +/- 0.5 mN) as compared with control hearts (8.0 +/- 1.0 mN; p less than 0.05). Ouabain remained effective in both groups (6.8 +/- 1.0 vs. 5.5 +/- 0.6 mN; NS). The positive inotropic response due to extracellular Ca2+ elevation (1.8-15 mM) was studied for comparison. Maximal Ca2+ effects were reduced by 30% in failing human myocardium (7.2 +/- 0.5 mN vs. 5.1 +/- 0.8 mN, p less than 0.05). Ouabain had effectiveness (95%) similar to that of Ca2+ in nonfailing and failing human cardiac muscle. It is concluded that treatment with cardiac glycosides may still be effective in end-stage heart failure with "downregulated" beta-adrenoceptors, as judged from these in vitro studies.

Adult↗
PubMed1991

Investigation of electrophysiologic mechanisms for the antiarrhythmic actions of R 56865 in cardiac glycoside toxicity.

R 56865 is an experimental compound that has been shown to ameliorate the effects of cardiac glycoside toxicity and myocardial ischemia. We evaluated the direct electrophysiological effects of R 56865 and its effects on the electrophysiological sequelae of ouabain toxicity in vivo and in vitro. In normal anesthetized dogs, R 56865 alone at doses of 0.04 to 0.16 mg/kg i.v. had no effect on atrial, AV nodal, or ventricular conduction times and refractoriness, but at doses of 0.64 to 2.5 mg/kg it tended to increase these parameters. In ouabain-pretreated dogs, R 56865 (0.08 to 0.32 mg/kg i.v.) dose-relatedly reduced ouabain-induced ventricular arrhythmias. In normal isolated canine Purkinje fibers, R 56865 (1-10 microM) reduced Vmax at short pacing cycle lengths and decreased the action potential duration at concentrations of 0.1 to 10 microM. R 56865 at concentrations through 10 microM had no significant effect on normal action potentials of canine ventricular muscle and slow response action potentials in guinea pig papillary muscles. In Purkinje fibers exposed to toxic concentrations of ouabain, R 56865 (1 microM) reduced the delayed after depolarization (DAD) amplitude and inhibited triggered activity. R 56865 had no effect on normal automaticity in canine Purkinje fibers at 1 microM, but 10 microM significantly slowed it. R 56865 at 10 microM did not affect isoproterenol-enhanced automaticity and only slightly reduced barium-induced abnormal automaticity that occurred at reduced membrane potentials. These results demonstrate that R 56865 reverses cardiac glycoside-induced arrhythmias in anesthetized dogs at doses that do not significantly affect conduction or refractoriness. Suppression of ouabain-induced DAD and triggered activity in isolated Purkinje fibers, at concentrations not affecting normal or abnormal automaticity, may be the mechanism of R 56865's antiarrhythmic actions in vivo. Suppression of DAD does not appear to be associated with blockade of voltage-dependent calcium channels, but R 56865 may prevent intracellular sodium overload by limiting excessive sodium entry during ouabain intoxication.

Action Potentials↗
PubMed1997

A case of nondigitalis cardiac glycoside toxicity.

A case is presented of cardiac glycoside poisoning in a 1-year-old patient from the plant Nerium oleander (common oleander). The patient had bradycardia, vomiting, altered level of consciousness, and no history of ingestion. Antibody-based digoxin assays may cross-react with other cardiac glycosides nonquantitatively. Chromatographic techniques can be used in the specific diagnosis.

Animals↗
PubMed2003

Crystallization and preliminary X-ray analysis of a family 51 glycoside hydrolase, the alpha-l-arabinofuranosidase from Geobacillus stearothermophilus T-6.

Alpha-l-arabinofuranosidases (EC 3.2.1.55) are hemicellulases that cleave the glycosidic bond between l-arabinofuranoside side chains and various oligosaccharides. In this study, the first crystallization and preliminary X-ray analysis of the alpha-l-arabinofuranosidase from Geobacillus stearothermophilus T-6 (AbfA T-6), a family 51 glycoside hydrolase, is described. AbfA T-6 is a hexameric protein consisting of six identical subunits of 502 amino acids and with a calculated molecular mass of 57 218 Da. Purified recombinant native and selenomethionine-containing AbfA T-6 were crystallized by the sitting-drop method in two different space groups, P2(1) (unit-cell parameters a = 100.8, b = 178.1, c = 196.2 A, beta = 96.1 degrees ) and R3 (unit-cell parameters a = b = 179.3, c = 100.4 A). The R3 crystals diffracted X-rays to a resolution of 1.8 A.

Bacterial Proteins↗
PubMed1991

Microbiological exploitation of cardiac glycosides and alkaloids from Garcinia kola, Borreria ocymoides, Kola nitida and Citrus aurantifolia.

The four medicinal plants, Garcinia kola (roots), Borreria ocymoides (leaves), Kola nitida (bark) and Citrus aurantifolia (roots) were screened for phytochemical components. They were found to contain tannins, phlobatannins, polyphenols, hydroxymethyl anthraquinones, glucides, saponins, alkaloids, cardiac glycosides, flavanoids and reducing compounds. The aqueous and alcoholic extracts as well as alkaloids and cardiac glycosides of the medicinal plants were tested on various pathogenic bacteria. They were found to inhibit such organisms as Staphylococcus aureus, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, beta-haemolytic streptococci, Escherichia coli and Neisseria gonorrhoeae. The usefulness of the phytochemical bases of these plants as potential sources of pharmaceutical drug preparation is discussed.

Alkaloids↗
PubMed1986

The mode of action of cardiac glycosides.

Throughout the 200 years during which the cardiac glycosides have been in therapeutic use, they have challenged the understanding of clinician and scientist alike. For the clinician the task has been to define the circumstances in which drugs of this class are indicated and to tread the narrow line between pharmacological activity and serious toxicity; neither problem has been entirely solved. For the scientific investigator, a curious paradox has emerged: whereas early workers sought to identify the precise site of action of digitalis, recent research has revealed that cardiac glycosides specifically inhibit a ubiquitous membrane transport process and this makes the apparent tissue specificity of these drugs the more surprising. The gap between the empirical knowledge of clinical experience and the scientific insights derived from laboratory biochemistry and electrophysiology has not yet been closed.

Cardiac Glycosides↗
PubMed1976

Coordinated induction and subsequent activity changes of two groups of metabolically interrelated enzymes. Light-induced synthesis of flavonoid glycosides in cell suspension cultures of Petroselinum hortense.

The enzymes of the flavonoid glycoside pathway were specifically induced upon irradiation of a 10-day-old, dark-grown cell suspension culture of Petroselinum hortense Hoffm. with ultraviolet light. The curves for the activity changes of a first sequence of three enzymes (group I) revealed only small, but significant, differences. Sharp peaks in these enzyme activities were observed at about 17, 22, and 23 h after the onset of the irradiation. The apparent half-lives during the subsequent periods of decline ranged, in the same order, from about 10 to 15 and 17 h. No significant differences were found for the lag periods preceding the increases in the three enzyme activities. The possibility is discussed that the slight differences in the patterns of the light-induced activity changes are mainly due to different rates of degradation of the enzymes, suggesting an otherwise largely interpendent regulation. The patterns of the activity changes of four enzymes of the second sequence (group II) differed greatly from those observed for group I, but were again similar to one another. Thus, the two groups of enzymes appear to be regulated differently, despite their concomitant induction. A sigmoidal curve for the accumulation of the flavonoid glycosides was obtained upon the induction of the enzymes. This curve corresponded closely to that derived by integration of the curve for the activity changes of the first enzyme of group I, phenylalanine ammonia-lyase. It is concluded that this enzyme might be rate-limiting for the entire pathway.

Acyltransferases↗
PubMed1984

Glycosidic linkages of swede cell walls and their residues recovered from the terminal ileum of the pig.

The glycosidic linkage pattern of unfractionated swede cell walls was determined by methylation analysis. The main linkages in descending order of concentration were: (1----4)-linked glucose, (1----4)-linked xylose, terminal galactose, (1----4)-linked mannose, terminal arabinose and (1----2)-linked rhamnose. The major branch points were to the O-2 or O-3 atoms of xylose, O-4 of rhamnose and O-6 of glucose. The subsequent degradation of swede cell walls by passage through the small intestine of the pig was studied by quantitative methylation analysis of material recovered from animals cannulated 150 mm before the ileo-caecal junction. In addition to a substantial loss of uronic acid and phenolic material, the proportions of the different glycosidic linkages recovered from the digesta varied greatly from those of the parent material. Pectic polysaccharides had apparent digestibilities in the range of 0.60-0.75 while those of hemicellulosic components varied between 0.15 and 0.57. Glucose units linked 1----4 (with an apparent digestibility of 0.24) accounted for the greatest weight loss of neutral sugars from the cell wall, followed by terminal galactose, terminal arabinose and 2-linked arabinose.

Animals↗
PubMed1988

Structural analysis of O-glycosidic type of sialyloligosaccharide-alditols derived from urinary glycopeptides of a sialidosis patient.

Sialidosis urine was fractionated by gel filtration on Bio-Gel P-6. All pooled fractions containing carbohydrates showed the presence of small amounts of GalNAc in non-reducing position, besides free N-acetyllactosamine type of oligosaccharides as major constituents. The fractions were subjected to reductive alkaline borohydride degradation, after which the major part of GalNAc was recovered as N-acetyl-D-galactosaminitol (GalNAc-ol). The GalNAc-ol-containing material was separated from the N-glycosidic oligosaccharides by a second gel-filtration step on AcA 202. Subsequently, the O-glycosidic sialyloligosaccharide-alditols were subfractionated by anion-exchange chromatography on Mono Q. Structural analysis by 500-MHz 1H-NMR spectroscopy revealed two major components in all fractions, namely: NeuAc alpha 2-3Gal beta 1-3GalNAc-ol and NeuAc alpha 2-3Gal beta 1-3[NeuAc alpha 2-6]GalNAc-ol. Furthermore, NeuAc alpha 2-3Gal beta 1-3[NeuAc alpha 2-3Gal beta 1-4GlcNAc beta 1-6]GalNAc-ol was found as a minor component in some of the fractions. The presence of these carbohydrate chains in Bio-Gel fractions differing in molecular mass suggested that they are derived from glycopeptides which are heterogeneous in their peptide part.

Carbohydrate Conformation↗