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At least 145 records · Page 8Linked to original sources
PubMed1993

Structural variation in the O-specific polysaccharides of Klebsiella pneumoniae serotype O1 and O8 lipopolysaccharide: evidence for clonal diversity in rfb genes.

The O-polysaccharide fraction of the lipopolysaccharide from Klebsiella pneumoniae serotype O8 was found to comprise two galactose-containing homopolymers. Structural analysis, using chemical and high-field nuclear magnetic resonance (NMR) techniques, established that the K. pneumoniae O8 polysaccharides are composed of the linear, disaccharide repeating units [formula: see text] K. pneumoniae O8 mutant RFK-1 was isolated by resistance to phage KO1-2; strain RFK-1 expressed only D-galactan I-OAc. The 1H- and 13C-NMR resonances from this O-polysaccharide indicate that all of the O-acetyl groups within the K. pneumoniae O8 polysaccharide are carried on D-galactan I and O-acetylation occurs only on the beta-D-galactofuranose residues; 60% of the available beta-D-galactofuranose residues are non-acetylated. The O-acetylation of the remaining residues is equally distributed between the O-2 and O-6 positions. The carbohydrate backbone structures in the O8 polysaccharide are identical to D-galactan I and II expressed by K. pneumoniae O1, accounting for the antigenic cross-reaction between strains belonging to serotypes O1 and O8. However, the O1 polysaccharides are not acetylated and the O-acetyl groups present in the K. pneumoniae serotype O8 polysaccharides provide a structural basis for their recognition as distinct serotypes. The rfb (O-polysaccharide biosynthesis) gene cluster of K. pneumoniae serotype O1 determines the synthesis of D-galactan I. rfbKpO1-specific gene probes were used to examine conservation in the rfb gene clusters of other K. pneumoniae serotypes which produce D-galactan I. Six O1 strains were examined and all showed hybridization with rfbKpO1 probes under conditions of high stringency. Three serotype O2 strains produce D-galactan I and these strains also contained DNA sequences recognized by rfbKpO1 probes under high stringency. The physical maps of these homologous rfb chromosomal regions showed some polymorphism. Surprisingly, the rfbKpO8 region from K. pneumoniae serotype O8 was only recognized by rfbKpO1 probes under low-stringency hybridization conditions, providing evidence for two substantially different clonal groups of rfb genes from K. pneumoniae strains with structurally related O-antigens.

Acetylation↗
PubMed1989

Phenotypic effects of apolipoprotein structural variation on lipid profiles. I. APO H and quantitative lipid measures in the healthy women study.

Apolipoprotein H (APO H), also known as beta 2-glycoprotein I, has been identified as a protein component of the major lipoprotein density fractions in human plasma. Recently, genetically determined structural polymorphism in white and black populations has been documented for this apolipoprotein. There are three common alleles in whites and blacks and a fourth allele found mainly in blacks. Family data confirm the autosomal codominant pattern of inheritance for the APO H structural gene. Little is known about the function of APO H, but it has demonstrated both lipid and platelet involvement. In this study we investigate the effect of APO H phenotypes on quantitative lipid measures in a group of 443 white women being followed through menopause for changes in cardiovascular risk. At baseline all women were premenopausal. None of the APO H phenotypes showed a statistically significant effect on lipid measures in this population.

Adult↗
PubMed1999

Structure and structural variations of the Escherichia coli 30 S ribosomal subunit as revealed by three-dimensional cryo-electron microscopy.

A three-dimensional reconstruction of the 30 S subunit of the Escherichia coli ribosome was obtained at 23 A resolution. Because of the improved resolution, many more structural details are seen as compared to those obtained in earlier studies. Thus, the new structure is more suitable for comparison with the 30 S subunit part of the 70 S ribosome, whose structure is already known at a better resolution. In addition, we observe relative and, to some extent, independent movements of three main structural domains of the 30 S subunit, namely head, platform and the main body, which lead to partial blurring of the reconstructed volume. An attempt to subdivide the data set into conformationally defined subsets reveals the existence of conformers in which these domains have different orientations with respect to one another. This result suggests the existence of dynamic properties of the 30 S subunit that might be required for facilitating its interactions with mRNA, tRNA and other ligands during protein biosynthesis.

Bacterial Proteins↗
PubMed1990

Sequence-dependent structural variations of hammerhead RNA enzymes.

The discovery of in vivo catalytic activity for the hammerhead RNA self-cleaving domain has led to the development of a new class of sequence-specific RNA endonucleases. Two such ribozymes have been synthesized using in vitro transcription with T7 polymerase and their structures have been studied by optical spectroscopy, nuclear magnetic resonance and nondenaturing gel electrophoresis. These data show the presence of a stable hairpin consisting of a double helical stem and a tetranucleotide loop in both RNA enzymes. Additional structure, with different stabilities, is also observed in both RNA enzymes. The half-lives for cleavage of the complementary RNA substrates by these two RNA enzymes have been previously shown to differ by a factor of 50. The data presented here suggest that this rate difference may be a result of the formation of catalytically inactive conformations in the RNA enzyme which interfere with formation of the enzyme-substrate complex.

Base Sequence↗
PubMed1992

Fluoroquinolones: relationships between structural variations, mammalian cell cytotoxicity, and antimicrobial activity.

Fluoroquinolones are potent inhibitors of bacterial topoisomerase II (DNA gyrase). They can also inhibit eukaryotic topoisomerases, which could possibly lead to clastogenicity and/or cellular toxicity. Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the fluoroquinolones and the potential of these compounds to induce micronuclei, a genetic toxicity endpoint. In an effort to identify potent nontoxic quinolone antibacterials, we have examined the structural features of the fluoroquinolones associated with mammalian cell cytotoxicity. An investigation of a wide variety of substituents at the 1, 5, 7, and 8 positions of a quinolone nucleus was conducted. The results indicate that no one position has a controlling effect on the observed cytotoxicity. Instead, a combination of the various substituents contributes to the effects seen. Certain trends were apparent, such as the fact that compounds with pyrrolidines at the R-7 position were more cytotoxic than those with piperazines, and halogens at R-8 (X-position) were associated with more cytotoxicity relative to hydrogen. A general trend also existed between the cytotoxicity of the compounds and their Gram-positive antibacterial activity. A detailed comparison between the various groups and positional variations as they controlled the cytotoxicity and antibacterial activity is presented.

Animals↗
PubMed1996

Structural variation of the pseudoautosomal region between and within inbred mouse strains.

The pseudoautosomal region (PAR) is a segment of shared homology between the sex chromosomes. Here we report additional probes for this region of the mouse genome. Genetic and fluorescence in situ hybridization analyses indicate that one probe, PAR-4, hybridizes to the pseudoautosomal telomere and a minor locus at the telomere of chromosome 9 and that a PCR assay based on the PAR-4 sequence amplifies only the pseudoautosomal locus (DXYHgu1). The region detected by PAR-4 is structurally unstable; it shows polymorphism both between mouse strains and between animals of the same inbred strain, which implies an unusually high mutation rate. Variation occurs in the region adjacent to a (TTAGGG)n array. Two pseudoautosomal probes can also hybridize to the distal telomeres of chromosomes 9 and 13, and all three telomeres contain DXYMov15. The similarity between these telomeres may reflect ancestral telomere-telomere exchange.

Animals↗
PubMed1987

Inhibitors of cyclic AMP phosphodiesterase. 2. Structural variations of N-cyclohexyl-N-methyl-4-[(1,2,3,5-tetrahydro- 2-oxoimidazo[2,1-b]quinazolin-7-yl)-oxy]butyramide (RS-82856).

A series of analogues of the cyclic AMP phosphodiesterase (PDE) inhibitor N-cyclohexyl-N-methyl-4-[(1,2,3,5-tetrahydro- 2-oxoimidazo[2,1-b]quinazolin-7-yl)oxy]butyramide (RS-82856, 1) was prepared by systematic variation of the side-chain substituent, length, position, connecting atom, and the parent heterocycle itself. The compounds were evaluated as inhibitors of cyclic AMP phosphodiesterase from both human platelets and rat or dog heart tissue and as inhibitors of ADP-induced platelet aggregation. Structure-activity correlations for the analogue series revealed significant limitations on the steric bulk of substituents on the 1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one heterocycle and the position and length of the side chain. As inhibitors of cyclic AMP phosphodiesterase (PDE), potency steadily increased with increasingly lipophilic side chains. In platelet aggregation inhibition studies, however, a maximum in activity was reached with 1, while more lipophilic compounds were significantly less active. Major changes in the heterocycle itself, represented by isomeric and other carbonyl variations, also decreased activity. The molecular features defined by this series of analogues of 1 correlate to a high degree with current understanding of the chemical and topographical requirements of the active site of the FIII (type IV) form of cyclic AMP PDE. Selective inhibition of this enzyme has been proposed as the principal component of the positive inotropic action of a number of cardiotonic agents.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1980

Immunoglobulin diversity in the phylogenetically primitive shark, Heterodontus francisci. Suggested lack of structural variation between light chains isolated from different animals.

A two-step procedure employing gel filtration and anion exchange chromatography has been utilized to isolate LMW immunoglobulin from the horned shark, Heterodontus francisci. Light chains obtained by complete reduction and alkylation of the parent protein have been compared by several analytical techniques. Amino acid composition data implies a limited degree of variation in the light chains isolated from individual animals. Polyacrylamide gel electrophoresis of the CNBr digests of the light chains reveal indistinguishable banding profiles of the major peptides. Isoelectric focusing indicates limited heterogeneity in the light chain spectrotype and identity in the pI of the majority of bands detectable by staining. The suggested degree of structural similarity in the light chains of this phylogenetically primitive shark is discussed in terms of the evolutionary position of the species and current theories concerning the origins of structural diversity in immunoglobulins.

Amino Acids↗
PubMed2002

Evolution of nitrate reductase: molecular and structural variations on a common function.

The biological transformation of nitrogen oxyanions is widespread in nature and gives rise to a robust biogeochemical cycle. The first step in nitrate reduction is carried out by the enzyme nitrate reductase (NR). Although NR always catalyzes the same chemical reaction (conversion of nitrate into nitrite), its location in the cell, structure, and function are organism-dependent. We use protein sequence data to determine phylogenetic relationships and to examine similarities in structure and function. Three distinct clades of NR are apparent: the eukaryotic assimilatory NR (Euk-NR) clade, the membrane-associated prokaryotic NR (Nar) clade, and a clade that includes both the periplasmic NR (Nap) and prokaryotic assimilatory NR (Nas). The high degree of sequence similarity and a phylogenetic distribution that follows taxonomic classification suggest a monophyletic origin for the Euk-NR early on in the evolution of eukaryotic cells. In contrast, sequence conservation, phylogenetic analysis, and physiology suggest that both Nar and Nap were acquired by horizontal gene transfer. Nap and Nas share a lesser degree of similarity, with Nap a subclade of Nas. Nap from strict anaerobic bacteria such as Desulfovibrio desulfuricans is ancestral to facultative species and may provide an evolutionary link between Nap and Nas. We observed conserved binding sites for molybdenum and pterin cofactors in all four proteins. In pathways involving Euk-NR, Nas, and Nar, for which ammonia is the end product, nitrite is reduced to ammonia by a siroheme nitrite reductase. Nap, however, is coupled to a pentaheme nitrite reductase. In denitrification, whether Nar or Nap is involved, nitrite is reduced to nitric oxide by either a cytochrome cd1 or a copper-containing nitrite reductase. This complexity underscores the importance of nitrate reduction as a key biological process.

Amino Acid Sequence↗
PubMed2026

RAG-mediated structural variation and its impact on relapse risk in acute lymphoblastic leukemia.

Relapse during treatment of B-cell acute lymphoblastic leukemia (B-ALL) is a harbinger of poor outcomes. Identifying biomarkers for subsequent relapse risk which are detectable at B-ALL diagnosis remains a priority. Off-target recombination-activating gene (RAG)-mediated structural variants (SVs) generate genomic instability that drives leukemogenesis and may underlie treatment resistance. Leveraging sequencing data in 1,496 pediatric B-ALL patients enriched for relapse status (relapse n=532; non-relapse n=964), we characterized RAG-mediated SVs across B-ALL molecular subtypes and examined their association with patient characteristics and their impact on clinical outcomes. Off-target RAG-mediated SVs were overall frequent, particularly in ETV6::RUNX1, ETV6::RUNX1-like, and Ph-like B-ALL subtypes, while increasing age-at-diagnosis was positively associated with burden of off-target RAG-mediated SVs (P<.001). Off-target RAG-mediated SVs with a recombination signal sequence (RSS) at one breakpoint, a hallmark of off-target RAG activity, were significantly more frequent at diagnosis in patients who subsequently relapsed (P=.001). This association remained significant in multivariable regression analysis (per SV odds ratio [OR]:1.08, 95%CI:1.04-1.12), in minimal residual disease (MRD)-negative patients (OR:1.09, 95%CI:1.04-1.14) and across subtypes. Excluding deletions, MRD-negative ETV6::RUNX1 patients with &#x2265;3 off-target RAG-mediated SVs had a >3-fold risk of relapse (hazard ratio:3.47, 95% CI:1.86-6.49). RAG-mediated SVs were also associated with relapse risk in T-cell ALL patients. Off-target RAG-mediated SV burden at diagnosis is a risk factor of relapse in pediatric ALL across molecular subtypes and independent of MRD status.

Journal Article↗
PubMed1999

Divalent cation-mediated interaction between cerebroside sulfate and cerebrosides: an investigation of the effect of structural variations of lipids by electrospray ionization mass spectrometry.

Divalent cations mediate a carbohydrate-carbohydrate association between the two major glycolipids, galactosylceramide (GalCer) and its sulfated form, cerebroside sulfate (CBS), of the myelin sheath. We have suggested that interaction between these glycolipids on apposed extracellular surfaces of myelin may be involved in the stability or function of this multilayered structure. A mutant mouse lacking galactolipids because of a disruption in the gene that encodes a galactosyltransferase forms myelin that initially appears relatively normal but is unstable. This myelin contains glucosylceramide (GlcCer) instead of GalCer. To better understand the role of GlcCer in myelin in this mutant, we have compared the ability of divalent cations to complex CBS (galactosyl form) with GlcCer or GalCer in methanol solution by using positive ion electrospray ionization mass spectrometry. Because both the alpha-hydroxylated fatty acid species (HFA) and the nonhydroxylated fatty acid species (NFA) of these lipids occur in myelin, we have also compared the HFA and NFA species. In addition to monomeric Ca2+ complexes of all three lipids and oligomeric Ca2+ complexes of both GalCer and GlcCer, Ca2+ also caused heterotypic complexation of CBS to both GalCer and GlcCer. The heterotypic complexes had the greatest stability of all oligomers formed and survived better at high declustering potentials. Complexes of CBS with GlcCer were less stable than those with GalCer. This was confirmed by using the free sugars and glycosides making up the carbohydrate headgroups of these lipids. HFA species of CBS and GalCer formed more stable complexes than NFA species, but hydroxylation of the fatty acid of GlcCer had no effect. The ability of GlcCer to also complex with CBS, albeit with lower stability, may allow GlcCer to partially compensate for the absence of GalCer in the mouse mutant.

Calcium↗
PubMed1996

Estrogenic triarylethylene acetic acids: effect of structural variation on estrogen receptor affinity and estrogenic potency and efficacy in MCF-7 cells.

Triarylethylenecarboxylic acids exemplified by (E,Z)-2-{4-[1-(p-hydroxyphenyl)-2-phenyl]-1-butenyl}phenoxyacetic acid (8) are a new class of estrogen receptor (ER) ligands capable of tissue selective estrogen agonist and antagonist effects. We report the syntheses of 8 and of analogues incorporating structural features known or anticipated to facilitate ER affinity in triarylethylenes. These studies revealed that the p-hydroxyphenyl moiety, ethylenic bond, and ether oxygen of 8 were all critical for high ER affinity. Although a 1,1-bisphenolic analogue bearing the p-(oxyacetic acid) moiety on its 2-phenyl ring, 12, had low ER affinity, it exhibited estrogenic potency approaching that of 8 in MCF-7 cells. Unlike 8 which was a partial agonist with weak antagonist potency, 12 was a full agonist. A similar profile of potency/efficacy in MCF-7 cells was seen in 9, an ethylenic bond saturated analogue of 8. Growth-promoting effects of 8, 9, and 12 were fully antagonized by the antiestrogen tamoxifen, suggesting that such effects were mediated solely via ER. Thus, our studies in MCF-7 cells have confirmed the estrogenicity of 8 and have enabled identification of two analogues with favorable estrogenic potency and full estrogen efficacy. On this basis, these three (triarylethylene)acetic acids have been selected for more intensive animal studies of their extrareproductive tract estrogenic effects.

Animals↗
PubMed2001

Distribution and structural variation of the she pathogenicity island in enteric bacterial pathogens.

Shigella flexneri serotype 2a carries a chromosomal pathogenicity island (PAI), termed the she PAI, that has been implicated in the pathogenesis of diarrhoeal disease. The complete nucleotide sequence and genetic organisation of the she PAI of S. flexneri 2a strain YSH6000T was determined recently. In the current study the distribution and structure of the she PAI was investigated by PCR and Southern analysis in 65 isolates of enteric pathogens including Shigella spp., enterohaemorrhagic Escherichia coli (EHEC), enteropathogenic E. coli (EPEC), enteroinvasive E. coli (EIEC), Yersinia enterocolitica and Salmonella enterica serovar Typhimurium. The study showed that the she PAI has undergone a variety of structural changes, defined by the presence or absence of specific marker genes in the PAI. The she PAI or structural variants of this element were found in all species of Shigella as well as in EIEC, EHEC and EPEC. No evidence of the PAI was found in Y. enterocolitica or Sal. Typhimurium. The structural form of the she PAI that exists in strain YSH6000T was present in all strains of S. flexneri serotype 2a and in some strains of S. flexneri serotypes 2b and 3c. Variants of the PAI that were missing one or more marker regions were found in all species of Shigella and in pathogenic strains of E. coli. In all strains, the PAIs have inserted into either pheV or a phe tRNA gene in another location on the chromosome. It was concluded that the she PAI is one of several closely related genetic elements that have disseminated throughout Shigella and pathogenic strains of E. coli and diverged into distinct stuctural forms.

DNA-Directed RNA Polymerases↗
PubMed1989

Phenotypic effects of apolipoprotein structural variation on lipid profiles: II. Apolipoprotein A-IV and quantitative lipid measures in the healthy women study.

Apolipoprotein A-IV (APO A-IV) is a major protein component of mesenteric lymph chylomicrons and very-low-density lipoproteins. It is found in plasma predominantly unassociated with major lipoprotein fractions and in high density lipoproteins. APO A-IV exhibits structural heterogeneity owing to two codominant alleles, APO A-IV*1 and APO A-IV*2, that occur in Caucasian and black populations. In vitro experimental evidence indicates that APO A-IV may be a cofactor for the lecithin:cholesterol acyltransferase enzyme, may be involved in reverse cholesterol transport, and may play an important role in the modulation of lipoprotein lipase activity. In this study we have investigated the effect of two APO A-IV phenotypes, APO A-IV 1-1 and APO A-IV 2-1, on quantitative lipid measures in a group of 453 white women being followed through menopause for changes in cardiovascular risk. At baseline all women were premenopausal. Of the nine lipid measures, triglycerides showed a marginally significant effect caused by phenotype. The APO A-IV 2-1 heterozygotes had lower average triglycerides than the 1-1 homozygotes (P = .053).

Adult↗
PubMed1997

The Phase Co(1)(-)(x)()Ni(x)()Sn(2): Structural Variations Based on the Stacking of Two Different Planar Nets.

The investigation of the tin-rich part of the ternary system Co/Ni/Sn yielded the phase Co(1)(-)(x)()Ni(x)()Sn(2) with the range of composition 0.23(3) < x < 0.59(3). When using a large excess of tin, Co(1)(-)(x)()Ni(x)()Sn(2) crystallizes at 500 degrees C in a structure isotypic to that of tetragonal PdSn(2) whereas a modification with the orthorhombic CoGe(2) structure type always forms from a stoichiometric mixture of the elemental components or from a tin melt at temperatures above 550 degrees C. The structures of Co(0.625)Ni(0.375)Sn(2) were determined by single-crystal X-ray diffraction methods (PdSn(2)-type space group I4(1)/acd, a = 6.2360(5) Å, c = 23.588(2) Å, Z = 16; CoGe(2)-type space group Aba2, a = 6.2439(4) Å, b = 6.2493(4) Å, c = 11.778(1) Å, Z = 8). Both structures have the same building unit consisting of three consecutive planar nets 4(4), 3(2)434, 4(4) formed by tin atoms. The condensation of the building blocks in the c direction gives rise to different stacking sequences. In the PdSn(2)-type, a ABCD sequence is realized and the c axis is doubled compared to the ideal CoGe(2)-type with AB stacking. Electron diffraction and high-resolution electron microscopy studies revealed the existence of other, complex, stacking variants as well as stacking faults in the Co(1)(-)(x)()Ni(x)()Sn(2) system.

Journal Article↗
PubMed2001

Surfactant-associated proteins: functions and structural variation.

Pulmonary surfactant is a barrier material of the lungs and has a dual role: firstly, as a true surfactant, lowering the surface tension; and secondly, participating in innate immune defence of the lung and possibly other mucosal surfaces. Surfactant is composed of approximately 90% lipids and 10% proteins. There are four surfactant-specific proteins, designated surfactant protein A (SP-A), SP-B, SP-C and SP-D. Although the sequences and post-translational modifications of SP-B and SP-C are quite conserved between mammalian species, variations exist. The hydrophilic surfactant proteins SP-A and SP-D are members of a family of collagenous carbohydrate binding proteins, known as collectins, consisting of oligomers of trimeric subunits. In view of the different roles of surfactant proteins, studies determining the structure-function relationships of surfactant proteins across the animal kingdom will be very interesting. Such studies may reveal structural elements of the proteins required for surface film dynamics as well as those required for innate immune defence. Since SP-A and SP-D are also present in extrapulmonary tissues, the hydrophobic surfactant proteins SP-B and SP-C may be the most appropriate indicators for the evolutionary origin of surfactant. SP-B is essential for air-breathing in mammals and is therefore largely conserved. Yet, because of its unique structure and its localization in the lung but not in extrapulmonary tissues, SP-C may be the most important indicator for the evolutionary origin of surfactant.

Amino Acid Sequence↗