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PubMed2005

1H NMR studies on the hydrogen-bonding network in mono-altro-beta-cyclodextrin and its complex with adamantane-1-carboxylic acid.

The hydrogen-bond network in mono-altro-beta-cyclodextrin and in its inclusion complex with adamantane-1-carboxylic acid were investigated by (1)H NMR spectroscopy using the chemical shifts, temperature coefficients and vicinal coupling constants of the exchangeable hydroxy protons. The chemical shifts of the 3-OH signals indicated that the hydrogen-bond network between the 2-OH and 3-OH groups was disturbed not only on each side of the altrose residue, but also along the whole dextrin chain. Upon addition of adamantane-1-carboxylic acid, altrose underwent a conformational change from the (1)C(4) to the (O)S(2) form, allowing a more continuous belt of hydrogen bonding, as evidenced by the downfield shift experienced by the 3-OH proton signals of the glucose residues.

Adamantane↗

PubMed2005

Determinants governing the potency of STAT3 activation via the individual STAT3-recruiting motifs of gp130.

In recent years, the elucidation of the structures of many signalling molecules has allowed new insights into the molecular mechanisms that govern signal transduction events. In the field of cytokine signalling, the solved structures of cytokine/receptor complexes and of key components involved in signal transduction such as STAT factors or the tyrosine phosphatase SHP2 have broadened our understanding of the molecular basis of the signalling events and provided key information for the rational design of therapeutic approaches to modulate or block cytokine signal transduction. Unfortunately, no structural data on the intracellular parts of cytokine receptors are available. The exact molecular mechanism underlying one of the first steps in signal transduction, namely the recruitment of signalling components to the cytoplasmic parts of cytokine receptors, remains elusive. Here we investigated possible mechanisms underlying the different potency of the STAT3-activating motifs of gp130 after IL-6 stimulation. Our data indicate that the extent of STAT3 activation by the different receptor motifs is not influenced by structural features such as contacts between the two gp130 chains. In addition, the proximity of the negatively regulating motif around tyrosine Y759 to the different STAT3-recruiting motifs does not seem to be responsible for their differential capacity to activate STAT3. However, the potency of a specific motif to activate STAT3 directly reflects the affinity for the binding of STAT3 to this motif.

Amino Acid Motifs↗

PubMed2005

Biosynthesis of the unique amino acid side chain of butirosin: possible protective-group chemistry in an acyl carrier protein-mediated pathway.

Butirosins A and B are naturally occurring aminoglycoside antibiotics that have a (2S)-4-amino-2-hydroxybutyrate (AHBA) side chain. Semisynthetic addition of AHBA to clinically valuable aminoglycoside antibiotics has been shown both to improve their pharmacological properties and to prevent their deactivation by a number of aminoglycoside-modifying enzymes involved in bacterial resistance. We report here that the biosynthesis of AHBA from L-glutamate, encoded within a previously identified butirosin biosynthetic gene cluster, proceeds via intermediates tethered to a specific acyl carrier protein (ACP). Five components of the pathway have been purified and characterized, including the ACP (BtrI), an ATP-dependent ligase (BtrJ), a pyridoxal phosphate-dependent decarboxylase (BtrK), and a two-component flavin-dependent monooxygenase system (BtrO and the previously unreported BtrV). The proposed biosynthetic pathway includes a gamma-glutamylation of an ACP-derived gamma-aminobutyrate intermediate, possibly a rare example of protective group chemistry in biosynthesis.

Acyl Carrier Protein↗

PubMed2006

Molecular epidemiology and household transmission of community-associated methicillin-resistant Staphylococcus aureus in Hong Kong.

This study evaluated the clinical and epidemiologic features of individuals with community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) in Hong Kong from January 2004 through December 2005. Twenty-four episodes of skin and soft tissue infections and 1 episode of meningitis due to CA-MRSA were identified. CA-MRSA infections or carriage was found in 6 (13%) of 46 household contacts. A total of 29 isolates were analyzed by the Staphylococcus cassette chromosome mec (SCCmec) typing, pulsed-field gel electrophoresis (PFGE), and multilocus sequence typing. In addition, polymerase chain reaction detection of the genes encoding Panton-Valentine leukocidin was also carried out. It was observed that 24 had SCCmec IV/IVA and 5 had SCCmec V, and 23 were pvl positive. PFGE analysis clustered all except 1 isolate into 3 pulsed-field types (PFTs), HKU100 through HKU300. The HKU100 isolates had genotype ST30-IV identical to the Southwest Pacific clone. The HKU200 isolates belonged to ST59-V and were multiresistant, including an ermB-mediated macrolide resistance trait, which is characteristic of the predominant CA-MRSA clone in Taiwan. The HKU300 isolates had unique features (ST8, Panton-Valentine leukocidin negative, and SCCmec IVA) typical of CA-MRSA in Japan. In conclusion, CA-MRSA has a propensity to spread within families. Our findings showed that CA-MRSA strains in Hong Kong have diverse genetic backgrounds.

Adolescent↗

PubMed2006

Glycosylation regulates turnover of cyclooxygenase-2.

Cyclooxygenase-2 (COX-2) catalyzes the rate-limiting step in the prostanoid biosynthesis pathway, converting arachidonic acid into prostaglandin H(2). COX-2 exists as 72 and 74kDa glycoforms, the latter resulting from an additional oligosaccharide chain at residue Asn(580). In this study, Asn(580) was mutated to determine the biological significance of this variable glycosylation. COS-1 cells transfected with the mutant gene were unable to express the 74kDa glycoform and were found to accumulate more COX-2 protein and have five times greater COX-2 activity than cells expressing both glycoforms. Thus, COX-2 turnover appears to depend upon glycosylation of the 72kDa glycoform.

Animals↗

PubMed2006

Mechanism of toxicity of the branched-chain fatty acid phytanic acid, a marker of Refsum disease, in astrocytes involves mitochondrial impairment.

Phytanic acid is a saturated branched-chain fatty acid, which is formed by bacterial degradation of chlorophyll in the intestinal tract of ruminants. The methyl group in beta-position prevents degradation of phytanic acid by the beta-oxidation pathway. Therefore, degradation of phytanic acid is initiated by alpha-oxidation in peroxisomes. The inherited peroxisomal disorder Refsum disease is characterised by accumulation of phytanic acid. Unusually high concentrations of phytanic acid can be found in the plasma of Refsum disease patients, who suffer from neurodegeneration and muscle dystrophy. Phytanic acid has been suggested to be causally involved in the clinical symptoms. To elucidate the pathogenic mechanism, we investigated the influence of phytanic acid in rat hippocampal astrocytes by monitoring the cytosolic Ca(2+) concentration, the mitochondrial membrane potential (Deltapsi(m)), the generation of reactive oxygen species as well as the cellular ATP level. In response to phytanic acid (100 microM) cytosolic Ca(2+) was quickly increased. The phytanic acid-evoked Ca(2+) response was transient and involved activation of intracellular Ca(2+) stores. In isolated rat brain mitochondria, phytanic acid dissipated Deltapsi(m) in a reversible and dose-dependent manner. Moreover, phytanic acid released cytochrome c from mitochondria. Depending on the mitochondrial activity state, phytanic acid either stimulated or inhibited the electron flux within the respiratory chain. In addition, phytanic acid induced substantial generation of reactive oxygen species in isolated mitochondria as well as in intact cells. Phytanic acid caused cell death of astrocytes within a few hours of exposure. In conclusion, we suggest that phytanic acid initiates astrocyte cell death by activating the mitochondrial route of apoptosis.

Animals↗

PubMed2005

Water-based latex dispersions 4. Exchange dynamics and residence times of nonylphenol ethoxylate in concentrated latex dispersions.

The equilibrium residence times of the nonionic surfactant nonylphenol ethoxylate (NP100) in a latex dispersion were determined using NMR diffusometry. At 16% w/w particle concentration and 0.12, 0.43 and 0.81% w/w NP100, the residence times of the surfactant were 0.16, 1.02 and 4.73 s in solution (tau(A)) and 0.3, 0.37 and 0.61 s on the surface of the particles (tau(B)), respectively. At even higher particle concentration (>45% w/w), tau(A) and tau(B) were 1.47 and 2.2 s. Calculating the number of collisions that ought to result in adsorbed species, at 16% w/w, only 2, 5 and 2 per thousand (corresponding to 0.12, 0.43 and 0.81% w/w NP100) resulted in adsorption, whereas at >45% w/w, only 12 per thousand resulted in adsorption, which suggested that the surfactant was irreversibly adsorbed on the particles. The small increase in collision frequency with increased particle concentration could be a result of a diffusion controlled adsorption, while an energy barrier for desorption controlled the overall exchange dynamics in the dispersion. The slow dynamics in the dispersion was controlled, mainly by the nonylphenol group, which gave NP100 a strong preference to surfaces. In addition, the chain length of the poly(ethylene glycol) (PEG) group changed the solution behavior from being that of a typical surfactant to that of a polymer.

Ethylene Glycols↗

PubMed2006

Linear poly(amido amine)s with secondary and tertiary amino groups and variable amounts of disulfide linkages: synthesis and in vitro gene transfer properties.

A group of novel poly(amido amine) homo- and copolymers (PAAs) containing secondary and tertiary amine groups in their main chain and different structures in the bisacrylamide segments were synthesized and evaluated as non-viral gene delivery vectors. Among these, also the disulfide-containing cystaminebisacrylamide was employed as a (co)monomer, yielding PAAs with variable amounts of bioreducible disulfide linkages in the main chain. Michael addition the trifunctional 1-(2-aminoethyl) piperazine to equimolar amounts of the appropriate bis(acrylamide) yielded linear polymers as was elucidated by their (13)C NMR spectra. The polymers possess buffering capacities between pH 5.1 and pH 7.4 higher than branched polyethylenimine (pEI) and are able to efficiently condense DNA into nanosized (<150 nm) and positively charged complexes. Transfection experiments with COS-7 cells showed that polyplexes from PAAs with disulfide linkages give significant higher transfections than those from PAAs lacking the disulfide linkage, and XTT assays showed that these polymers are essentially non-toxic. Variation of the disulfide content revealed that polyplexes of PAA copolymers with appropriate disulfide content have largely improved biophysical properties, yielding enhanced levels of gene expression along with low toxicity. The results demonstrate that bioreducible poly(amido amine)s are a very promising class of polymers for safe and efficient gene delivery.

Acrylamides↗

PubMed2005

Pb(II)-binding capability of aminohydroxamic acids: primary hydroxamic acid derivatives of alpha-amino acids as possible sequestering agents for Pb(II).

Complexes of aminohydroxamic acids, D,L-alpha-alaninehydroxamic acid (alpha-Alaha), sarcosinehydroxamic acid (Sarha), D,L-N-methyl-alpha-alaninehydroxamic acid (N-Me-alpha-Alaha), beta-alaninehydroxamic (beta-Alaha), L-aspartic acid-beta-hydroxamic acid (Asp-beta-ha), L-glutamic acid-gamma-hydroxamic acid (Glu-gamma-ha) and L-histidinehydroxamic acid (Hisha) with lead(II) in aqueous solution were studied by pH-potentiometric, 1H NMR and electrospray ionization mass spectrometric (ESI MS) methods. The results were compared to those of a simple monohydroxamic acid, acetohydroxamic acid and the effects of the amino group, hydroxamate-N, as well as, additional side chain donors on the co-ordination mode and on the stability of the complexes formed were evaluated. It was found that the amino nitrogen atom situating in beta- or in gamma-position (beta-Alaha, Asp-beta-ha, Glu-gamma-ha) does not co-ordinate to Pb(II), only hydroxamate type chelates are formed before the hydrolytic processes. However, the amino-N in alpha-position (alpha-Alaha, Sarha, Hisha) seems to form a stable 5-membered (N,N)-type chelate together with the deprotonated hydroxamate-N above pH 6. On the other hand, the hydroxamate (O,O)-type chelate also exists. Since steric reasons do not allow the coordination of these two chelates of a molecule to the same Pb(II) ion, polynuclear complexes with mixed co-ordination modes are formed with the alpha-derivatives above pH 6. Simple hydroxamate type complexes are formed with N-Me-alpha-Alaha, where the hydroxamate-N is not able to co-ordinate. The co-ordination of the side chain imidazole of Hisha is not measurable, while a weak interaction of the side chain carboxylates of Asp-beta-ha and especially of Glu-gamma-ha can be suggested.

Amino Acids↗

PubMed2006

Structural basis for molecular recognition in an affibody:affibody complex.

Affibody molecules constitute a class of engineered binding proteins based on the 58-residue three-helix bundle Z domain derived from staphylococcal protein A (SPA). Affibody proteins are selected as binders to target proteins by phage display of combinatorial libraries in which typically 13 side-chains on the surface of helices 1 and 2 in the Z domain have been randomized. The Z(Taq):anti-Z(Taq) affibody-affibody complex, consisting of Z(Taq), originally selected as a binder to Taq DNA polymerase, and anti-Z(Taq), selected as binder to Z(Taq), is formed with a dissociation constant K(d) approximately 100 nM. We have determined high-precision solution structures of free Z(Taq) and anti-Z(Taq), and the Z(Taq):anti-Z(Taq) complex under identical experimental conditions (25 degrees C in 50 mM NaCl with 20 mM potassium phosphate buffer at pH 6.4). The complex is formed with helices 1 and 2 of anti-Z(Taq) in perpendicular contact with helices 1 and 2 of Z(Taq). The interaction surface is large ( approximately 1670 A(2)) and unusually non-polar (70 %) compared to other protein-protein complexes. It involves all varied residues on anti-Z(Taq), most corresponding (Taq DNA polymerase binding) side-chains on Z(Taq), and several additional side-chain and backbone contacts. Other notable features include a substantial rearrangement (induced fit) of aromatic side-chains in Z(Taq) upon binding, a close contact between glycine residues in the two subunits that might involve aliphatic glycine Halpha to backbone carbonyl hydrogen bonds, and four hydrogen bonds made by the two guanidinium N(eta)H(2) groups of an arginine side-chain. Comparisons of the present structure with other data for affibody proteins and the Z domain suggest that intrinsic binding properties of the originating SPA surface might be inherited by the affibody binders. A thermodynamic characterization of Z(Taq) and anti-Z(Taq) is presented in an accompanying paper.

Amino Acid Sequence↗

PubMed2005

Crystallization and preliminary X-ray crystallographic analysis of the N-terminal photosensory module of phytochrome Agp1, a biliverdin-binding photoreceptor from Agrobacterium tumefaciens.

Phytochromes are photochromic photoreceptors with a bilin chromophore that have been found in plants and bacteria. Typical bacterial phytochromes are composed of an N-terminal photosensory chromophore module and a C-terminal protein kinase. The former contains the chromophore, which allows phytochromes to adopt the two interconvertible spectral forms, Pr and Pfr. The N-terminal photosensory module of Agrobacterium phytochrome Agp1, Agp1-M15, was used for crystallization studies. The protein was either assembled with the natural chromophore biliverdin or a sterically locked synthetic biliverdin-derivative, termed 15Za. The last-named adduct does not undergo photoisomerization due to an additional carbon chain between the rings C and D of the chromophore. Both adducts could be crystallized, but the resolution was largely improved by the use of 15Za. Crystals of biliverdin-Agp1-M15 diffract to 6A resolution and belong to the tetragonal space group I422 with unit cell dimensions a = b = 171 Angstroms, c = 81 Angstroms, crystals of 15Za-Agp1-M15 belong to the same space group with similar unit cell dimensions a = b = 174 Angstroms, c = 80 Angstroms, but diffract to 3.4 Angstroms resolution. Assuming the asymmetric unit to be occupied by one monomer of 55kDa, the unit cell contains 54-55% solvent with a crystal volume per protein mass, V(m), of 2.7 Angstroms(3) Da(-1).

Agrobacterium tumefaciens↗

PubMed2004

Synthesis of [26,27-2H6]brassinosteroids from 23,24-bisnorcholenic acid methyl ester.

A number of hexadeuterated brassinosteroids (BS) containing a hydroxy group at C-22 or a 22R,23R-diol function were prepared starting from 23,24-bisnorcholenic acid methyl ester for biosynthetic studies. Synthesis of the cyclic part was accomplished via the initial hydroboration-oxidation of Delta(5)-double bond. The key step in the synthesis of the side chain involved addition of (2S)-[3,4-(2)H(6)]2,3-dimethylbutylphenyl sulfone to the corresponding C-22 aldehydes.

Brassinosteroids↗

PubMed2004

Collagens, modifying enzymes and their mutations in humans, flies and worms.

Collagens and proteins with collagen-like domains form large superfamilies in various species, and the numbers of known family members are increasing constantly. Vertebrates have at least 27 collagen types with 42 distinct polypeptide chains, >20 additional proteins with collagen-like domains and approximately 20 isoenzymes of various collagen-modifying enzymes. Caenorhabditis elegans has approximately 175 cuticle collagen polypeptides and two basement membrane collagens. Drosophila melanogaster has far fewer collagens than many other species but has approximately 20 polypeptides similar to the catalytic subunits of prolyl 4-hydroxylase, the key enzyme of collagen synthesis. More than 1300 mutations have so far been characterized in 23 of the 42 human collagen genes in various diseases, and many mouse models and C. elegans mutants are also available to analyse the collagen gene family and their modifying enzymes.

Animals↗

PubMed2002

The dog as model for chemotherapy of the Chagas' disease.

In the present study, we investigated the role of dogs as experimental models for acute and chronic phases of Chagas' disease, before and after therapeutic treatments. Dogs were infected with Trypanosoma cruzi strains of different susceptibilities to benznidazole (Bz) and treated with the same therapeutic scheme as used for human chagasic. The treatment with Bz was able to prevent death and induced parasitological cure in 62.5% (acute phase) and 38.7% (chronic recent phase) of the tested animals. These results were similar to those reported in clinical trials for treated human patients (cured and uncured) in both phases of the disease. We also showed that parasitologic and serologic tests for monitoring the cure were similar to those obtained for human trials. In addition, Polymerase chain reaction showed the highest sensitivity when compared with hemoculture as an indicator of parasite clearance. In conclusion, the proposed experimental model should be relevant for chemotherapy studies for the control of Chagas' disease.

Administration, Oral↗

PubMed2002

Reversibility of structural rearrangements in the negative vesicular membrane upon electrostatic adsorption/desorption of the polycation.

Interaction of small unilamellar vesicles (SUVs), composed of negative diphosphatidylglycerol (cardiolipin, CL(2-)) and neutral dipalmitoylphosphatidylcholine (DPPC), with poly(N-ethyl-4-vinylpyridinium bromide) (PEVP) was studied in water solution above and below the vesicular membrane melting point by means of differential scanning calorimetry, photon correlation spectroscopy, microelectrophoresis, conductometry, and fluorescence techniques. It has been found that CL(2-) species are homogeneously distributed within DPPC-CL(2-) SUV membrane leaflets and between them. Interaction of PEVP with DPPC-CL(2-) SUVs led to drastic structural rearrangements in the membrane if it was in the fluid state (liquid SUVs). Negative CL(2-) molecules migrated from the inner to the outer membrane leaflet and segregated in the vicinity of adsorbed PEVP chains. In addition, PEVP adsorption terminated completely the exchange of lipid molecules between the SUVs. At the same time, the integrity of liquid SUVs contacting PEVP remained unchanged. Since the interaction of PEVP with liquid SUVs was predominantly electrostatic in nature, the polycation could be completely removed from the vesicular membrane by addition of an excess of polyacrylic acid (PAA) polyanions forming a more stable electrostatic complex with PEVP. Removal of PEVP resulted in complete resumption of the original distribution of lipids in lateral and transmembrane directions as well as intervesicular lipid exchange. In contrast, PEVP interacting with DPPC-CL(2-) SUVs formed defects in the vesicular membrane if it was in the gel state (solid SUVs). Such interaction was contributed not only by electrostatic but most likely by hydrophobic interactions involving the defected membrane sites. PEVP kept contacting solid SUVs in the presence of an abundant amount of PAA. The established phenomena may be important for understanding the biological effects of polycations.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed1999

Solid-state NMR and FTIR studies on bilayer membranes from 1,2- dioctadec-(14-ynoyl)-sn-glycero-3-phosphatidylcholine.

Multilamellar dispersions from a new model phospholipid, 1, 2-dioctadec-(14-ynoyl)-sn-glycero-3-phosphatidylcholine (DO(14-yne)PC), bearing a triple bond in the fatty acid chains are studied by (2)H, (31)P NMR and Fourier transform infrared (FTIR) spectroscopy. The investigations are focused on the evaluation of the molecular properties of the lipid molecules as function of temperature and sample composition. Information about the fatty acid chain conformations are obtained from FTIR measurements by analysing the CH(2) wagging and stretching modes. (2)H NMR studies are performed on two selectively deuterated compounds that provide further insights into the molecular characteristics at two specific positions along the fatty acid chains. These studies demonstrate that the introduction of the triple bond is accompanied by a reduction of fatty acid chain order which holds for both the conformational and the orientational order. Likewise, (31)P NMR spectroscopy is used for the determination of the dynamics and ordering in the head group region. Here, particular emphasis is given to the evaluation of the lipid lateral motions that are quantified over a large temperature range within the liquid crystalline phase. It is found that the lateral mobility of the lipid molecules is almost unaffected by the triple bond in the fatty acid chains. The addition of cholesterol gives rise to a reduction in lateral mobility for DO(14-yne)PC, as can be followed by spin echo, 2D-exchange NMR and stimulated echo experiments.

Crystallization↗

PubMed2001

Structural determination of the phytotoxic mannan exopolysaccharide from Pseudomonas syringae pv. ciccaronei.

The structural determination was performed of a mannan exopolysaccharide from the gram negative bacterium Pseudomonas syringae pv. ciccaronei, which is the pathogenic agent responsible for the leaf spots of carob plants. The structure, obtained by chemical, enzymatic and spectroscopic methods, consisted of a backbone of alpha-(1-->6)-linked mannopyranose units with 80% substituted at C-2 by mono-, di- and trisaccharide side chains. In addition, terminal glucose units and phosphate groups were found to be present. This is, to the best of our knowledge, the first report of a mannan exopolysaccharide structure from a phytopathogenic bacterium. The pure polysaccharide showed phytotoxic effects, i.e., chlorosis and necrosis on tobacco leaves.

Carbohydrate Conformation↗

PubMed1997

Biochemistry of glycosphingolipid degradation.

Glycosphingolipids (GSLs) form cell-type-specific patterns on the surface of eukaryotic cells. Degradation of GSLs requires endocytotic membrane flow of plasma membrane-derived GSLs into the lysosomes as the digesting organelles. Recent research focused on the mechanisms leading to selective membrane degradation in the lysosomes and on the mechanism and physiological function of sphingolipid activator proteins, which are needed for degradation of GSLs with short oligosaccharide chains in addition to hydrolysing enzymes. Both, the inherited deficiency of lysosomal hydrolases and of sphingolipid activator proteins give rise to sphingolipid storage diseases. In some cases it was possible to correlate residual enzyme activities with the onset and the course of the disease.

Animals↗