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101.
Christoph Rademacher Jens Landström Nora Sindhuwinata Monica M. Palcic Göran Widmalm Thomas Peters 《Glycoconjugate journal》2010,27(3):349-358
A substantial body of work has been devoted to the design and synthesis of glycosyltransferase inhibitors. A major obstacle
has always been the demanding chemistry. Therefore, only few potent and selective inhibitors are known to date. Glycosyltransferases
possess two distinct binding sites, one for the donor substrate, and one for the acceptor substrate. In many cases binding
to the donor site is well defined but data for acceptor binding is sparse. In particular, acceptor binding sites are often
shallow, and in many cases the dimensions of the binding pocket are not well defined. One approach to glycosyltransferase
inhibitors is to chemically link donor site and acceptor site ligands to generate high affinity binders. Here, we describe
a novel approach to identify acceptor site ligands from a fragment library. We have chosen human blood group B galactosyltransferase
(GTB) as a biologically important model target. The approach utilizes a combination of STD NMR, spin-lock filtered NMR experiments
and surface plasmon resonance measurements. Following this route we have identified molecular fragments from a fragment library
that bind to the acceptor site of GTB with affinities of the order of a natural acceptor substrate. Unlike natural substrates
these fragments allow for straightforward chemical modifications and, therefore will serve as scaffolds for potent GTB inhibitors.
In general, the approach described is applicable to any glycosyltransferase and may assist in the development of novel glycosyltransferase
inhibitors. 相似文献
102.
103.
Attila Vig Attila Igloi Nora Adanyi Gyongyi Gyemant Csaba Csutoras Attila Kiss 《Bioprocess and biosystems engineering》2010,33(8):947-952
An amperometric detector and an enzymatic reaction were combined for the measurement of l-ascorbic acid. The enzyme cell (containing immobilized ascorbate oxidase) was connected to a flow injection analyzer (FIA)
system with a glassy carbon electrode as an amperometric detector. During optimization and measurements two sample injectors
were used, one before and one after the enzyme cell, thus eliminating the background interferences. Subtraction of the signal
area given in the presence of enzyme from the one given in the absence of enzyme was applied for measuring analyte concentrations
and calibration at 400 mV. Analysis capacity of system is 25 samples/hour. The relative standard deviation (RSD) was below
5% (5 times repeated, 400 μmol/L conc.), linearity up to 400 μmol/L, limit of detection (LOD) 5 μmol/L, fitting of calibration
curve in 25–400 μmol/L range was R
2 = 0.99. 相似文献
104.
Manuel E. Patarroyo Gladys Cifuentes Nora L. Martínez Manuel A. Patarroyo 《Progress in biophysics and molecular biology》2010,102(1):38-3507
The tri-dimensional (3D) structure determined by NMR of functionally relevant High Activity Binding Peptides (HABPs) of chemically-synthesized malarial proteins, involved in invasion to target cells, is practically identical, at the atomic level, to their corresponding recombinantly produced proteins, determined by X-ray crystallography. Both recombinant proteins as well as these chemically-synthesized HABPs bind to host-cell receptors through channels or troughs formation, stabilized by hydrogen bonding; most of them are located on distant segments to the highly polymorphic, highly antigenic, strain specific amino acid sequences the parasite uses to evade immune pressure. When these immunologically silent conserved HABPs are specifically modified, they become highly immunogenic and capable of inducing protective immune responses, supporting the specifically modified minimal subunit-based, multiepitopic, chemically-synthesized vaccines concept. 相似文献
105.
106.
Nora M. Casey Dan Milbourne Susanne Barth Melanie Febrer Glyn Jenkins Michael T. Abberton Charlotte Jones Daniel Thorogood 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2010,121(3):567-576
White clover (Trifolium repens L.) is a forage legume of considerable economic importance in temperate agricultural systems. It has a strong self-incompatibility
system. The molecular basis of self-incompatibility in T. repens is unknown, but it is under the control of a single locus, which is expressed gametophytically. To locate the self-incompatibility
locus (S locus) in T. repens, we carried out cross-pollination experiments in an F1 mapping population and constructed a genetic linkage map using amplified fragment length polymorphism and simple sequence
repeat markers. As the first step in a map-based cloning strategy, we locate for the first time the S locus in T. repens on a genetic linkage map, on the homoeologous linkage group pair 1 (E), which is broadly syntenic to Medicago truncatula L. chromosome 1. On the basis of this syntenic relationship, the possibility that the S locus may or may not possess an S-RNase gene is discussed. 相似文献
107.
María Alejandra Mussi Nora B. Calcaterra 《Comparative biochemistry and physiology. Toxicology & pharmacology : CBP》2010,151(2):240-247
In addition to the endogenous production of reactive oxygen species (ROS) as a result of normal development, amphibian external development often forces embryos to deal with oxidative stress-producing agents present in the environment. Embryos should therefore develop protective systems to reduce ROS toxicity and achieve successful development. The present work was aimed to characterize the effects produced by the widespread-used ROS-generator pesticide Paraquat during early embryonic development in the toad Chaunus arenarum, as well as to get insights into the defense response elicited by amphibian embryos. The approach consisted in generating a sharp and brief oxidative stress condition early during embryonic development to stimulate the cellular mechanisms involved in ROS-antioxidant response. Results revealed that Paraquat-treatment reduced the ability of embryos to develop normally, leading to arrests of development and severe malformations such as tail abnormalities, abdominal edema, reduced head development and curved dorsal structures. Although Paraquat effects were morphologically evident from gastrula stage on, alterations such as chromatin condensation were observed even at blastula stage by histological examinations. Regarding detoxifying enzymes, a significant induction of Mn-superoxide dismutase activity was detected at stages beyond gastrula in embryos surviving Paraquat treatment, suggesting a major role of this enzyme in the antioxidant response during early embryonic development. 相似文献
108.
Carolina Vizcaíno Daniel Restrepo-Montoya Diana Rodríguez Luis F. Ni?o Marisol Ocampo Magnolia Vanegas María T. Reguero Nora L. Martínez Manuel E. Patarroyo Manuel A. Patarroyo 《PLoS computational biology》2010,6(6)
The mycobacterial cell envelope has been implicated in the pathogenicity of tuberculosis and therefore has been a prime target for the identification and characterization of surface proteins with potential application in drug and vaccine development. In this study, the genome of Mycobacterium tuberculosis H37Rv was screened using Machine Learning tools that included feature-based predictors, general localizers and transmembrane topology predictors to identify proteins that are potentially secreted to the surface of M. tuberculosis, or to the extracellular milieu through different secretory pathways. The subcellular localization of a set of 8 hypothetically secreted/surface candidate proteins was experimentally assessed by cellular fractionation and immunoelectron microscopy (IEM) to determine the reliability of the computational methodology proposed here, using 4 secreted/surface proteins with experimental confirmation as positive controls and 2 cytoplasmic proteins as negative controls. Subcellular fractionation and IEM studies provided evidence that the candidate proteins Rv0403c, Rv3630, Rv1022, Rv0835, Rv0361 and Rv0178 are secreted either to the mycobacterial surface or to the extracellular milieu. Surface localization was also confirmed for the positive controls, whereas negative controls were located on the cytoplasm. Based on statistical learning methods, we obtained computational subcellular localization predictions that were experimentally assessed and allowed us to construct a computational protocol with experimental support that allowed us to identify a new set of secreted/surface proteins as potential vaccine candidates. 相似文献
109.
Robert Karoly Nora Lenkey Andras O. Juhasz E. Sylvester Vizi Arpad Mike 《PLoS computational biology》2010,6(6)
Sodium channels are one of the most intensively studied drug targets. Sodium channel inhibitors (e.g., local anesthetics, anticonvulsants, antiarrhythmics and analgesics) exert their effect by stabilizing an inactivated conformation of the channels. Besides the fast-inactivated conformation, sodium channels have several distinct slow-inactivated conformational states. Stabilization of a slow-inactivated state has been proposed to be advantageous for certain therapeutic applications. Special voltage protocols are used to evoke slow inactivation of sodium channels. It is assumed that efficacy of a drug in these protocols indicates slow-inactivated state preference. We tested this assumption in simulations using four prototypical drug inhibitory mechanisms (fast or slow-inactivated state preference, with either fast or slow binding kinetics) and a kinetic model for sodium channels. Unexpectedly, we found that efficacy in these protocols (e.g., a shift of the “steady-state slow inactivation curve”), was not a reliable indicator of slow-inactivated state preference. Slowly associating fast-inactivated state-preferring drugs were indistinguishable from slow-inactivated state-preferring drugs. On the other hand, fast- and slow-inactivated state-preferring drugs tended to preferentially affect onset and recovery, respectively. The robustness of these observations was verified: i) by performing a Monte Carlo study on the effects of randomly modifying model parameters, ii) by testing the same drugs in a fundamentally different model and iii) by an analysis of the effect of systematically changing drug-specific parameters. In patch clamp electrophysiology experiments we tested five sodium channel inhibitor drugs on native sodium channels of cultured hippocampal neurons. For lidocaine, phenytoin and carbamazepine our data indicate a preference for the fast-inactivated state, while the results for fluoxetine and desipramine are inconclusive. We suggest that conclusions based on voltage protocols that are used to detect slow-inactivated state preference are unreliable and should be re-evaluated. 相似文献
110.
Ferrer EG López Tévez LL Baeza N Correa MJ Okulik N Lezama L Rojo T Castellano EE Piro OE Williams PA 《Journal of inorganic biochemistry》2007,101(5):741-749
Two Cu(II) complexes with cyanoguanidine (cnge) and o-phenanthroline, [Cu(o-phen)(2)(cnge)](NO(3))(2).2H(2)O (1) and [Cu(o-phen)(cnge)(H(2)O)(NO(3))(2)] (2), have been synthesized using different experimental techniques and characterized by elemental analyses, FTIR, diffuse and UV-vis spectra and EPR and magnetic moment measurements techniques. The crystal structures of both complexes were solved by X-ray diffraction methods. Complex (1) crystallizes in the monoclinic space group C2/c with a=12.621(5), b=31.968(3), c=15.39(1)A, beta=111.68(4) degrees, and Z=8 and complex (2) in the monoclinic space group P2(1)/n with a=10.245(1), b=13.923(2), c=12.391(2)A, beta=98.07(1) degrees, and Z=4. The environments of the copper(II) center are trigonal bipyramidal (TBP) for [Cu(o-phen)(2)(cnge)](2+) and an elongated octahedron for [Cu(o-phen)(cnge)(H(2)O)(NO(3))(2)]. Solution studies have been performed to determine the species distribution. The superoxide dismutase (SOD) activities of both complexes have also been tested in order to determine if these compounds mimic the enzymatic action of the enzyme SOD that protects cells against peroxide radicals. 相似文献