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61.
Cobra venom cardiotoxins have the effect, inter alia, of causing systolic arrest of the heart. We have observed significant binding in vitro of 35S-labelled cardiotoxins to mouse heart cell membranes. Part of the binding was saturable and could be displaced with homologous unlabelled cardiotoxins but not by neurotoxins or cardiotoxins inactivated by chemical modification. The specifically bound component represented more than 70% of total binding at saturation. Inclusion of Triton X-100 and NaCl in the phosphate-buffered incubation medium prevented nonspecific adsorption to centrifuge tube walls, and gave lower but more reproducible specific binding results, respectively. An apparent dissociation constant of 5·10?7 M and a binding density of 500 pmol toxin/mg membrane protein were derived from the saturation isotherms. 相似文献
62.
Birkholtz LM Williams M Niemand J Louw AI Persson L Heby O 《The Biochemical journal》2011,438(2):229-244
New drugs are urgently needed for the treatment of tropical and subtropical parasitic diseases, such as African sleeping sickness, Chagas' disease, leishmaniasis and malaria. Enzymes in polyamine biosynthesis and thiol metabolism, as well as polyamine transporters, are potential drug targets within these organisms. In the present review, the current knowledge of unique properties of polyamine metabolism in these parasites is outlined. These properties include prozyme regulation of AdoMetDC (S-adenosylmethionine decarboxylase) activity in trypanosomatids, co-expression of ODC (ornithine decarboxylase) and AdoMetDC activities in a single protein in plasmodia, and formation of trypanothione, a unique compound linking polyamine and thiol metabolism in trypanosomatids. Particularly interesting features within polyamine metabolism in these parasites are highlighted for their potential in selective therapeutic strategies. 相似文献
63.
J. van Dijk M.D.E. de Louw L.P.A. Kalis E.R. Morgan 《International journal for parasitology》2009,39(10):1151-1156
Despite its documented effects on the viability of living organisms, the impact of ultraviolet (UV) light on the survival of parasitic nematode larvae has received surprisingly little attention. Infective L3s of the trichostrongyloid nematodes Haemonchus contortus, Teladorsagia circumcinta and Nematodirus battus, suspended in water, were exposed to direct UV irradiation in two experiments. In the first, during 6 days of constant illumination with UVA lamps at intensities simulating sunlight at ground level, the mortality rate was increased up to 100-fold compared with controls sheltered by UV-impermeable perspex. Significant differences in mortality rates were detected between the three species, with H. contortus the least sensitive. In the second experiment, larvae were exposed to natural sunlight during the temperate spring and summer, for 24-h periods on seven separate days representing a range of weather and UV doses. Mortality was again increased by UV exposure in all species, but was less in H. contortus than in T. circumcincta or N. battus. At higher daily UV doses, the mortality rate was on average 2.27 times higher in exposed larvae than in sheltered controls. Increased mortality caused by UV irradiation could help to explain patterns of abundance of infective stages at pasture, especially pronounced population declines in spring when solar radiation rises rapidly and temperature is still low. Implications for the epidemiology of gastrointestinal nematode infection in ruminants, and for trade-offs in parasite life history, are discussed. 相似文献
64.
Abraham I. Louw Leon Visser 《Biochimica et Biophysica Acta (BBA)/General Subjects》1977,498(1):143-153
Hemolysis of guinea pig erythrocytes by snake venom cardiotoxins was investigated with a semi-automatic method based on light-scattering changes of erythrocyte suspensions at 700 nm which are directly related to hemoglobin release. Small amounts of phospholipase-free cardiotoxin (<100 μg) could be conveniently and rapidly assayed with the high reproducibility in a recording spectrophotometer, and reliable kinetic data were accumulated.Cardiotoxins from two different genera (Hemachatus haemachates and Naja mossambica mossambica) displayed virtually identical hemolytic properties. Hemolysis increased linearly with time, in contrast with a sigmoidal pattern when phospholipase was present as an impurity. Low concentrations of Ca2+ (<1 mM) stimulated cardiotoxin action. A limiting plateau rate of hemolysis reached during concentration dependence experiments in which the level of either cardiotoxin or of erythrocytes was varied, suggested that the interaction of cardiotoxin with erythrocyte membranes is a saturation phenomenon only at a high ratio of cardiotoxin: erythrocytes. No hemolysis was observed with an homologous neurotoxin of S-methylated cardiotoxin, providing evidence for specificity. The linear Arrhenius plots obtained for the temperature dependence of cardiotoxin-induced hemolysis strengthened the conclusion that its action involves more than a detergent-like effect on membrane phospholipids. 相似文献
65.
Daniel F. Visser Fritha Hennessy Konanani Rashamuse Maureen E. Louw Dean Brady 《Extremophiles : life under extreme conditions》2010,14(2):185-192
A purine nucleoside phosphorylase from the alkaliphile Bacillus halodurans Alk36 was cloned and overexpressed in Escherichia coli. The enzyme was purified fivefold by membrane filtration and ion exchange. The purified enzyme had a V
max of 2.03 × 10−9 s −1 and a K
m of 206 μM on guanosine. The optimal pH range was between 5.7 and 8.4 with a maximum at pH 7.0. The optimal temperature for
activity was 70°C and the enzyme had a half life at 60°C of 20.8 h. 相似文献
66.
Drug resistance in Mycobacterium tuberculosis 总被引:3,自引:0,他引:3
67.
Resistance of the most virulent human malaria parasite, Plasmodium falciparum, to antifolates is spreading with increasing speed, especially in Africa. Antifolate resistance is mainly caused by point mutations in the P. falciparum dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR) target proteins. Homology models of the bifunctional P. falciparum dihydropterin pyrophosphokinase-dihydropteroate synthase (PPPK-DHPS) enzyme as well as the separate domains complete with bound substrates were constructed using the crystal structures of Saccharomyces cerevisiae (PPPK-DHPS), Mycobacterium tuberculosis (DHPS), Bacillus anthracis (DHPS), and Escherichia coli (PPPK) as templates. The resulting structures were subsequently solvated and refined using molecular dynamics. The active site residues of DHPS are highly conserved in S. cerevisiae, M. tuberculosis, E. coli, S. aureus, and B. anthracis, an attribute also shared by P. falciparum DHPS. Sulfadoxine was superimposed into the equivalent position of the p-aminobenzoic acid substrate and its binding parameters were refined using minimization and molecular dynamics. Sulfadoxine appears to interact mainly with P. falciparum DHPS mainly through hydrophobic interactions. Rational explanations are provided by the model for the sulfadoxine resistance-causing effects of four of the five known mutations in P. falciparum DHPS. A possible structure for the bifunctional PPPK-DHPS was derived from the structure from the S. cerevisiae bifunctional enzyme. The active site residues of P. falciparum PPPK are also conserved when compared to S. cerevisiae, Haemophilus influenzae, and E. coli. The informative nature of these models opens up avenues for structure-based drug design approaches toward the development of alternative and more effective inhibitors of P. falciparum PPPK-DHPS. 相似文献
68.
Ho KK Auld DS Bohnstedt AC Conti P Dokter W Erickson S Feng D Inglese J Kingsbury C Kultgen SG Liu RQ Masterson CM Ohlmeyer M Rong Y Rooseboom M Roughton A Samama P Smit MJ Son E van der Louw J Vogel G Webb M Wijkmans J You M 《Bioorganic & medicinal chemistry letters》2006,16(10):2724-2728
An imidazolylpyrimidine was identified in a CXCR2 chemokine receptor antagonist screen and was optimized for potency, in vitro metabolic stability, and oral bioavailability. It was found that subtle structural modification within the series affected the oral bioavailability. Potent and orally available CXCR2 antagonists are herein reported. 相似文献
69.
Louw L 《Prostaglandins, leukotrienes, and essential fatty acids》2000,63(5):255-262
In the third part of this study a basic lipid model (regarding phospholipids, triglycerides, cholesterol esters and free fatty acids) for keloids (n=20), compared with normal skin of keloid prone and non-keloid prone patients (n=20 of each), was constructed according to standard methods, to serve as a sound foundation for essential fatty acid supplementation strategies in the prevention and treatment of keloid formations. Essential fatty acid deficiency (EFAD) of the omega-6 series (linoleic acid (LA), g-linolenic acid (GLA), and dihomo-g-linolenic acid (DGLA)) and the omega-3 series (a-linolenic acid (ALA) and eicosapentaenoic acid (EPA)), but enhanced arachidonic acid (AA) levels, were prevalent in keloid formations. Enhanced AA, but a deficiency of AA precursors (LA, GLA and DGLA) and inflammatory competitors (DGLA and EPA), are inevitably responsible for the overproduction of pro-inflammatory metabolites (prostaglandin E(2)(PGE(2))) participating in the pathogenesis of inflammation. Of particular interest was the extremely high free oleic acid (OA) levels present, apart from the high free AA levels, in the keloid formations. OA stimulates PKC activity which, in turn, activates PLA(2)activity for the release or further release of AA from membrane pools. Interactions between EFAs, eicosanoids, cytokines, growth factors and free radicals can modulate the immune response and the immune system in undoubtedly involved in keloid formation. The histopathology of keloids can be adequately explained by: persistence of inflammatory- and cytokine-mediated reactions in the keloid/dermal interface and peripheral areas, where fibroblast proliferation and continuous depletion of membrane linoleic acid occur; microvascular regeneration and circulation of sufficient EFAs in the interface and peripheral areas, where maintenance of metabolic active fibroblasts for collagen production occur; microvessel occlusion and hypoxia in the central areas, where deprivation of EFAs and oxygen with consequent fibroblast apoptosis occur, while excessive collagen remain. All these factors contribute to different fibroblast populations present in: the keloid / dermal interface and peripheral areas where increases in fibroblast proliferation and endogenous TGF-b occur, and these metabolic active fibroblast populations are responsible for enhanced collagen production: the central areas where fibroblast populations under hypoxic conditions occur, and these fibroblasts are responsible for excessive collagen production. It was concluded that: fibroblast membrane EFAD of AA precursors and inflammatory competitors, but prevailing enhanced AA levels, can contribute to a chain of reactions eventually responsible for keloid formations. 相似文献
70.
Karin Terburgh Janeé Coetzer Jeremy Z. Lindeque Francois H. van der Westhuizen Roan Louw 《生物化学与生物物理学报:疾病的分子基础》2021,1867(5):166082
The dysfunction of respiratory chain complex I (CI) is the most common form of mitochondrial disease that most often presents as Leigh syndrome (LS) in children — a severe neurometabolic disorder defined by progressive focal lesions in specific brain regions. The mechanisms underlying this region-specific vulnerability to CI deficiency, however, remain elusive. Here, we examined brain regional respiratory chain enzyme activities and metabolic profiles in a mouse model of LS with global CI deficiency to gain insight into regional vulnerability to neurodegeneration. One lesion-resistant and three lesion-prone brain regions were investigated in Ndufs4 knockout (KO) mice at the late stage of LS. Enzyme assays confirmed significantly decreased (60–80%) CI activity in all investigated KO brain regions, with the lesion-resistant region displaying the highest residual CI activity (38% of wild type). A higher residual CI activity, and a less perturbed NADH/NAD+ ratio, correlate with less severe metabolic perturbations in KO brain regions. Moreover, less perturbed BCAA oxidation and increased glutamate oxidation seem to distinguish lesion-resistant from -prone KO brain regions, thereby identifying key areas of metabolism to target in future therapeutic intervention studies. 相似文献