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141.
Norbert Schormann Sadanandan E. Velu Srinivasan Murugesan Olga Senkovich Kiera Walker Bala C. Chenna Bidhan Shinkre Amar Desai Debasish Chattopadhyay 《Bioorganic & medicinal chemistry》2010,18(11):4056-4066
Dihydrofolate reductase (DHFR) of the parasite Trypanosoma cruzi (T. cruzi) is a potential target for developing drugs to treat Chagas’ disease. We have undertaken a detailed structure–activity study of this enzyme. We report here synthesis and characterization of six potent inhibitors of the parasitic enzyme. Inhibitory activity of each compound was determined against T. cruzi and human DHFR. One of these compounds, ethyl 4-(5-[(2,4-diamino-6-quinazolinyl)methyl]amino-2-methoxyphenoxy)butanoate (6b) was co-crystallized with the bifunctional dihydrofolate reductase-thymidylate synthase enzyme of T. cruzi and the crystal structure of the ternary enzyme:cofactor:inhibitor complex was determined. Molecular docking was used to analyze the potential interactions of all inhibitors with T. cruzi DHFR and human DHFR. Inhibitory activities of these compounds are discussed in the light of enzyme–ligand interactions. Binding affinities of each inhibitor for the respective enzymes were calculated based on the experimental or docked binding mode. An estimated 60–70% of the total binding energy is contributed by the 2,4-diaminoquinazoline scaffold. 相似文献
142.
Environmental pollutants have a significant impact on the ecosystem and disrupt balance between environment, human and non-human components that result in deleterious effects to all forms of life. Identifying environmental factors for potential imbalance are extremely crucial for devising strategies for combating such toxic dysregulation. Automobile exhaust (in air), heavy metals (in food and water) and pesticides (in air, food, soil and water) are the most common environmental pollutants and their short and long-term exposures can cause hazardous effects in humans leading to systemic disorders involving lungs, kidney and immune systems. Mechanisms involved in genesis of such toxic effects have revealed complex, interactive pathways. Strategies for the protection of homeostasis and health, viz., general preventive measures, nutritional supplements and herbal agents have been described, to counter these pollutants induced damaging effects on various body systems. 相似文献
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Thirupathi Karuppanapandian Pritam Bala Sinha Abdul Majeeth Kamarul Haniya Kumariah Mamoharan 《Journal of Plant Biology》2006,49(6):440-447
Chromium-induced antioxidative responses of ascorbate-glutathione cycle enzymes and metabolites in green gram(Vigna radiata L. Wilczek) leaves were investigated in both dose and time-dependent manners. Rapid uptake of Cr was observed immediately
after the start of treatment. Significant reduction was observed in leaf biomass under 300 μM Cr-treatment. Treatment with
300 μM Cr increases the content of hydrogen peroxide and Superoxide dismytase activity upto initial 96 h, and then gradually
declined to the basal level. Ascorbate peroxidase and guaiacol peroxidase activities were low in 300 μM Cr-treated leaves
during the first 96 h, but significantly increased therefore, suggesting that increased enzyme activities would be responsible
for the removal of H2O2. Catalase activities were always suppressed under Cr stress. Contents of reduced ascorbate and dehydroascorbate were significantly
decreased under 300 uM Cr-treatment. The reduced glutathione content decreased at early stages of Cr-treatment. However, it
was restored to the normal level as in controls thereafter. In contrast, the glutathione disulphide content showed a progressive
increase during the initial hours of Cr-treatment. The non-protein thiol content was shown to increase during the first several
hours, but it declines at later stages. The present results demonstrate that Cr-induced oxidative stress is an important component
of the plant’s reaction to toxic levels of Cr. 相似文献
146.
Edelman E Porrello A Guinney J Balakumaran B Bild A Febbo PG Mukherjee S 《Bioinformatics (Oxford, England)》2006,22(14):e108-e116
MOTIVATION: Gene expression profiling experiments in cell lines and animal models characterized by specific genetic or molecular perturbations have yielded sets of genes annotated by the perturbation. These gene sets can serve as a reference base for interrogating other expression datasets. For example, a new dataset in which a specific pathway gene set appears to be enriched, in terms of multiple genes in that set evidencing expression changes, can then be annotated by that reference pathway. We introduce in this paper a formal statistical method to measure the enrichment of each sample in an expression dataset. This allows us to assay the natural variation of pathway activity in observed gene expression data sets from clinical cancer and other studies. RESULTS: Validation of the method and illustrations of biological insights gleaned are demonstrated on cell line data, mouse models, and cancer-related datasets. Using oncogenic pathway signatures, we show that gene sets built from a model system are indeed enriched in the model system. We employ ASSESS for the use of molecular classification by pathways. This provides an accurate classifier that can be interpreted at the level of pathways instead of individual genes. Finally, ASSESS can be used for cross-platform expression models where data on the same type of cancer are integrated over different platforms into a space of enrichment scores. AVAILABILITY: Versions are available in Octave and Java (with a graphical user interface). Software can be downloaded at http://people.genome.duke.edu/assess. 相似文献
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148.
Mazura P Fohlerová R Brzobohatý B Kiran NS Janda L 《Journal of biochemical and biophysical methods》2006,68(1):55-63
The maize β-glucosidase Zm-p60.1 is important for the regulation of plant development through its role in the targeted release of free cytokinins from cytokinin-O-glucosides, their inactive storage forms. Enzyme kinetics studies using these scarce substrates close to physiological concentrations are difficult due to two reasons: (a) Available methods are mainly suited for end-point kinetics. (b) These methods are not sufficiently sensitive when using scarce glucoside substrates.We developed a glucose assay using a system comprising three enzymes β-glucosidase, glucose oxidase and horseradish peroxidase, with the new substrate N-acetyl-3,7-dihydroxyphenoxazine-Amplex Ultra Red reagent (Molecular Probes). A calibration curve was constructed for resorufin and validation was carried out by comparing our method with the standard spectrophotometric method using p-nitrophenyl-β-d-glucopyranoside. In comparison with the other methods, this method is more sensitive, precise and accurate. The assay is rapid and hence suited for continuous kinetics, it is readily adapted to suit automated procedures, and potential applications include its use in studying the physiological role(s) of enzymes that cleave scarce glucoside substrates. 相似文献
149.
Ravi Kiran T Subramanyam MV Prathima S Asha Devi S 《Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology》2006,176(8):749-762
Region-wise interactive effects of age, swim intensity, and duration on exercise performance in the myocardium and serum lipid profile in young (4 months) and middle-aged (12 months) rats were examined. Animals were allocated to the sedentary control (SE-C) or one of the nine trainee groups. Swim training was for 6 days/week and for 4 weeks at 3 durations (20, 40, and 60 min/day) and intensities (2%, low; 3%, medium; 5%, high). Swim velocity and external work showed an age-related decline with low-intensity of 20 min/day in the middle aged. Reduction in serum cholesterol, low-density lipoproteins (LDLs), and triglycerides were accompanied by elevated levels in high-density lipoprotein in the low-to-moderately trained ones for 20 and 40 min/day. Training at 2%, intensity for 20 min/day was sufficient to alter the blood lipid profile and improve swim performance, and endurance in terms of blood lactate. A concomitant increase in Mn-superoxide dismutase (Mn-SOD) activity and reduced malondialdehyde in the left ventricle (LV) and right ventricle (RV) were evident. Lipofuscin was higher in the LV compared to RV. Our results reflect the minimization of free radical generation through appropriate exercise protocols. Our findings on improved blood lipid profile could be related to lower free radicals, which would otherwise oxidize LDLs. Further, swim training when initiated in the young and middle age for as low as 20 min/day at 2% intensity improves the Mn-SOD in the LV and RV. However, the adaptive response of the LV was weaker when compared to the RV, more so in the middle aged. 相似文献
150.