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991.
Mark A. Hilfiker Ning Wang Xiaoping Hou Zhimin Du Mark A. Pullen Melanie Nord Rakesh Nagilla Harvey E. Fries Charlene W. Wu Anthony C. Sulpizio Jon-Paul Jaworski Dwight Morrow Richard M. Edwards Jian Jin 《Bioorganic & medicinal chemistry letters》2009,19(15):4292-4295
This Letter discloses a series of 2-aminothiadiazole amides as selective EP3 receptor antagonists. SAR optimization resulted in compounds with excellent functional activity in vitro. In addition, efforts to optimize DMPK properties in the rat are discussed. These efforts have resulted in the identification of potent, selective EP3 receptor antagonists with excellent DMPK properties suitable for in vivo studies. 相似文献
992.
993.
Barro Soria R Spitzner M Schreiber R Kunzelmann K 《The Journal of biological chemistry》2009,284(43):29405-29412
Epithelial cells express calcium-activated Cl(-) channels of unknown molecular identity. These Cl(-) channels play a central role in diseases such as secretory diarrhea, polycystic kidney disease, and cystic fibrosis. The family of bestrophins has been suggested to form calcium-activated Cl(-) channels. Here, we demonstrate molecular and functional expression of bestrophin-1 (BEST1) in mouse and human airways, colon, and kidney. Endogenous calcium-activated whole cell Cl(-) currents coincide with endogenous expression of the Vmd2 gene product BEST1 in murine and human epithelial cells, whereas calcium-activated Cl(-) currents are absent in epithelial tissues lacking BEST1 expression. Blocking expression of BEST1 with short interfering RNA or applying an anti-BEST1 antibody to a patch pipette suppressed ATP-induced whole cell Cl(-) currents. Calcium-dependent Cl(-) currents were activated by ATP in HEK293 cells expressing BEST1. Thus, BEST1 may form the Ca2+-activated Cl(-) current, or it may be a component of a Cl(-) channel complex in epithelial tissues. 相似文献
994.
995.
996.
Analysis of structure and function of the giant protein Pf332 in Plasmodium falciparum 总被引:1,自引:0,他引:1
Anthony N. Hodder Alexander G. Maier Melanie Rug Monica Brown Mirja Hommel Ivan Pantic Marina Puig-de-Morales-Marinkovic Brian Smith Tony Triglia James Beeson Alan F. Cowman 《Molecular microbiology》2009,71(1):48-65
Virulence of Plasmodium falciparum , the most lethal parasitic disease in humans, results in part from adhesiveness and increased rigidity of infected erythrocytes. Pf332 is trafficked to the parasite-infected erythrocyte via Maurer's clefts, structures for protein sorting and export in the host erythrocyte. This protein has a domain similar to the Duffy-binding-like (DBL) domain, which functions by binding to receptors for adherence and invasion. To address structure of the Pf332 DBL domain, we expressed this region, and validated its fold on the basis of the disulphide bond pattern, which conformed to the generic pattern for DBL domains. The modelled structure for Pf332 DBL had differences compared with the erythrocyte-binding region of the αDBL domain of Plasmodium knowlesi Duffy-binding protein (Pkα-DBL). We addressed the function of Pf332 by constructing parasites that either lack expression of the protein or express an altered form. We found no evidence that Pf332 is involved in cytoadhesion or merozoite invasion. Truncation of Pf332 had a significant effect on deformability of the P. falciparum -infected erythrocyte, while loss of the full protein deletion did not. Our data suggest that Pf332 may contribute to the overall deformability of the P. falciparum -infected erythrocyte by anchoring and scaffolding. 相似文献
997.
Metabolomic analysis reveals a common pattern of metabolic re-programming during invasion of three host plant species by Magnaporthe grisea 总被引:1,自引:0,他引:1
David Parker Manfred Beckmann Hassan Zubair David P. Enot Zaira Caracuel-Rios David P. Overy Stuart Snowdon Nicholas J. Talbot John Draper 《The Plant journal : for cell and molecular biology》2009,59(5):723-737
The mechanisms by which biotrophic and hemi-biotrophic fungal pathogens simultaneously subdue plant defences and sequester host nutrients are poorly understood. Using metabolite fingerprinting, we show that Magnaporthe grisea , the causal agent of rice blast disease, dynamically re-programmes host metabolism during plant colonization. Identical patterns of metabolic change occurred during M. grisea infections in barley, rice and Brachypodium distachyon . Targeted metabolite profiling by GC-MS confirmed the modulation of a conserved set of metabolites. In pre-symptomatic tissues, malate and polyamines accumulated, rather than being utilized to generate defensive reactive oxygen species, and the levels of metabolites associated with amelioration of redox stress in various cellular compartments increased dramatically. The activity of NADP-malic enzyme and generation of reactive oxygen species were localized to pathogen penetration sites, and both appeared to be suppressed in compatible interactions. Early diversion of the shikimate pathway to produce quinate was observed, as well as accumulation of non-polymerized lignin precursors. These data are consistent with modulation of defensive phenylpropanoid metabolism by M. grisea and the inability of susceptible hosts to mount a hypersensitive reaction or produce lignified papillae (both involving reactive oxygen species) to restrict pathogen invasion. Rapid proliferation of M. grisea hyphae in plant tissue after 3 days was associated with accelerated nutrient acquisition and utilization by the pathogen. Conversion of photoassimilate into mannitol and glycerol for carbon sequestration and osmolyte production appear to drive hyphal growth. Taken together, our results suggest that fungal pathogens deploy a common metabolic re-programming strategy in diverse host species to suppress plant defence and colonize plant tissue. 相似文献
998.
999.
Melanie J. Morris 《生物化学与生物物理学报:生物膜》2009,1788(3):676-5289
Glutathione transferases are a family of enzymes that are traditionally known to contribute to the phase II class of detoxification reactions. However, a novel property of the Schistosoma japonicum glutathione transferase (Sj.GST26) involves its translocation from the external medium into a variety of different cell types. Here we explore the efficiency and mechanism of cell entry for this class of protein. Using flow cytometry and confocal microscopy, we have examined the internalisation of Sj.GST26 into live cells under a variety of conditions designed to shed light on the mode of cellular uptake. Our results show that Sj.GST26 can effectively enter cells through an energy-dependent event involving endocytosis. More specifically, Sj.GST26 was found to colocalise with transferrin within the cell indicating that the endocytosis process involves clathrin-coated pits. A comprehensive study into the cellular internalisation of proteins from other classes within the GST structural superfamily has also been conducted. These experiments suggest that the ‘GST-fold’ structural motif influences cellular uptake, which presents a novel glimpse into an unknown aspect of GST function. 相似文献