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991.
Aliche-Djoudi F Podechard N Chevanne M Nourissat P Catheline D Legrand P Dimanche-Boitrel MT Lagadic-Gossmann D Sergent O 《Free radical biology & medicine》2011,51(11):2018-2030
Dietary n-3 polyunsaturated fatty acids (n-3 PUFAs) have been reported to modulate lipid raft-dependent signaling, but not yet lipid raft-dependent oxidative stress. Previously, we have shown that ethanol-induced membrane remodeling, i.e., an increase in membrane fluidity and alterations in physical and biochemical properties of lipid rafts, participated in the development of oxidative stress. Thus, we decided to study n-3 PUFA effects in this context, by pretreating hepatocytes with eicosapentaenoic acid (EPA), a long-chain n-3 PUFA, before addition of ethanol. EPA was found to increase ethanol-induced oxidative stress through membrane remodeling. Addition of EPA resulted in a marked increase in lipid raft aggregation compared to ethanol alone. In addition, membrane fluidity of lipid rafts was markedly enhanced. Interestingly, EPA was found to preferentially incorporate into nonraft membrane regions, leading to raft cholesterol increase. Lipid raft aggregation by EPA enhanced phospholipase Cγ translocation into these microdomains. Finally, phospholipase Cγ was shown to participate in the potentiation of oxidative stress by promoting lysosome accumulation, a major source of low-molecular-weight iron. To conclude, the ability of EPA to modify lipid raft physical and chemical properties plays a key role in the enhancement, by this dietary n-3 PUFA, of ethanol-induced oxidative stress. 相似文献
992.
Bromba CM Mason JW Brant MG Chan T Lunke MD Petric M Boulanger MJ Wulff JE 《Bioorganic & medicinal chemistry letters》2011,21(23):7137-7141
The guanidine function in the potent neuraminidase inhibitor peramivir was included early on in the drug design process, and examination of X-ray structural data for the enzyme-inhibitor complex would seem to indicate that the guanidine plays a critical role in promoting binding. However, this functional group may also contribute to the poor oral availability of the drug. Given that the relative stereochemistry on the guanidine-bearing carbon in peramivir is opposite to that in zanamivir (a related neuraminidase inhibitor, for which the guanidine function is known to contribute substantially to the potency), we sought to determine the importance of the guanidine group to peramivir's overall potency. Here we report that the de-guanidinylated analogue of peramivir is only ca. 1-order of magnitude less potent than peramivir itself in two in vitro inhibition assays. This suggests that next-generation inhibitors designed to improve on peramivir's properties might profitably dispense with the guanidine function. 相似文献
993.
Gallant M Beaulieu C Berthelette C Colucci J Crackower MA Dalton C Denis D Ducharme Y Friesen RW Guay D Gervais FG Hamel M Houle R Krawczyk CM Kosjek B Lau S Leblanc Y Lee EE Levesque JF Mellon C Molinaro C Mullet W O'Neill GP O'Shea P Sawyer N Sillaots S Simard D Slipetz D Stocco R Sørensen D Truong VL Wong E Wu J Zaghdane H Wang Z 《Bioorganic & medicinal chemistry letters》2011,21(1):288-293
994.
Gauthier JY Belley M Deschênes D Fournier JF Gagné S Gareau Y Hamel M Hénault M Hyjazie H Kargman S Lavallée G Levesque JF Li L Mamane Y Mancini J Morin N Mulrooney E Robichaud J Thérien M Tranmer G Wang Z Wu J Black WC 《Bioorganic & medicinal chemistry letters》2011,21(10):2836-2839
A weak, UDP-competitive antagonist of the pyrimidinergic receptor P2RY14 with a naphthoic acid core was identified through high-throughput screening. Optimization provided compounds with improved potency but poor pharmacokinetics. Acylglucuronidation was determined to be the major route of metabolism. Increasing the electron-withdrawing nature of the substituents markedly reduced glucuronidation and improved the pharmacokinetic profile. Additional optimization led to the identification of compound 38 which is an 8 nM UDP-competitive antagonist of P2Y14 with a good pharmacokinetic profile. 相似文献
995.
Glasner JD Yang CH Reverchon S Hugouvieux-Cotte-Pattat N Condemine G Bohin JP Van Gijsegem F Yang S Franza T Expert D Plunkett G San Francisco MJ Charkowski AO Py B Bell K Rauscher L Rodriguez-Palenzuela P Toussaint A Holeva MC He SY Douet V Boccara M Blanco C Toth I Anderson BD Biehl BS Mau B Flynn SM Barras F Lindeberg M Birch PR Tsuyumu S Shi X Hibbing M Yap MN Carpentier M Dassa E Umehara M Kim JF Rusch M Soni P Mayhew GF Fouts DE Gill SR Blattner FR Keen NT Perna NT 《Journal of bacteriology》2011,193(8):2076-2077
Dickeya dadantii is a plant-pathogenic enterobacterium responsible for the soft rot disease of many plants of economic importance. We present here the sequence of strain 3937, a strain widely used as a model system for research on the molecular biology and pathogenicity of this group of bacteria. 相似文献
996.
Kozlov G Denisov AY Girard M Dicaire MJ Hamlin J McPherson PS Brais B Gehring K 《The Journal of biological chemistry》2011,286(23):20407-20412
Sacsin is a 520-kDa protein mutated in the early-onset neurodevelopmental and neurodegenerative disease autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The C terminus of the protein contains an HEPN (higher eukaryotes and prokaryotes nucleotide-binding) domain of unknown function. Here, we determined the high-resolution 1.9-Å crystal structure of the HEPN domain from human sacsin. The structure is composed of five parallel α-helices with a large loop of several short helical segments. Two HEPN protomers assemble as a dimer to form a large positively charged cavity at the dimer interface that binds GTP and other nucleotides. The crystal structure reveals that the ARSACS N4549D mutation disrupts dimerization and protein folding. This study provides novel insights into the oligomerization state of sacsin and functions that are lost in mutations that cause ARSACS. 相似文献
997.
Liebminger E Veit C Pabst M Batoux M Zipfel C Altmann F Mach L Strasser R 《The Journal of biological chemistry》2011,286(12):10793-10802
Most plant glycoproteins contain substantial amounts of paucimannosidic N-glycans instead of their direct biosynthetic precursors, complex N-glycans with terminal N-acetylglucosamine residues. We now demonstrate that two β-N-acetylhexosaminidases (HEXO1 and HEXO3) residing in different subcellular compartments jointly account for the formation of paucimannosidic N-glycans in Arabidopsis thaliana. Total N-glycan analysis of hexo knock-out plants revealed that HEXO1 and HEXO3 contribute equally to the production of paucimannosidic N-glycans in roots, whereas N-glycan processing in leaves depends more heavily on HEXO3 than on HEXO1. Because hexo1 hexo3 double mutants do not display any obvious phenotype even upon exposure to different forms of abiotic or biotic stress, it should be feasible to improve the quality of glycoprotein therapeutics produced in plants by down-regulation of endogenous β-N-acetylhexosaminidase activities. 相似文献
998.
Layre E Paepe DC Larrouy-Maumus G Vaubourgeix J Mundayoor S Lindner B Puzo G Gilleron M 《Journal of lipid research》2011,52(6):1098-1110
For 4 decades, in vivo and in vitro studies have suggested that sulfoglycolipids (SGLs) play a role in the virulence or pathogenesis of the tubercle bacilli. However, the SGL structure and biosynthesis pathway remain only partially elucidated. Using the modern tools of structural analysis, including MALDI-time-of-flight MS, MS/MS, and two-dimensional NMR, we reevaluated the structure of the different SGL acyl (di-, tri-, and tetra-acylated) forms of the reference strain Mycobacterium tuberculosis H37Rv, as well as those produced by the mmpL8 knockout strains previously described to intracellularly accumulate di-acylated SGL. We report here the identification of new acyl forms: di-acylated SGL esterified by simple fatty acids only, as well as mono-acylated SGL bearing a hydroxyphthioceranoic acid, which were characterized in the wild-type strain. In a clinical strain, a complete family of mono-acylated SGLs was characterized in high abundance for the first time. For the mmpL8 mutant, SGLs were found to be esterified i) by an oxophthioceranoic acid, never observed so far, and ii) at nonconventional positions in the case of the unexpected tri-acylated forms. Our results further confirm the requirement of MmpL8 for the complete assembly of the tetra-acylated forms of SGL and also provide, by the discovery of new intermediates, insights in terms of the possible SGL biosynthetic pathways. 相似文献
999.
1000.
Biesta-Peters EG Reij MW Zwietering MH Gorris LG 《Applied and environmental microbiology》2011,77(16):5707-5715
This research aims to test the absence (gamma hypothesis) or occurrence of synergy between two growth-limiting factors, i.e., pH and water activity (a(w)), using a systematic approach for model selection. In this approach, preset criteria were used to evaluate the performance of models. Such a systematic approach is required to be confident in the correctness of the individual components of the combined (synergy) models. With Bacillus cereus F4810/72 as the test organism, estimated growth boundaries for the a(w)-lowering solutes NaCl, KCl, and glucose were 1.13 M, 1.13 M, and 1.68 M, respectively. The accompanying a(w) values were 0.954, 0.956, and 0.961, respectively, indicating that equal a(w) values result in similar effects on growth. Out of the 12 models evaluated using the preset criteria, the model of J. H. T. Luong (Biotechnol. Bioeng. 27:280-285, 1985) was the best model to describe the effect of a(w) on growth. This a(w) model and the previously selected pH model were combined into a gamma model and into two synergy models. None of the three models was able to describe the combined pH and a(w) conditions sufficiently well to satisfy the preset criteria. The best matches between predicted and experimental data were obtained with the gamma model, followed by the synergy model of Y. Le Marc et al. (Int. J. Food Microbiol. 73:219-237, 2002). No combination of models that was able to predict the impact of both individual and combined hurdles correctly could be found. Consequently, in this case we could not prove the existence of synergy nor falsify the gamma hypothesis. 相似文献