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91.
Background
Oncolytic adenoviruses are promising agents for the multimodal treatment of cancer. However, tumor-selectivity is crucial for their applicability in patients. Recent studies by several groups demonstrated that oncolytic adenoviruses with tumor-/tissue-specific expression of the E1 and E4 genes, which are pivotal for adenoviral replication, have a specificity profile that is superior to viruses that solely target the expression of E1 or E4 genes. Presently the E1 and E4 regions are modified in a time consuming sequential fashion. 相似文献92.
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Singh SK Roberts SA McDevitt SF Weichsel A Wildner GF Grass GB Rensing C Montfort WR 《The Journal of biological chemistry》2011,286(43):37849-37857
The multicopper oxidase CueO oxidizes toxic Cu(I) and is required for copper homeostasis in Escherichia coli. Like many proteins involved in copper homeostasis, CueO has a methionine-rich segment that is thought to be critical for copper handling. How such segments function is poorly understood. Here, we report the crystal structure of CueO at 1.1 Å with the 45-residue methionine-rich segment fully resolved, revealing an N-terminal helical segment with methionine residues juxtaposed for Cu(I) ligation and a C-terminal highly mobile segment rich in methionine and histidine residues. We also report structures of CueO with a C500S mutation, which leads to loss of the T1 copper, and CueO with six methionines changed to serine. Soaking C500S CueO crystals with Cu(I), or wild-type CueO crystals with Ag(I), leads to occupancy of three sites, the previously identified substrate-binding site and two new sites along the methionine-rich helix, involving methionines 358, 362, 368, and 376. Mutation of these residues leads to a ∼4-fold reduction in kcat for Cu(I) oxidation. Ag(I), which often appears with copper in nature, strongly inhibits CueO oxidase activities in vitro and compromises copper tolerance in vivo, particularly in the absence of the complementary copper efflux cus system. Together, these studies demonstrate a role for the methionine-rich insert of CueO in the binding and oxidation of Cu(I) and highlight the interplay among cue and cus systems in copper and silver homeostasis. 相似文献
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Paula Zwicker Nadin Schultze Sarah Niehs Karen Methling Martina Wurster Dirk Albrecht Jörg Bernhardt Gerhild Wachlin Michael Lalk Ulrike Lindequist Beate Haertel 《Proteomics》2016,16(23):2997-3008
The immune system is permanently exposed to several environmental influences that can have adverse effects on immune cells or organs leading to immunosuppression or inappropriate immunostimulation, called direct immunotoxicity. The natural compound Tulipalin A (TUPA), a lactone with α‐methylene‐γ‐butyrolactone moiety, can influence the immune system and lead to allergic contact dermatitis. This in vitro study focused on effects of TUPA using two immune cell lines (Jurkat T cells and THP‐1 monocytes). To evaluate the immunotoxic potential of the compound, a proteomic approach applying 2D gel electrophoresis and MALDI‐TOF/TOF‐MS in combination with metabolomic analysis was used after exposure of the cells to IC10 of TUPA. THP‐1 cells showed a strong robustness to TUPA treatment since only five proteins were altered. In contrast, in Jurkat T cells an increase in the abundance of 66 proteins and a decrease of six proteins was determined. These intracellular proteins were mapped to biological processes. Especially an accumulation of chaperones and an influence on the purine synthesis were observed. The changes in purine synthesis were confirmed by metabolomic analysis. In conclusion, the data indicate possible target processes of low doses of TUPA in Jurkat T cells and provides knowledge of how TUPA affects the functionality of immune cells. 相似文献
97.
Rubisco assumes the double role of accumulating biomass by fixing carbon dioxide to ribulose-1,5-bisphosphate and binding of molecular oxygen to the same substrate. The specificity factor of this mutually competitive activity, defined as the ratio of carboxylation to oxygenation efficiency, varies considerably for reasons which remain obscure. The explanation and the enhancement of specificity are of high theoretical and practical interest. Despite a wealth of structures and experimental findings, the systematic analysis of available data is still at its beginning. Here, we (a) present an analysis of sequences of the large subunit which reliably finds specificity-enhancing mutations and ranks them according to the probability of success. For mutations near the C-terminus, we (b) show by simulations that the positive influence they have on specificity can be explained by the time-window hypothesis. 相似文献
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The effect of divalent metal ions on the activity of Mg++ depleted ribulose-1,5-bisphosphate oxygenase 总被引:1,自引:0,他引:1
Ribulose-1,5-bisphosphate carboxylase-oxygenase is deactivated by removal of Mg++. The enzyme activities can be restored to a different extent by the addition of various divalent ions in the presence of CO2. Incubation with Mg++ and CO2 restores both enzyme activities, whereas, the treatment of the enzyme with the transition metal ions (Mn++, Co++, and Ni++) and CO2 fully reactivates the oxygenase: however, the carboxylase activity remains low. In experiments where CO2-free conditions were conscientiously maintained, no reactivation of RuBP oxygenase was observed, although Mn++ ions were present. Other divalent cations such as Ca++ and Zn++, restore neither the carboxylase nor the oxygenase reaction. Furthermore, the addition of Mn++ to the Mg++ and CO2 preactivated enzyme significantly inhibited carboxylase reactions, but increased the oxygenase reaction.Abbreviation RuBP
ribulose-1,5-bisphosphate. The enyme unit for RuBP carboxylase is defined as mol CO2 fixed·min-1 and for the RuBP oxygenase as mol O2 consumed · min-1 相似文献
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