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Unlike numerous pore-forming amphiphilic peptide antibiotics, the lantibiotic nisin is active in nanomolar concentrations, which results from its ability to use the lipid-bound cell wall precursor lipid II as a docking molecule for subsequent pore formation. Here we use genetically engineered nisin variants to identify the structural requirements for the interaction of the peptide with lipid II. Mutations affecting the conformation of the N-terminal part of nisin comprising rings A through C, e.g. [S3T]nisin, led to reduced binding and increased the peptide concentration necessary for pore formation. The binding constant for the S3T mutant was 0.043 x 10(7) m(-1) compared with 2 x 10(7) m(-1) for the wild-type peptide, and the minimum concentration for pore formation increased from the 1 nm to the 50 nm range. In contrast, peptides mutated in the flexible hinge region, e.g. [DeltaN20/DeltaM21]nisin, were completely inactive in the pore formation assay, but were reduced to some extent in their in vivo activity. We found the remaining in vivo activity to result from the unaltered capacity of the mutated peptide to bind to lipid II and thus to inhibit its incorporation into the peptidoglycan network. Therefore, through interaction with the membrane-bound cell wall precursor lipid II, nisin inhibits peptidoglycan synthesis and forms highly specific pores. The combination of two killing mechanisms in one molecule potentiates antibiotic activity and results in nanomolar MIC values, a strategy that may well be worth considering for the construction of novel antibiotics.  相似文献   
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Essential fatty acid (EFA) deficiency during cholestasis is mainly due to malabsorption of dietary EFA (23). Theoretically, dietary phospholipids (PL) may have a higher bioavailability than dietary triglycerides (TG) during cholestasis. We developed murine models for EFA deficiency (EFAD) with and without extrahepatic cholestasis and compared the efficacy of oral supplementation of EFA as PL or as TG. EFAD was induced in mice by feeding a high-fat EFAD diet. After 3 wk on this diet, bile duct ligation was performed in a subgroup of mice to establish extrahepatic cholestasis. Cholestatic and noncholestatic EFAD mice continued on the EFAD diet (controls) or were supplemented for 3 wk with EFA-rich TG or EFA-rich PL. Fatty acid composition was determined in plasma, erythrocytes, liver, and brain. After 4 wk of EFAD diet, induction of EFAD was confirmed by a sixfold increased triene-to-tetraene ratio (T/T ratio) in erythrocytes of noncholestatic and cholestatic mice (P < 0.001). EFA-rich TG and EFA-rich PL were equally effective in preventing further increase of the erythrocyte T/T ratio, which was observed in cholestatic and noncholestatic nonsupplemented mice (12- and 16-fold the initial value, respectively). In cholestatic mice, EFA-rich PL was superior to EFA-rich TG in decreasing T/T ratios of liver TG and PL (each P < 0.05) and in increasing brain PL concentrations of the long-chain polyunsaturated fatty acids (LCPUFA) docosahexaenoic acid and arachidonic acid (each P < 0.05). We conclude that oral EFA supplementation in the form of PL is more effective than in the form of TG in increasing LCPUFA concentrations in liver and brain of cholestatic EFAD mice.  相似文献   
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Potato synthesises high levels of proteinase inhibitors in response to insect attack. This can adversely affect protein digestion in the insects, leading to reduced growth, delayed development and lowered fecundity. Colorado potato beetle overcomes this defence mechanism by changing the composition of its digestive proteinases. The induced cysteine proteinases in the adapted gut sustain a normal rate of protein hydrolysis either by inactivating the inhibitors by cleavage or by insensitivity to the inhibitors as a result of high Kis. In this study cDNA clones of cysteine proteinases in adapted guts were isolated by nested PCR on the basis of N-terminal sequences previously determined for purified enzymes (Gruden et al., 2003). The cysteine proteinase cDNAs can be classified into three groups: intestains A, B and C. The amino acid identity is more than 91% within and 35-62% between the groups. They share 43-50% identity to mammalian cathepsins S, L, K, H, J and cathepsin-like enzymes from different arthropods. Homology modelling predicts that intestains A, B and C follow the general fold of papain-like proteinases. Intestains from each group, however, differ in some specific structural characteristics in the S1 and S2 binding sites that could influence enzyme-inhibitor interaction and thus, provide different mechanisms of resistance to inhibitors for the different enzymes. Gene expression analysis revealed that the intestains A and C, but not B, are induced twofold by potato plants with high levels of proteinase inhibitors.  相似文献   
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We present an in silico, structure-based approach for design and evaluation of conformationally restricted peptide-vaccines. In particular, we designed four cyclic peptides of ten or 11 residues mimicking the crystallographically observed beta-turn conformation of a predicted immunodominant loop of PorA from Neisseria meningitidis. Conformational correctness and stability of the peptide designs, as evaluated by molecular dynamics simulations, correctly predicted the immunogenicity of the peptides. We observed a peptide-induced functional antibody response that, remarkably, exceeded the response induced by the native protein in outer membrane vesicles, without losing specificity for related strains. The presented approach offers tools for a priori design and selection of peptide-vaccine candidates with full biological activity. This approach could be widely applicable: to outer membrane proteins of Gram-negative bacteria, and to other epitopes in a large range of pathogens.  相似文献   
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Scavenger receptor class B, type I (SRBI) is a key regulator of high density lipoprotein (HDL) metabolism. It facilitates the efflux of cholesterol from cells in peripheral tissues to HDL and mediates the selective uptake of cholesteryl esters from HDL in the liver. We investigated the effects of SRBI deficiency in the arterial wall and in the liver using SRBI-deficient mice and wild-type littermates fed a Western-type diet. The SRBI-deficient mice showed massive accumulation of cholesterol-rich HDL in the circulation, reflecting impaired delivery to the liver. Strikingly, SRBI deficiency did not alter hepatic cholesterol (ester) content nor did it affect the expression of key regulators of hepatic cholesterol homeostasis, including HMG-CoA reductase, the low density lipoprotein receptor, and cholesterol 7alpha-hydroxylase. However, a approximately 40% reduction in biliary cholesterol content was observed, and the expression of ABCG8 and ABCG5, ATP half-transporters implicated in the transport of sterols from the liver to the bile, was attenuated by 70 and 35%, respectively. In contrast to the situation in the liver, SRBI deficiency did result in lipid deposition in the aorta and atherosclerosis. Vascular mRNA analysis showed increased expression of inflammatory markers as well as of genes involved in cellular cholesterol homeostasis. Our data show that, although hepatic cholesterol homeostasis is maintained upon feeding a Western-type diet, SRBI deficiency is associated with de-regulation of cholesterol homeostasis in the arterial wall that results in an increased susceptibility to atherosclerosis.  相似文献   
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In vivo studies of hepatic carbohydrate metabolism in (genetically modified) conscious mice are hampered by limitations of blood and urine sample sizes. We developed and validated methods to quantify stable isotope dilution and incorporation in small blood and urine samples spotted onto filter paper. Blood glucose and urinary paracetamol-glucuronic acid were extracted from filter paper spots reproducibly and with high yield. Fractional isotopomer distributions of glucose and paracetamol-glucuronic acid when extracted from filter paper spots were almost identical to those isolated from the original body fluids. Rates of infusion of labeled compounds could be adjusted without perturbing hepatic glucose metabolism. This approach was used in mice to find the optimal metabolic condition for the study of hepatic carbohydrate metabolism. In fed mice, no isotopic steady state was observed during a 6-h label-infusion experiment. In 9-h-fasted mice, isotopic steady state was reached after 3 h of label infusion and important parameters in hepatic glucose metabolism could be calculated. The rate of de novo glucose-6-phosphate synthesis was 143 +/- 17 micromol kg(-1) min(-1) and partitioning to plasma glucose was 79.0 +/- 5.2%. In 24-h-fasted mice, abrupt changes were noticed in whole body and in hepatic glucose metabolism at the end of the experiment.  相似文献   
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Fructans are a group of fructose-based oligo- and polysaccharides, which appear to be involved in membrane preservation during dehydration by interacting with the membrane lipids. To get further understanding of the protective mechanism, the consequences of the fructan-membrane lipid interaction for the molecular organization and dynamics in the dry state were studied. POPC and DMPC were investigated in the dry state by (2)H, (31)P NMR, and Fourier transform infrared spectroscopy using two types of fructan and dextran. The order-disorder transition temperature of dry POPC was reduced by 70 degrees C in the presence of fructan. Fructan increased the mobility of the acyl chains, but immobilized the lipid headgroup region. Most likely, fructans insert between the headgroups of lipids, thereby spacing the acyl chains. This results in a much lower phase transition temperature. The headgroup is immobilized by the interaction with fructan. The location of the interaction with the lipid headgroup is different for the inulin-type fructan compared to the levan-type fructan, since inulin shows interaction with the lipid phosphate group, whereas levan does not. Dextran did not influence the phase transition temperature of dry POPC showing that reduction of this temperature is not a general property of polysaccharides.  相似文献   
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