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A sensitive two-stage enzymatic reaction for mammalian and bacterial metalloendopeptidases has been developed using the substrate 3-carboxypropanoyl-alanyl-alanyl-leucine-4-nitroanilide supplemented with Streptomyces griseus amino-peptidase. Neutral endopeptidase EC 3.4.24.11 from bovine kidney hydrolyzes the substrate (pH 7.5, 25 degrees C) with a catalytic efficiency (kcat = 1.2 x 10(2) s-1, Km = 0.15 mM) of the highest ever reported for the enzyme acting on synthetic chromophoric and fluorogenic substrates. Thermolysin hydrolyzes the substrate at a faster rate (kcat = 1.2 x 10(3) s-1) but the overall efficiency is diminished by a higher Km (4.2 mM). Suspensions of human neutrophil cells and culture filtrates of Bacillus cereus have been assayed sensitively for their neutral endopeptidases and neutral proteinase activities, respectively. The assay provides a convenient tool for the kinetic investigation of neutral endopeptidases and neutral proteinases and for assessing their function in biological systems. 相似文献
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Hagit Shapira Meir Mouallem Menachem S. Shapiro Yosef Weisman Zvi Farfel 《Human genetics》1996,97(1):73-75
Pseudohypoparathyroidism type Ia (PHP-Ia) is a hereditary disease characterized by resistance to PTH and other hormones that act via cAMP. Patients have deficient activity of Gs, the subunit of the G protein, which couples hormone receptors to stimulation of adenylate cyclase. We describe two new mutations discovered in two sporadic patients with PHP-Ia. Using genomic DNA, we have amplified exons 2–13 of the Gs gene (GNAS1) by PCR, and sequenced the resulting products. Both patients had Albright's hereditary osteodystrophy, resistance to multiple hormones, and deficient Gs activity. In the first patient, a deletion of a C in exon 5 at codon 115 was found. In the second patient, an insertion of a C in exon 10 at codon 267 was detected. Both these heterozygous mutations cause frameshift, and predict decreased production of Gs. This report adds two new Gs mutations to the known ten mutations recently described. 相似文献
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Deletion of PsbM in tobacco alters the QB site properties and the electron flow within photosystem II 总被引:1,自引:0,他引:1
Umate P Schwenkert S Karbat I Dal Bosco C Mlcòchová L Volz S Zer H Herrmann RG Ohad I Meurer J 《The Journal of biological chemistry》2007,282(13):9758-9767
Photosystem II, the oxygen-evolving complex of photosynthetic organisms, includes an intriguingly large number of low molecular weight polypeptides, including PsbM. Here we describe the first knock-out of psbM using a transplastomic, reverse genetics approach in a higher plant. Homoplastomic Delta psbM plants exhibit photoautotrophic growth. Biochemical, biophysical, and immunological analyses demonstrate that PsbM is not required for biogenesis of higher order photosystem II complexes. However, photosystem II is highly light-sensitive, and its activity is significantly decreased in Delta psbM, whereas kinetics of plastid protein synthesis, reassembly of photosystem II, and recovery of its activity are comparable with the wild type. Unlike wild type, phosphorylation of the reaction center proteins D1 and D2 is severely reduced, whereas the redox-controlled phosphorylation of photosystem II light-harvesting complex is reversely regulated in Delta psbM plants because of accumulation of reduced plastoquinone in the dark and a limited photosystem II-mediated electron transport in the light. Charge recombination in Delta psbM measured by thermoluminescence oscillations significantly differs from the 2/6 patterns in the wild type. A simulation program of thermoluminescence oscillations indicates a higher Q(B)/Q(-)(B) ratio in dark-adapted mutant thylakoids relative to the wild type. The interaction of the Q(A)/Q(B) sites estimated by shifts in the maximal thermoluminescence emission temperature of the Q band, induced by binding of different herbicides to the Q(B) site, is changed indicating alteration of the activation energy for back electron flow. We conclude that PsbM is primarily involved in the interaction of the redox components important for the electron flow within, outward, and backward to photosystem II. 相似文献
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Talior I Yarkoni M Bashan N Eldar-Finkelman H 《American journal of physiology. Endocrinology and metabolism》2003,285(2):E295-E302
Increased oxidative stress is believed to be one of the mechanisms responsible for hyperglycemia-induced tissue damage and diabetic complications. In these studies, we undertook to characterize glucose uptake and oxidative stress in adipocytes of type 2 diabetic animals and to determine whether these promote the activation of PKC-delta. The adipocytes used were isolated either from C57Bl/6J mice that were raised on a high-fat diet (HF) and developed obesity and insulin resistance or from control animals. Basal glucose uptake significantly increased (8-fold) in HF adipocytes, and this was accompanied with upregulation of GLUT1 expression levels. Insulin-induced glucose uptake was inhibited in HF adipocytes and GLUT4 content reduced by 20% in these adipocytes. Reactive oxygen species (ROS) increased twofold in HF adipocytes compared with control adipocytes and were largely reduced with decreased glucose concentrations. At zero glucose, ROS levels were reduced to the normal levels seen in control adipocytes. The activity of PKC-delta increased twofold in HF adipocytes compared with control adipocytes and was further activated by H2O2. Moreover, PKC-delta activity was inhibited in HF adipocytes either by glucose deprivation or by treatment with the antioxidant N-acetyl-l-cysteine. In summary, we propose that increased glucose intake in HF adipocytes increases oxidative stress, which in turn promotes the activation of PKC-delta. These consequential events may be responsible, at least in part, for development of HF diet-induced insulin resistance in the fat tissue. 相似文献
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Khateeb S Flusser H Ofir R Shelef I Narkis G Vardi G Shorer Z Levy R Galil A Elbedour K Birk OS 《American journal of human genetics》2006,79(5):942-948
Infantile neuroaxonal dystrophy (INAD) is an autosomal recessive progressive neurodegenerative disease that presents within the first 2 years of life and culminates in death by age 10 years. Affected individuals from two unrelated Bedouin Israeli kindreds were studied. Brain imaging demonstrated diffuse cerebellar atrophy and abnormal iron deposition in the medial and lateral globus pallidum. Progressive white-matter disease and reduction of the N-acetyl aspartate : chromium ratio were evident on magnetic resonance spectroscopy, suggesting loss of myelination. The clinical and radiological diagnosis of INAD was verified by sural nerve biopsy. The disease gene was mapped to a 1.17-Mb locus on chromosome 22q13.1 (LOD score 4.7 at recombination fraction 0 for SNP rs139897), and an underlying mutation common to both affected families was identified in PLA2G6, the gene encoding phospholipase A2 group VI (cytosolic, calcium-independent). These findings highlight a role of phospholipase in neurodegenerative disorders. 相似文献
8.
Kantor R Katzenstein DA Efron B Carvalho AP Wynhoven B Cane P Clarke J Sirivichayakul S Soares MA Snoeck J Pillay C Rudich H Rodrigues R Holguin A Ariyoshi K Bouzas MB Cahn P Sugiura W Soriano V Brigido LF Grossman Z Morris L Vandamme AM Tanuri A Phanuphak P Weber JN Pillay D Harrigan PR Camacho R Schapiro JM Shafer RW 《PLoS medicine》2005,2(4):e112
BackgroundThe genetic differences among HIV-1 subtypes may be critical to clinical management and drug resistance surveillance as antiretroviral treatment is expanded to regions of the world where diverse non-subtype-B viruses predominate.ConclusionGlobal surveillance and genotypic assessment of drug resistance should focus primarily on the known subtype B drug-resistance mutations. 相似文献
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Deep mutational scanning provides unprecedented wealth of quantitative data regarding the functional outcome of mutations in proteins. A single experiment may measure properties (eg, structural stability) of numerous protein variants. Leveraging the experimental data to gain insights about unexplored regions of the mutational landscape is a major computational challenge. Such insights may facilitate further experimental work and accelerate the development of novel protein variants with beneficial therapeutic or industrially relevant properties. Here we present a novel, machine learning approach for the prediction of functional mutation outcome in the context of deep mutational screens. Using sequence (one-hot) features of variants with known properties, as well as structural features derived from models thereof, we train predictive statistical models to estimate the unknown properties of other variants. The utility of the new computational scheme is demonstrated using five sets of mutational scanning data, denoted “targets”: (a) protease specificity of APPI (amyloid precursor protein inhibitor) variants; (b-d) three stability related properties of IGBPG (immunoglobulin G-binding β1 domain of streptococcal protein G) variants; and (e) fluorescence of GFP (green fluorescent protein) variants. Performance is measured by the overall correlation of the predicted and observed properties, and enrichment—the ability to predict the most potent variants and presumably guide further experiments. Despite the diversity of the targets the statistical models can generalize variant examples thereof and predict the properties of test variants with both single and multiple mutations. 相似文献
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