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301.
Szénási G Vegh M Szabo G Kertesz S Kapus G Albert M Greff Z Ling I Barkoczy J Simig G Spedding M Harsing LG 《Neurochemistry international》2008,52(1-2):166-183
AMPA receptors are fast ligand-gated members of glutamate receptors in neuronal and many types of non-neuronal cells. The heterotetramer complexes are assembled from four subunits (GluR1-4) in region-, development- and function-selective patterns. Each subunit contains three extracellular domains (a large amino terminal domain, an agonist-binding domain and a transducer domain), and three transmembrane segments with a loop (pore forming domain), as well as the intracellular carboxy terminal tail (traffic and conductance regulatory domain). The binding of the agonist (excitatory amino acids and their derivatives) initiates conformational realignments, which transmit to the transducer domain and membrane spanning segments to gate the channel permeable to Na+, K+ and more or less to Ca2+. Several 2,3-benzodiazepines act as non-competitive antagonists of the AMPA receptor (termed also negative allosteric modulators), which are thought to bind to the transducer domains and inhibit channel gating. Analysing their effects in vitro, it has been possible to recognize a structure-activity relationship, and to describe the critical parts of the molecules involved in their action at AMPA receptors. Blockade of AMPA receptors can protect the brain from apoptotic and necrotic cell death by preventing neuronal excitotoxicity during pathophysiological activation of glutamatergic neurons. Animal experiments provided evidence for the potential usefulness of non-competitive AMPA antagonists in the treatment of human ischemic and neurodegenerative disorders including stroke, multiple sclerosis, Parkinson's disease, periventricular leukomalacia and motoneuron disease. 2,3-benzodiazepine AMPA antagonists can protect against seizures, decrease levodopa-induced dyskinesia in animal models of Parkinson's disease demonstrating their utility for the treatment of a variety of CNS disorders. 相似文献
302.
303.
Biogenesis of cytosolic ribosomes requires the essential iron-sulphur protein Rli1p and mitochondria
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Kispal G Sipos K Lange H Fekete Z Bedekovics T Janáky T Bassler J Aguilar Netz DJ Balk J Rotte C Lill R 《The EMBO journal》2005,24(3):589-598
Mitochondria perform a central function in the biogenesis of cellular iron-sulphur (Fe/S) proteins. It is unknown to date why this biosynthetic pathway is indispensable for life, the more so as no essential mitochondrial Fe/S proteins are known. Here, we show that the soluble ATP-binding cassette (ABC) protein Rli1p carries N-terminal Fe/S clusters that require the mitochondrial and cytosolic Fe/S protein biogenesis machineries for assembly. Mutations in critical cysteine residues of Rli1p abolish association with Fe/S clusters and lead to loss of cell viability. Hence, the essential character of Fe/S clusters in Rli1p explains the indispensable character of mitochondria in eukaryotes. We further report that Rli1p is associated with ribosomes and with Hcr1p, a protein involved in rRNA processing and translation initiation. Depletion of Rli1p causes a nuclear export defect of the small and large ribosomal subunits and subsequently a translational arrest. Thus, ribosome biogenesis and function are intimately linked to the crucial role of mitochondria in the maturation of the essential Fe/S protein Rli1p. 相似文献
304.
Mapping modifiers affecting muscularity of the myostatin mutant (Mstn(Cmpt-dl1Abc)) compact mouse 总被引:1,自引:0,他引:1
The hypermuscular Compact phenotype was first noted in a line of mice selected for high body weight and protein content. A new line, based on mice showing the Compact phenotype, was formed and selected for maximum expression of the Compact phenotype. Previously we mapped and identified a 12-bp deletion in the myostatin gene, denoted Mstn(Cmpt-dl1Abc), which can be considered as a major gene responsible for the hypermuscular phenotype. Genetic analysis revealed that full expression of the hypermuscular phenotype requires the action of modifier loci in addition to Mstn(Cmpt-dl1Abc). To map these modifier loci, an interspecific F(2) population was generated between Comp9, an inbred line homozygous for Mstn(Cmpt-dl1Abc), and CAST/Ei, an inbred line generated from Mus musculus castaneus. Selective DNA pooling and genotyping, separately by gender, was carried out within a subpopulation of the F(2) consisting of individuals homozygous for Mstn(Cmpt-dl1Abc). Significant association with hypermuscularity at a false discovery rate (FDR) of 0.05 was found for markers on chromosomes 3, 5, 7, 11, 16, and X. In all cases, the marker allele derived from the Comp9 parent showed a higher frequency in the hypermuscular group and the CAST/Ei allele in the normal group. The modifier loci apparently exerted their effects on muscularity only in the presence of Mstn(Cmpt-dl1Abc). 相似文献
305.
An effective epimerization of the normal estrone 3-methyl and 3-benzyl ethers by using o-phenylenediamine and AcOH made the possibility for facile entry into the 13alpha-estrone series. Combination of this synthetic methodology with an isolation step carried out by means of the Girard-P reagent, the corresponding ethers of 13-epi-estrone were obtained in excellent yields. The 3-hydroxy and 3-methoxy D-homoestrone derivatives in both the normal and the 13alpha-estrone series were then synthesized and tested in vitro in a radioligand-binding assay. The estrogen receptor recognizes these compounds, but their relative binding affinities (RBAs) are lower than that of the reference compound 3,17beta-estradiol. The progesterone receptor-binding affinities of the four D-homo derivatives were also tested showing low values for 13alpha-D-homoestrone and its 3-methyl ether. Pharmacologically, these 13alpha-D-homoestrone derivatives are estrogen receptor-selective molecules. 相似文献
306.
Palczewska M Groves P Batta G Heise B Kuźnicki J 《Protein science : a publication of the Protein Society》2003,12(1):180-184
The domain organization of calretinin (CR) was predicted to involve all six EF-hand motifs (labeled I to VI) condensed into a single domain, as characterized for calbindin D28k (Calb), the closest homolog of calretinin. Unperturbed (1)H,(15)N HSQC NMR spectra of a (15)N-labeled calretinin fragment (CR III-VI, residues 100-271) in the presence of the unlabeled complimentary fragment (CR I-II, residues 1-100) show that these fragments do not interact. Size exclusion chromatography and affinity chromatography data support this conclusion. The HSQC spectrum of (15)N-labeled CR is similar to the overlaid spectra of individual (15)N-labeled CR fragments (CR I-II and CR III-VI), also suggesting that these regions do not interact within intact CR. In contrast to these observations, but in accordance with the Calb studies, we observed interactions between other CR fragments: CR I (1-60) with CR II-VI (61-271), and CR I-III (1-142) with CR IV-VI (145-271). We conclude that CR is formed from at least two independent domains consisting of CR I-II and CR III-VI. The differences in domain organization of Calb and CR may explain the specific target interaction of Calb with caspase-3. Most importantly, the comparison of CR and Calb domain organizations questions the value of homologous modeling of EF-hand proteins, and perhaps of other protein families. 相似文献
307.
Bajor Z Sági G Tegyey Z Kraicsovits F 《Nucleosides, nucleotides & nucleic acids》2003,22(10):1963-1983
Three chimeric dimer synthons (oeg_t(NH)T, oeg_up(NH)T and oeg_uh(NH)T) containing thymine (t), 5-(1-propynyl)-uracil (up) and 5-(1-hexyn-1-yl)-uracil (uh) PNA units with N-(2-hydroxyethyl)glycine (oeg) backbone were synthesized in solution and incorporated into T20 oligonucleotide analogues, using standard P-amidite chemistry. Insertion of dimer blocks led to destabilization of duplexes with dA20 target. The smallest Tm drops were found for chimeras containing oeg_up(NH)T dimers. Incorporation of the chimeric synthons into the 3'-end of T20 brought about growing resistance to 3'-exonucleolytic (SV PDE) cleavage in the order of oeg_t(NH)T < oeg_up(NH)T < oeg_uh(NH)T. Due to different endonuclease activities of 3'- and 5'-exonucleases applied, placing of five consecutive dimers at the 5'-terminus resulted in a relatively smaller, but also side-chain dependent, stabilization towards the hydrolysis by 5'-exonuclease (BS PDE). Neither exonucleases (SV and BS PDE) nor an endonuclease (Nuclease P1) could hydrolyse the unnatural phosphodiester bond linking the 3'-OH of thymidine to the terminal OH of N-(2-hydroxyethyl)glycine PNA backbone. 相似文献
308.
Tiamulin, a diterpene antibiotic, is used for treatment of pulmonary and gastrointestinal infections in swine and poultry. Combined administration of tiamulin and ionophores (e.g. monensin) to farm animals may lead to intoxication manifested in severe clinical symptoms. Tiamulin metabolite complex with cytochrome P450 has been suggested to be the basis of drug-interactions. However, the formation of metabolic intermediate complex is questionable. The effect of tiamulin-treatment on cytochrome P450 activities was investigated in rats. Ethylmorphine and aminopyrine N-demethylation activities as well as monensin metabolism (O-demethylation) increased in liver microsomes of tiamulin-treated (200 mg/kg) animals. CYP3A1 induction caused by tiamulin was confirmed by the results of Western blot analysis. To test metabolic intermediate complex formation as a result of tiamulin treatment, cytochrome P450 activities were also determined in the presence of potassium ferricyanide. The findings together with those of in vitro complex formation suggested that formation of metabolic intermediate complexes of tiamulin with cytochrome P450 could be excluded. On the other hand, the results of inhibition studies showed significant decrease of ethylmorphine or aminopyrine as well as monensin demethylation in the presence of tiamulin. Our results proved that tiamulin has dual effect on cytochromes P450. It is able to induce and directly inhibit CYP3A enzymes, which are predominantly responsible for monensin O-demethylation. The direct effect of tiamulin as an inhibitor might play a more important role in toxicity than its putative effect as a chemical inducer of CYP3A enzymes. 相似文献
309.
Törökné A Asztalos M Bánkiné M Bickel H Borbély G Carmeli S Codd GA Fastner J Huang Q Humpage A Metcalf JS Rábai E Sukenik A Surányi G Vasas G Weiszfeiler V 《Analytical biochemistry》2004,332(2):280-284
The hepatotoxin cylindrospermopsin (CYN) is a potent inhibitor of protein synthesis in mammalian cells. It is produced by freshwater cyanobacterial blooms in countries such as Australia, the United States, Israel, Thailand, and Brazil. An interlaboratory comparison was organized as a first step to evaluate the measurement of CYN in lyophilized cyanobacterial cells. Six laboratories from Europe, Israel, and Australia participated in the trial. All of the methods used for extraction of the toxin and the high-performance liquid chromatography (HPLC) analysis were satisfactory on the basis of statistical evaluation, according to ISO standards 5725-1 and -2. Further comparison of all the extraction methods by the organizer indicated that the most effective extraction procedure used 5% formic acid to prevent interference in chromatograms by contaminant compounds when analyzed using HPLC employing isocratic conditions of 5% (v/v) aqueous methanol plus 0.1% (v/v) trifluoroacetic acid as the mobile phase. 相似文献
310.
Lange H Mühlenhoff U Denzel M Kispal G Lill R 《The Journal of biological chemistry》2004,279(28):29101-29108
Mitochondria are responsible for the synthesis of both iron-sulfur clusters and heme, but the potential connection between the two major iron-consuming pathways is unknown. Here, we have shown that mutants in the yeast mitochondrial iron-sulfur cluster (ISC) assembly machinery displayed reduced cytochrome levels and diminished activity of the heme-containing cytochrome c oxidase, in addition to iron-sulfur protein defects. In contrast, mutants in components of the mitochondrial ISC export machinery, which are specifically required for maturation of cytosolic iron-sulfur proteins, were not decreased in heme synthesis or cytochrome levels. Heme synthesis does not involve the function of mitochondrial ISC components, because immunological depletion of various ISC proteins from mitochondrial extracts did not affect the formation and amounts of heme. The heme synthesis defects of ISC mutants were found in vivo in isolated mitochondria and in mitochondrial detergent extracts and were confined to an inhibition of ferrochelatase, the enzyme catalyzing the insertion of iron into protoporphyrin IX. In support of these findings, immunopurification of ferrochelatase from ISC mutants restored its activity to wild-type levels. We conclude that the reversible inhibition of ferrochelatase is the molecular reason for the heme deficiency in ISC assembly mutants. This inhibitory mechanism may be used for regulation of iron distribution between the two iron-consuming processes. 相似文献