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121.
Yuan H Chai SC Lam CK Howard Xu H Ye QZ 《Bioorganic & medicinal chemistry letters》2011,21(11):3395-3398
Drug resistance in Gram-negative bacteria, such as Acinetobacter baumannii, is emerging as a significant healthcare problem. New antibiotics with a novel mechanism of action are urgently needed to overcome the drug resistance. Methionine aminopeptidase (MetAP) carries out an essential cotranslational methionine excision in many bacteria and is a potential target to develop such novel antibiotics. Two putative MetAP genes were identified in A. baumannii genome, but whether they actually function as MetAP enzymes was not known. Therefore, we established an efficient E. coli expression system for their production as soluble and metal-free proteins for biochemical characterization. We demonstrated that both could carry out the metal-dependent catalysis and could be activated by divalent metal ions with the order Fe(II) ≈ Ni(II) > Co(II) > Mn(II) for both. By using a set of metalloform-selective inhibitors discovered on other MetAP enzymes, potency and metalloform selectivity on the A. baumannii MetAP proteins were observed. The similarity of their catalysis and inhibition to other MetAP enzymes confirmed that both may function as competent MetAP enzymes in A. baumannii and either or both may serve as the potential drug target. 相似文献
122.
目的:探讨有氧运动对高蛋氨酸饮食大鼠血浆总一氧化氮合成酶(T-NOS)、一氧化氮(NO)、内皮素(ET)和NO/ET系统的影响。方法:雄性Wistar大鼠随机分为正常饮食对照组(对照组)、高蛋氨酸饲料组(高蛋氨酸组)和有氧运动+高蛋氨酸饮食组(运动干预组)。对照组喂饲普通饲料,高蛋氨酸组和运动干预组喂饲含3%蛋氨酸的高蛋氨酸饲料,运动干预组同时每日同时进行90 min无负重游泳运动,实验共8周。分别测定血浆同型半胱氨酸(Hcy)、ET、NO和T-NOS含量。结果:高蛋氨酸组血浆Hcy含量显著高于对照组达2倍以上(P〈0.01),T-NOS和NO含量显著降低,ET含量显著升高(P〈0.01),且NO/ET比值均显著降低(P〈0.05);与高蛋氨酸组相比,运动干预组血浆Hcy含量显著下降(P〈0.05),T-NOS,NO含量和NO/ET比值显著升高(P〈0.05),且与对照组相比上述各项指标无显著差异。结论:高蛋氨酸饮食可诱发大鼠高同型半胱氨酸血症,血浆NO/ET失衡;有氧运动可降低高蛋氨酸饮食大鼠血浆Hcy水平,改善NO/ET失衡,预防高同型半胱氨酸血症。 相似文献
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Lountos GT Jobson AG Tropea JE Self CR Zhang G Pommier Y Shoemaker RH Waugh DS 《Journal of structural biology》2011,(3):292-301
Chk2 (checkpoint kinase 2) is a serine/threonine kinase that participates in a series of signaling networks responsible for maintaining genomic integrity and responding to DNA damage. The development of selective Chk2 inhibitors has recently attracted much interest as a means of sensitizing cancer cells to current DNA-damaging agents used in the treatment of cancer. Additionally, selective Chk2 inhibitors may reduce p53-mediated apoptosis in normal tissues, thereby helping to mitigate adverse side effects from chemotherapy and radiation. Thus far, relatively few selective inhibitors of Chk2 have been described and none have yet progressed into clinical trials. Here, we report crystal structures of the catalytic domain of Chk2 in complex with a novel series of potent and selective small molecule inhibitors. These compounds exhibit nanomolar potencies and are selective for Chk2 over Chk1. The structures reported here elucidate the binding modes of these inhibitors to Chk2 and provide information that can be exploited for the structure-assisted design of novel chemotherapeutics. 相似文献
126.
Li C Wang X Wang G Wu C Li N 《Comparative biochemistry and physiology. Part D, Genomics & proteomics》2011,6(3):264-270
Roxarsone is a commonly used additive in chicken (Gallus gallus) industry. However, little is known on the intrinsic molecular mechanism via which the growth performance of birds improves. This study was therefore performed to investigate the expression profiles of genes induced by roxarsone. Fifty-six broiler chickens were divided into two groups, namely treated and untreated with roxarsone. The treated group was provided a diet of 45.4 mg/kg roxarsone medication and the other group acted as control. Data analysis showed that roxarsone consistently and significantly (P < 0.05) increased chicken growth performance. In addition to this a significant (P < 0.05) increase of arsenic residue in liver has been seen. Microarray expression analysis of 8935 genes in liver showed that 22 genes (10 up- and 12 down-regulated) had altered expression throughout the experimental periods. Two novel genes (GenBank accession no. GU724343 and GU724344) were cloned through rapid amplification of cDNA ends (RACE). Gene GU724343 was predicted to encode an unidentified protein and the second gene GU724344 was presumed to encode a new member of immunoglobulin-like receptor (CHIR) family. Our results suggested for the first time that the role of roxarsone could be mainly to modify the expression levels of cell growth, immunity/defense and energy metabolism associated genes, as a result promoting animal growth. Further research on these genes should help to increase the knowledge of improving animal productivity safely and effectively. 相似文献
127.
Sahgal N Canham LN Konno T Wolfe MW Soares MJ 《Differentiation; research in biological diversity》2005,73(9-10):452-462
Trophoblast giant cells are located at the maternal-embryonic interface and have fundamental roles in the invasive and endocrine phenotypes of the rodent placenta. In this report, we describe the experimental modulation of trophoblast stem cell and trophoblast giant cell phenotypes using the Rcho-1 trophoblast cell model. Rcho-1 trophoblast cells can be manipulated to proliferate or differentiate into trophoblast giant cells. Differentiated Rcho-1 trophoblast cells are invasive and possess an endocrine phenotype, including the production of members of the prolactin (PRL) family. Dimethyl sulfoxide (DMSO), a known differentiation-inducing agent, was found to possess profound effects on the in vitro development of trophoblast cells. Exposure to DMSO, at non-toxic concentrations, inhibited trophoblast giant cell differentiation in a dose-dependent manner. These concentrations of DMSO did not significantly affect trophoblast cell proliferation or survival. Trophoblast cells exposed to DMSO exhibited an altered morphology; they were clustered in tightly packed colonies. Trophoblast giant cell formation was disrupted, as was the expression of members of the PRL gene family. The effects of DMSO were reversible. Removal of DMSO resulted in the formation of trophoblast giant cells and expression of the PRL gene family. The phenotype of the DMSO-treated cells was further determined by examining the expression of a battery of genes characteristic of trophoblast stem cells and differentiated trophoblast cell lineages. DMSO treatment had a striking stimulatory effect on eomesodermin expression and a reciprocal inhibitory effect on Hand1 expression. In summary, DMSO reversibly inhibits trophoblast differentiation and induces a quiescent state, which mimics some but not all aspects of the trophoblast stem cell phenotype. 相似文献
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Enolase-phosphatase E1 (MASA) is a bifunctional enzyme in the ubiquitous methionine salvage pathway that catalyzes the continuous reactions of 2,3-diketo-5-methylthio-1-phosphopentane to yield the aci-reductone metabolite using Mg2+ as cofactor. In this study, we have determined the crystal structure of MASA and its complex with a substrate analog to 1.7A resolution by multi-wavelength anomalous diffraction and molecular replacement techniques, respectively. The structures support the proposed mechanism of phosphatase activity and further suggest the probable mechanism of enolization. We establish a model for substrate binding to describe in detail the enzymatic reaction and the formation of the transition state, which will provide insight into the reaction mechanisms of other enzymes in the same family. 相似文献
130.
Eukaryotic methionine aminopeptidase type 2 (MetAP2, MetAP2 gene (MAP2)), together with eukaryotic MetAP1, cotranslationally hydrolyzes initiator methionine from nascent polypeptides when the side chain of the second residue is small and uncharged. In this report, we took advantage of the yeast (Saccharomyces cerevisiae) map1 null strain's reliance on MetAP2 activity for the growth and viability to provide evidence of the first dominant negative mutant of eukaryotic MetAP2. Replacement of the conserved His(174) with alanine within the C-terminal catalytic domain of yeast MetAP2 eliminated detectable catalytic activity against a peptide substrate in vitro. Overexpression of MetAP2 (H174A) under the strong GPD promoter in a yeast map1 null strain was lethal, whereas overexpression under the weaker GAL1 promoter slightly inhibited map1 null growth. Deletion mutants further revealed that the N-terminal region of MetAP2 (residues 2-57) is essential but not sufficient for MetAP2 (H174A) to fully interfere with map1 null growth. Together, these results indicate that catalytically inactive MetAP2 is a dominant negative mutant that requires its N-terminal region to interfere with wild-type MetAP2 function. 相似文献