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151.
Fucini RV Hanan EJ Romanowski MJ Elling RA Lew W Barr KJ Zhu J Yoburn JC Liu Y Fahr BT Fan J Lu Y Pham P Choong IC VanderPorten EC Bui M Purkey HE Evanchik MJ Yang W 《Bioorganic & medicinal chemistry letters》2008,18(20):5648-5652
A series of 2-amino-pyrazolopyridines was designed and synthesized as Polo-like kinase (Plk) inhibitors based on a low micromolar hit. The SAR was developed to provide compounds exhibiting low nanomolar inhibitory activity of Plk1; the phenotype of treated cells is consistent with Plk1 inhibition. A co-crystal structure of one of these compounds with zPlk1 confirms an ATP-competitive binding mode. 相似文献
152.
Benda R Tse Sum Bui B Schünemann V Florentin D Marquet A Trautwein AX 《Biochemistry》2002,41(50):15000-15006
Biotin synthase, the enzyme that catalyzes the last step of the biosynthesis of biotin, contains only [2Fe-2S](2+) clusters when isolated under aerobic conditions. Previous results showed that reconstitution with an excess of FeCl(3) and Na(2)S under reducing and anaerobic conditions leads to either [4Fe-4S](2+), [4Fe-4S](+), or a mixture of [4Fe-4S](2+) and [2Fe-2S](2+) clusters. To determine whether any of these possibilities or other different cluster configuration could correspond to the physiological in vivo state, we have used (57)Fe M?ssbauer spectroscopy to investigate the clusters of biotin synthase in whole cells. The results show that, in aerobically grown cells, biotin synthase contains a mixture of [4Fe-4S](2+) and [2Fe-2S](2+) clusters. A mixed [4Fe-4S](2+):[2Fe-2S](2+) cluster form has already been observed under certain in vitro conditions, and it has been proposed that both clusters might each play a significant role in the mechanism of biotin synthase. Their presence in vivo is now another argument in favor of this mixed cluster form. 相似文献
153.
The Brevibacterium R 312 strain has an amidase with a wide substrate spectrum previously named acetamidase. The study of its activity showed that this enzyme was able to hydrolyze a large number of amides into their corresponding organic acids. The affinity of this enzyme for the substrates varied according to the length of the carbon chain and the spatial crowding of the molecule. The comparison of the specific rates of hydrolysis showed that propionamide was the amide substrate most quickly hydrolyzed.We confirmed the inducible feature of this enzyme and noted that only acetamide and N-methylacetamide were inducers of this enzyme among the compounds tested. Thioacetamide and N-methylpropionamide, both as amide analogues, were shown to inhibit the biosynthesis of acetamidase. Similarly, the organic acids, products of the hydrolysis reaction, showed a strong repression action on the biosynthesis of the enzyme. 相似文献
154.
The mitogen-activated protein kinase p38 plays a critical role in inflammation, cell cycle progression, differentiation, and apoptosis. The activity of p38 is stimulated by a variety of extracellular stimuli, such as the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha), and subjected to regulation by other intracellular signaling pathways, including the cyclic AMP (cAMP) pathway. Yet the underlying mechanism by which cAMP inhibits p38 activation is unknown. Here we show that the induction of dynein light chain (DLC) by cAMP response element-binding protein (CREB) is required for cAMP-mediated inhibition of p38 activation. cAMP inhibits p38 activation via the protein kinase A-CREB pathway. The inhibition is mediated by the CREB target gene Dlc, whose protein product, DLC, interferes with the formation of the MKK3/6-p38 complex, thereby suppressing p38 phosphorylation activation by MKK3/6. The inhibition of p38 activation by cAMP leads to suppression of NF-kappaB activity and promotion of apoptosis in response to TNF-alpha. Thus, our results identify DLC as a novel inhibitor of the p38 pathway and provide a molecular mechanism by which cAMP suppresses p38 activation and promotes apoptosis. 相似文献
155.
Differences in resolution of mwr-containing plasmid dimers mediated by the Klebsiella pneumoniae and Escherichia coli XerC recombinases: potential implications in dissemination of antibiotic resistance genes 下载免费PDF全文
Bui D Ramiscal J Trigueros S Newmark JS Do A Sherratt DJ Tolmasky ME 《Journal of bacteriology》2006,188(8):2812-2820
Xer-mediated dimer resolution at the mwr site of the multiresistance plasmid pJHCMW1 is osmoregulated in Escherichia coli containing either the Escherichia coli Xer recombination machinery or Xer recombination elements from K. pneumoniae. In the presence of K. pneumoniae XerC (XerC(Kp)), the efficiency of recombination is lower than that in the presence of the E. coli XerC (XerC(Ec)) and the level of dimer resolution is insufficient to stabilize the plasmid, even at low osmolarity. This lower efficiency of recombination at mwr is observed in the presence of E. coli or K. pneumoniae XerD proteins. Mutagenesis experiments identified a region near the N terminus of XerC(Kp) responsible for the lower level of recombination catalyzed by XerC(Kp) at mwr. This region encompasses the second half of the predicted alpha-helix B and the beginning of the predicted alpha-helix C. The efficiencies of recombination at other sites such as dif or cer in the presence of XerC(Kp) or XerC(Ec) are comparable. Therefore, XerC(Kp) is an active recombinase whose action is impaired on the mwr recombination site. This characteristic may result in restriction of the host range of plasmids carrying this site, a phenomenon that may have important implications in the dissemination of antibiotic resistance genes. 相似文献
156.
157.
Rat pancreatic acinar cells AR 4-2J respond to dexamethasone by differentiation and a decreased proliferation rate. Protein labelling by [3H]-mevalonolactone, used as a precursor of farnesyl and geranylgeranyl isoprenoid groups, was increased in the presence of dexamethasone. In these same conditions, dexamethasone decreased HMG-CoA reductase activity, leading to a diminished isotopic dilution of the mevalonate precursor. As ras proteins, known to be involved in the regulation of proliferation and differentiation, need to be farnesylated for full biological function, we also measured the level of farnesyl transferase activity and found a dose-dependent decrease in dexamethasone treated cells. Despite these negative effects of dexamethasone on mevalonate pathway, there was no appearance of non-isoprenylated forms of ras, indicating that the level of isoprenoid precursors and farnesyl transferase activity were not limiting in this model. 相似文献
158.
Transport of proteins along the exocytotic pathway is primarily achieved by vesicular intermediates. Two proteins, Golgi SNAREs of 27 kDa, GS27, and of 28 kDa, GS28 (HGMW-approved nomenclature GOSR2 and GOSR1, respectively), are important trafficking membrane proteins between the endoplasmic reticulum and the Golgi and between Golgi subcompartments. Here, we present the human GS27 and GS28 cDNA sequences. They encode predicted proteins of 212 and 250 amino acids, respectively. Chromosomal mapping analyses reveal that human GS27 is located on chromosome 17q21 and GS28 on approximately 17q11. The chromosomal location of GS27 near a locus implicated in familial essential hypertension and its known function in trafficking indicate that it is a potential candidate gene for this disease. 相似文献
159.
Wolff M Seemann M Tse Sum Bui B Frapart Y Tritsch D Garcia Estrabot A Rodríguez-Concepción M Boronat A Marquet A Rohmer M 《FEBS letters》2003,541(1-3):115-120
The last enzyme (LytB) of the methylerythritol phosphate pathway for isoprenoid biosynthesis catalyzes the reduction of (E)-4-hydroxy-3-methylbut-2-enyl diphosphate into isopentenyl diphosphate and dimethylallyl diphosphate. This enzyme possesses a dioxygen-sensitive [4Fe-4S] cluster. This prosthetic group was characterized in the Escherichia coli enzyme by UV/visible and electron paramagnetic resonance spectroscopy after reconstitution of the purified protein. Enzymatic activity required the presence of a reducing system such as flavodoxin/flavodoxin reductase/reduced nicotinamide adenine dinucleotide phosphate or the photoreduced deazaflavin radical. 相似文献
160.
A specific genetic background is required for acquisition and expression of virulence factors in Escherichia coli 总被引:1,自引:0,他引:1
Escobar-Páramo P Clermont O Blanc-Potard AB Bui H Le Bouguénec C Denamur E 《Molecular biology and evolution》2004,21(6):1085-1094
In bacteria, the evolution of pathogenicity seems to be the result of the constant arrival of virulence factors (VFs) into the bacterial genome. However, the integration, retention, and/or expression of these factors may be the result of the interaction between the new arriving genes and the bacterial genomic background. To test this hypothesis, a phylogenetic analysis was done on a collection of 98 Escherichia coli/Shigella strains representing the pathogenic and commensal diversity of the species. The distribution of 17 VFs associated to the different E. coli pathovars was superimposed on the phylogenetic tree. Three major types of VFs can be recognized: (1) VFs that arrive and are expressed in different genetic backgrounds (such as VFs associated with the pathovars of mild chronic diarrhea: enteroaggregative, enteropathogenic, and diffusely-adhering E. coli), (2) VFs that arrive in different genetic backgrounds but are preferentially found, associated with a specific pathology, in only one particular background (such as VFs associated with extraintestinal diseases), and (3) VFs that require a particular genetic background for the arrival and expression of their virulence potential (such as VFs associated with pathovars typical of severe acute diarrhea: enterohemorragic, enterotoxigenic, and enteroinvasive E. coli strains). The possibility of a single arrival of VFs by chance, followed by a vertical transmission, was ruled out by comparing the evolutionary histories of some of these VFs to the strain phylogeny. These evidences suggest that important changes in the genome of E. coli have occurred during the diversification of the species, allowing the virulence factors associated with severe acute diarrhea to arrive in the population. Thus, the E. coli genome seems to be formed by an "ancestral" and a "derived" background, each one responsible for the acquisition and expression of different virulence factors. 相似文献