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151.
The oxy-ferrous complex of cytochrome P450 2B4 (2B4) has been prepared at -40 degrees C with and without bound substrate [butylated hydroxytoluene (BHT)] and radiolytically one-electron cryoreduced at 77 K. Electron paramagnetic resonance (EPR) shows that in both cases the observed product of cryoreduction is the hydroperoxo-ferriheme species, indicating that the microsomal P450 contains an efficient distal-pocket proton-delivery network. In the absence of substrate, two distinct hydroperoxo-ferriheme signals are observed, reflecting the presence of two major conformational substates in the oxy-ferrous precursor. Only one species is observed when BHT is bound, indicating a more ordered active site. BHT binding also changes the g-tensor components of the hydroperoxo-ferric 2B4 intermediate, indicating that the substrate modulates the properties of this intermediate. Step annealing the cryoreduced ternary 2B4 complex at >or=175 K causes the loss of hydroperoxo-ferric 2B4 and the parallel appearance of high-spin ferric 2B4; liquid chromatography-tandem mass spectroscopy (LC-MS/MS) analysis shows that in this process BHT is quantitatively converted to two products, hydroxymethyl BHT (1) and 3-hydroxy- tert-butyl BHT (2). This implies that the hydroperoxo-ferric 2B4 prepared by cryoreduction is catalytically active and that the high-spin state observed after annealing contains an enzyme-bound product of BHT monooxygenation. The ratio of products generated during cryoreduction and annealing (6.2/1) is significantly different from the ratio (2.5/1) at ambient temperature. These findings suggest that substrate is held more rigidly relative to the oxidizing species at low temperatures and/or that dissociation of FeOOH is inhibited at low temperature. As in experiments under ambient conditions, product formation is not observed with the inactive F429H 2B4 mutant. 相似文献
152.
Five G protein-coupled receptors (S1P(1)/Edg-1, S1P(3)/Edg-3, S1P(2)/Edg-5, S1P(4)/Edg-6, and S1P(5)/Edg-8) for the intercellular lipid mediator sphingosine 1-phosphate have been cloned and characterized. We found human and mouse sequences closely related to rat S1P(5) (97% identical amino acids) and report now the characterization of the human and mouse S1P(5) gene products as encoding sphingosine 1-phosphate receptors. When HEK293T cells were cotransfected with S1P(5) and G protein DNAs, prepared membranes showed sphingosine 1-phosphate concentration-dependent increases in [gamma-(35)S]GTP binding (EC(50) = 12.7 nM). The lipid mediator inhibited forskolin-driven rises in cAMP by greater than 80% after introduction of the mouse or human S1P(5) DNAs into rat hepatoma RH7777 cells (IC(50) = 0.22 nM). This response is blocked fully by prior treatment of cultures with pertussis toxin, thus implicating signaling through G(i/o)alpha proteins. Northern blot analysis showed high expression of human S1P(5) mRNA in spleen, corpus collosum, peripheral blood leukocytes, placenta, lung, aorta, and fetal tissues. Mouse S1P(5) mRNA is also expressed in spleen and brain. Finally, we found that one enantiomer of a sphingosine 1-phosphate analogue wherein the 3-hydroxyl and 4,5-olefin are replaced by an amide functionality shows some selectivity as an agonist S1P(1) and S1P(3) vs S1P(2) and S1P(5). 相似文献
153.
154.
D K Kim D H Ryu N Lee J Y Lee J S Kim S Lee J Y Choi J H Ryu N H Kim G J Im W S Choi T K Kim 《Bioorganic & medicinal chemistry》2001,9(7):1895-1899
New sildenafil analogues with an N-acylamido group at the 5'-position of the phenyl ring, 6a--e, were prepared from the readily available starting compound 2 in four straightforward steps. Enzyme assays demonstrated that all the target compounds 6a-e showed higher PDE5 inhibitory activities than sildenafil. It was observed that the PDE5 inhibitory activity was enhanced as the chain length of R group increased, but introduction of the branched alkyl groups such as isopropyl (6d) and cyclohexyl (6e) resulted in the drop of potency compared with 6c. In particular the N-butyrylamido derivative 6c exhibited the highest PDE5 inhibitory activity, and was about 6-fold more potent than sildenafil. However, all the compounds exhibited somewhat weak selectivity (1--3-fold) over PDE6, indicating that the compounds 6a--e have intrinsically lower selectivity than sildenafil. 相似文献
155.
Synthesis and phosphodiesterase 5 inhibitory activity of novel phenyl ring modified sildenafil analogues. 总被引:2,自引:0,他引:2
D K Kim N Lee J Y Lee D H Ryu J S Kim S H Lee J Y Choi K Chang Y W Kim G J Im W S Choi T K Kim J H Ryu N H Kim K Lee 《Bioorganic & medicinal chemistry》2001,9(6):1609-1616
New sildenafil analogues containing an ether ring fused into the phenyl moiety, 6a--d and 7a--d, were efficiently synthesized from the readily available starting materials, 1a--d and 2, in five steps. Ab initio calculations indicated that introduction of a cyclic ether to the phenyl group might enhance the co-planarity of the molecule. The torsional angles were calculated to be 2--3 degrees for the 5-membered cyclic ether derivatives, 6a, 6c, 7a, and 7c, and 12--16 degrees for the 6-membered ones, 6b, 6d, 7b, and 7d. On the other hand, sildenafil showed the least co-planarity with the torsional angle of 23 degrees compared with the target compounds, 6a--d and 7a--d. In the enzyme assay, however, the in vitro PDE 5 inhibitory activity was found out to be inversely related to the degree of co-planarity. In other words, the least planar sildenafil showed the highest activity, and the most planar 5-membered cyclic ether derivatives were least active by 100--200-fold compared with sildenafil. Our study clearly demonstrated that the open chain 2'-alkoxy group of the phenyl ring, although less effective for inducing the co-planarity, seemed to act as a much better lipophilic requirement than the cyclic alkoxy moiety. 相似文献
156.
157.
Streptococcus pyogenes is commonly found on pharynx, mouth and rarely on skin, lower gastrointestinal tract. It is a potential pathogen causing tonsillitis, pneumonia, endocarditis. The present study was undertaken to study the effects of low shear modeled microgravity on growth, morphology, antibiotic resistance, cross-stress resistance to various stresses and alteration in gene expression of S. pyogenes. The growth analysis performed using UV–Visible spectroscopy indicated decrease in growth of S. pyogenes under low shear modeled microgravity. Morphological analysis by Bio-transmission electron microscopy (TEM), Bio-scanning electron microscopy (SEM) did not reveal much difference between normal and low shear modeled microgravity grown S. pyogenes. The sensitivity of S. pyogenes to antibiotics ampicillin, penicillin, streptomycin, kanamycin, hygromycin, rifampicin indicates that the bacterium is resistant to hygromycin. Further S. pyogenes cultured under low shear modeled microgravity was found to be more sensitive to ampicillin and rifampicin as compared with normal gravity grown S. pyogenes. The bacteria were tested for the acid, osmotic, temperature and oxidative cross stress resistances. The gene expression of S. pyogenes under low shear modeled microgravity analyzed by microarray revealed upregulation of 26 genes and down regulation of 22 genes by a fold change of 1.5. 相似文献
158.
Changku Kang Jong‐Yeol Moon Sang‐Im Lee Piotr G. Jablonski 《Biological journal of the Linnean Society. Linnean Society of London》2014,111(4):900-904
Camouflage conceals animals from predators and depends on the interplay between the morphology and behaviour of animals. Behavioural elements of animals, such as the choice of a resting spot or posture, are important for effective camouflage, as well as the animals’ cryptic appearance. To date, the type of sensory input that mediates resting site choice remains poorly understood. Previously, we showed that bark‐like moths perceive and rely on bark structure to seek out cryptic resting positions and body orientations on tree trunks. In the present study, we investigated the sensory organs through which moths perceive the structure of bark when positioning their bodies in adaptive resting orientations. We amputated (or blocked) each one of the hypothetical sensory organs in moths (antennae, forelegs, wings, and eyes) and tested whether they were still able to perceive bark structure properly and adopt adaptive resting orientations. We found that visual information or stimulation is crucial for adaptively orienting their bodies when resting and tactile information from wings may play an additional role. The present study reveals multimodal information use by moths to achieve visual camouflage and highlights the sensory mechanism that is responsible for the adaptive behaviour of cryptic insects. © 2014 The Linnean Society of London, Biological Journal of the Linnean Society, 2014, 111 , 900–904. 相似文献
159.
The noncovalently associated 125I-insulin-receptor complex was isolated from human erythrocyte membranes after allowing 125I-insulin to interact with the membranes followed by extraction of the 125I-insulin-receptor complex with Triton X-102 or, alternatively, by complete solubilization of the membranes with sodium dodecyl sulfate (SDS), removal of SDS, and then treatment of the solubilized sample with 125I-insulin. Sepharose CL-6B column chromatography of the 125I-insulin-receptor complex obtained by both of the above procedures yielded a highly radioactive 140,000-Da complex which was dissociated into small peptides when subjected to SDS-polyacrylamide gel electrophoresis. In contrast, when the 125I-insulin-treated membrane sample was extracted with Triton X-102, purified by DEAE-Sephacel ion exchange chromatography, covalently cross-linked with disuccinimidyl suberate, and then subjected to SDS-polyacrylamide gel electrophoresis, a highly radioactive component with Mr = 53,000 was obtained. On the other hand, when the Triton X-102-solubilized membrane receptor sample was fractionated by DEAE-Sephacel ion exchange chromatography, complexed with 125I-insulin, covalently crosslinked, and then applied to a Sepharose CL-6B column, a 95,000-Da complex with high specific radioactivity was obtained. Upon SDS-polyacrylamide gel electrophoresis, the 95,000-Da complex was dissociated into a 53,000-Da component which appeared identical with that obtained from the receptor complex described above which was obtained by direct interaction of the membranes with 125I-insulin. 相似文献
160.
Carolina Elejalde-Palmett Ignacio Martinez San Segundo Imène Garroum Laurence Charrier Damien De Bellis Antonio Mucciolo Aurore Guerault Jie Liu Viktoria Zeisler-Diehl Asaph Aharoni Lukas Schreiber Bénédicte Bakan Mads H. Clausen Markus Geisler Christiane Nawrath 《Current biology : CB》2021,31(10):2111-2123.e9
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