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141.
A theoretical study of alkene epoxidation, by the high-valent iron-oxo species (Compound I) of cytochrome P450, reveals a multi-state scenario in which the different products are generated in a state specific manner. All the low-spin doublet state processes are effectively concerted epoxide producing pathways. By contrast, all the high-spin quartet processes are stepwise and either lead to epoxide that does not conserve the isomeric identity of the alkene (cis or trans), or/and to by-products such as suicidal complexes and aldehydes. The product/state inventory is the following: (a) The epoxide with conserved alkene stereochemistry is generated from the low-spin doublet states of Compound I in a nonsynchronous but effectively concerted pathways that involve carbon radical (with Fe(III) and Fe(IV)) and cationic intermediates. (b) The epoxide with scrambled alkene stereochemistry is obtained from the quartet high-spin radical intermediate (with Fe(IV)). (c) The suicidal complex, with a C-N bond between the alkene and the porphyrin, is obtained from the high-spin cationic state that possesses one electron in the sigma xy* orbital (the antibonding Fe-N orbital made from dxy and nitrogen sigma-hybrids). (d) The aldehyde by-product is obtained from the high-spin cationic state that possesses one electron in the sigma xy* orbital (the antibonding O-Fe-S orbital made from dz2 and the oxo and sulfur sigma-hybrids). Factors controlling the competition between these processes are discussed. 相似文献
142.
Solution-phase and solid-phase permanganate oxidation reactions of thymine acetic acid were investigated by spectroscopy. The spectral data showed the formation of a stable organomanganese intermediate, which was responsible for the rise in the absorbance at 420 nm. This result enables unambiguous interpretation of the absorbance change at 420 nm, as the intermediate permanganate ions could be isolated on the solid supports. 相似文献
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Vaz RJ Gao Z Pribish J Chen X Levell J Davis L Albert E Brollo M Ugolini A Cramer DM Cairns J Sides K Liu F Kwong J Kang J Rebello S Elliot M Lim H Chellaraj V Singleton RW Li Y 《Bioorganic & medicinal chemistry letters》2004,14(24):6053-6056
We exploit the concept of using hydrogen bonds to link multiple ligands for maintaining simultaneous interactions with polyvalent binding sites. This approach is demonstrated by the syntheses and evaluation of pseudo-bivalent ligands as potent inhibitors of human β-tryptase. 相似文献
145.
Airenne TT Torkko JM Van den plas S Sormunen RT Kastaniotis AJ Wierenga RK Hiltunen JK 《Journal of molecular biology》2003,327(1):47-59
Candida tropicalis enoyl thioester reductase Etr1p and the Saccharomyces cerevisiae homologue Mrf1p catalyse the NADPH-dependent reduction of trans-2-enoyl thioesters in mitochondrial fatty acid synthesis (FAS). Unlike prokaryotic enoyl thioester reductases (ETRs), which belong to the short-chain dehydrogenases/reductases (SDR), Etr1p and Mrf1p represent structurally distinguishable ETRs that belong to the medium-chain dehydrogenases/reductases (MDR) superfamily, indicating independent origin of two separate classes of ETRs. The crystal structures of Etr1p, the Etr1p-NADPH complex and the Etr1Y79Np mutant were refined to 1.70A, 2.25A and 2.60A resolution, respectively. The native fold of Etr1p was maintained in Etr1Y79Np, but the mutant had only 0.1% of Etr1p catalytic activity remaining and failed to rescue the respiratory deficient phenotype of the mrf1Delta strain. Mutagenesis of Tyr73 in Mrf1p, corresponding to Tyr79 in Etr1p, produced similar results. Our data indicate that the mitochondrial reductase activity is indispensable for respiratory function in yeast, emphasizing the significance of Mrf1p (Etr1p) and mitochondrial FAS for the integrity of the respiratory competent organelle. 相似文献
146.
Sandberg JK Fast NM Jordan KA Furlan SN Barbour JD Fennelly G Dobroszycki J Spiegel HM Wiznia A Rosenberg MG Nixon DF 《Journal of immunology (Baltimore, Md. : 1950)》2003,170(8):4403-4410
The immunology of vertical HIV transmission differs from that of adult infection in that the immune system of the infant is not fully matured, and the factors that influence the functionality of CD8(+) T cell responses against HIV in children remain largely undefined. We have investigated CD8(+) T cell responses in 65 pediatric subjects with vertically acquired HIV-1 infection. Vigorous, broad, and Ag dose-driven CD8(+) T cell responses against HIV Ags were frequently observed in children who were older than 3 years of age and maintained CD4(+) T cell counts >400 cells/ micro l. In contrast, younger age or a CD4(+) T cell count <400 cells/ micro l was associated with poor CD8(+) T cell responses and high HIV loads. Furthermore, subjects with a severely depleted and phenotypically altered CD4(+) T cell compartment had circulating Gag-specific CD8(+) T cells with impaired IFN-gamma production. When viral load was not suppressed by antiviral treatment, subjects that fell below the putative age and CD4(+) T cell count thresholds had significantly reduced CD8(+) T cell responses and significantly higher viral loads. Thus, the data suggest that fully effective HIV-specific CD8(+) T cell responses take years to develop despite an abundance of Ag in early life, and responses are further severely impaired, independent of age, in children who have a depleted or skewed CD4(+) T cell compartment. The results are discussed in relation to differences between the neonatal and adult immune systems in the ability to respond to HIV infection. 相似文献
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148.
Fossilized flowers and fruits from the Upper Cretaceous (Turonian, ca. 90 million years [my] before present) Raritan Formation of New Jersey are described as the new genus Divisestylus with two species, D. brevistamineus and D. longistamineus. The fossils are fusainized and three-dimensionally preserved. Morphological characteristics suggest affinities with extant Saxifragaceae and Iteaceae, two closely related families in Saxifragales. Similarities include a pentamerous perianth, calyx fused below into a hypanthium with free sepal lobes above, haplostemonous androecium with stamens situated opposite the calyx lobes, inferior ovary, bicarpellate gynoecium, numerous ovules on axile placentas, conspicuous intrastaminal nectary ring, and capsulate fruit opening apically. The unique fusion of the gynoecium, with carpels and stigmas fused but styles free, indicates closer affinities with extant Iteaceae, whereas other characters, such as basifixed anthers in D. brevistamineus, tricolpate and striate pollen grains, and anomocytic stomata, indicate closer affinities to Saxifragaceae. Cladistic analyses utilizing molecular data from a previously published analysis and morphological data as well as morphological data alone demonstrate the fossils share a more recent common ancestor with Iteaceae than Saxifragaceae, thereby making Divisestylus the oldest fossils known with clear affinities to Iteaceae. 相似文献
149.
Self-stabilized CpG DNAs optimally activate human B cells and plasmacytoid dendritic cells 总被引:6,自引:0,他引:6
Cong YP Song SS Bhagat L Pandey RK Yu D Kandimalla ER Agrawal S 《Biochemical and biophysical research communications》2003,310(4):1133-1139
We recently showed that 5'-terminal secondary structures in CpG DNA affect activity significantly more than those at the 3'-end [Biochem. Biophys. Res. Commun. 306 (2003) 948]. The need for an accessible 5'-end of CpG DNA for activity suggested that the receptor reads the DNA sequence from this end. In continuation of these studies, we have designed immunomodulatory oligonucleotides (IMOs), consisting of a nine-mer stimulatory domain, containing a CpG motif and a hairpin-loop structure at the 3'-end, referred to as self-stabilized CpG DNAs. We studied the ability of self-stabilized CpG DNAs to stimulate human B-cell proliferation and interferon-alpha (IFN-alpha) secretion in plasmacytoid dendritic cell (pDC) culture assays. Self-stabilized CpG DNAs activated human B cells and induced plasmacytoid dendritic cells to secrete high levels of IFN-alpha. While both stimulatory and secondary structures in CpG DNAs were required for pDC activation, CpG motifs were sufficient to activate B cells. Interestingly, CpG motifs were not required for activity in the hairpin duplex region. Further modifications of the hairpin duplex region with a mixture of oligodeoxynucleotides and oligo-2'-O-methylribonucleotides in a heteroduplex formation permitted activation of both human B cells and pDCs. 相似文献
150.
Rajebhosale M Greenwood S Vidugiriene J Jeromin A Hilfiker S 《The Journal of biological chemistry》2003,278(8):6075-6084
Neuronal calcium sensor-1 (NCS-1), the mammalian orthologue of frequenin, belongs to a family of EF-hand-containing Ca(2+) sensors. NCS-1/frequenin has been shown to enhance synaptic transmission in PC12 cells and Drosophila and Xenopus, respectively. However, the precise molecular mechanism for the enhancement of exocytosis is largely unknown. In PC12 cells, NCS-1 potentiated exocytosis evoked by ATP, an agonist to phospholipase C-linked receptors, but had no effect on depolarization-evoked release. NCS-1 also enhanced exocytosis triggered by ionomycin, a Ca(2+) ionophore that bypasses K(+) and Ca(2+) channels. Overexpression of NCS-1 caused a shift in the dose-response curve of inhibition of ATP-evoked secretion using phenylarsine oxide, an inhibitor of phosphatidylinositol 4-OH kinase (PI4K). Plasma membrane phosphatidylinositol 4,5-bisphosphate pools were increased upon NCS-1 transfection as visualized using a phospholipase C-delta pleckstrin homology domain-green fluorescent protein construct. NCS-1-transfected cell extracts displayed increased phosphatidylinositol-4-phosphate biosynthesis, indicating an increase in PI4K activity. Mutations in NCS-1 equivalent to those that abolish the interaction of recoverin, another EF-hand-containing Ca(2+) sensor, with its downstream target rhodopsin kinase, lost their ability to enhance exocytosis. Taken together, the present data indicate that NCS-1 modulates the activity of PI4K, leading to increased levels of phosphoinositides and concomitant enhancement of exocytosis. 相似文献