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131.
Nitrogen-containing bisphosphonates as carbocation transition state analogs for isoprenoid biosynthesis. 总被引:2,自引:0,他引:2
M B Martin W Arnold H T Heath J A Urbina E Oldfield 《Biochemical and biophysical research communications》1999,263(3):754-758
Nitrogen-containing bisphosphonates are potent bone antiresorptive agents as well as having herbicidal and antiparasitic activity, and are thought to act by inhibiting enzymes of the mevalonate pathway. Using molecular modeling and ab initio quantum chemical calculations, we show that bisphosphonates can act as aza-isoprenoid transition state analogs, thereby inhibiting isoprenoid biosynthesis. The two phosphonate groups of the 1,1-bisphosphonates readily dock into the diphosphate-Mg(2+) binding site in farnesyl diphosphate synthase, while the charged ammonium (or pyridinium or imidazolium) groups act as carbocation transition state analogs, whose binding is stabilized by a cluster of oxygen atoms in the active site cleft, and an overall negative electrostatic potential in this region. Enhanced activity is shown to correlate with increasing van der Waals stabilization due to N-alkylation, or the presence of a charged, planar (sp(2)-hybridized) aromatic residue in the carbocation binding site. These results are of general interest since they suggest a rational approach to bisphosphonate drug design. 相似文献
132.
133.
Phylogenetic analysis of the outer-membrane-protein genes of Chlamydiae, and its implication for vaccine development 总被引:9,自引:0,他引:9
Examination of 18 complete and 6 partial sequences of the major outer-
membrane protein from 24 chlamydiae isolates was used to reconstruct their
evolutionary relationships. From this analysis, assuming that the clades
with 100% bootstrap support are correct, come the following conclusions:
(1) The tree of these sequences is not congruent with the phylogeny of the
hosts, and thus host switching would seem to have occurred, thereby
limiting the extent to which there has been coevolution of parasite and
host. (2) The tree is also noncongruent with clustering by type of cell
infected, thereby limiting the extent to which there has been coevolution
of parasite and the cell type that it infects. (3) The tree is also
noncongruent with clustering by the organ infected (eyes or genitalia),
thereby limiting the extent to which there has been coevolution of parasite
and the organ that it infects. (4) The tree is also noncongruent with
genital strains arising from lymphogranuloma venereum strains. (5) The tree
is also noncongruent with the geographic site at which the isolates were
obtained, thereby limiting the extent of divergence explained by geographic
separation. (6) There are estimated to be 185 amino acid positions that are
invariable (as opposed to unvaried) in the major outer-membrane protein.
There are 10 unvaried positions in the variable domains, of which 9 appear
to be invariable, giving some reason to hope that development of a vaccine
might be possible. (7) The rate of change of this protein is too small to
see increased divergence over the time span of isolation of these genes,
giving hope to any vaccine having longevity. Bootstrapping supports those
portions of the tree on which the first five conclusions above depend. The
picture that these results provide is more one of pathogen versatility than
one of coevolutionary constraints. In addition, we examined 10 60-KDa,
outer-membrane protein- 2 genes, all but one of which were from these same
strains. The tree was not, among the trachomatis strains, congruent with
the major-outer- membrane protein tree, suggesting that gene exchange could
be occurring among strains. Moreover, there is an apparent slowdown in
divergence in this gene, among the trachomatis strains.
相似文献
134.
135.
Angelika Wientzek María‐José Tormo Díaz Jose Maria Huerta Castaño Pilar Amiano Larraitz Arriola Kim Overvad Jane Nautrup Østergaard Marie‐Aline Charles Guy Fagherazzi Domenico Palli Benedetta Bendinelli Guri Skeie Kristin Benjaminsen Borch Wanda Wendel‐Vos Ellen de Hollander Anne M. May Marjolein EM den Ouden Antonia Trichopoulou Elissavet Valanou Stefan Söderberg Paul W. Franks Soren Brage Matthäus Vigl Heiner Boeing Ulf Ekelund 《Obesity (Silver Spring, Md.)》2014,22(5):E127-E134
136.
137.
Steenvoorden MM Tolboom TC van der Pluijm G Löwik C Visser CP DeGroot J Gittenberger-DeGroot AC DeRuiter MC Wisse BJ Huizinga TW Toes RE 《Arthritis research & therapy》2006,8(6):R165-10
The healthy synovial lining layer consists of a single cell layer that regulates the transport between the joint cavity and the surrounding tissue. It has been suggested that abnormalities such as somatic mutations in the p53 tumor-suppressor gene contribute to synovial hyperplasia and invasion in rheumatoid arthritis (RA). In this study, expression of epithelial markers on healthy and diseased synovial lining tissue was examined. In addition, we investigated whether a regulated process, resembling epithelial to mesenchymal transition (EMT)/fibrosis, could be responsible for the altered phenotype of the synovial lining layer in RA. Synovial tissue from healthy subjects and RA patients was obtained during arthroscopy. To detect signs of EMT, expression of E-cadherin (epithelial marker), collagen type IV (indicator of the presence of a basement membrane) and alpha-smooth muscle actin (alpha-sma; a myofibroblast marker) was investigated on frozen tissue sections using immunohistochemistry. Fibroblast-like synoviocytes (FLSs) from healthy subjects were isolated and subjected to stimulation with synovial fluid (SF) from two RA patients and to transforming growth factor (TGF)-beta. To detect whether EMT/fibrotic markers were increased, expression of collagen type I, alpha-sma and telopeptide lysylhydroxylase (TLH) was measured by real time PCR. Expression of E-cadherin and collagen type IV was found in healthy and arthritic synovial tissue. Expression of alpha-sma was only found in the synovial lining layer of RA patients. Stimulation of healthy FLSs with SF resulted in an upregulation of alpha-sma and TLH mRNA. Collagen type I and TLH mRNA were upregulated after stimulation with TGF-beta. Addition of bone morphogenetic protein (BMP)-7 to healthy FLS stimulated with SF inhibited the expression of alpha-sma mRNA. The finding that E-cadherin and collagen type IV are expressed in the lining layer of healthy and arthritic synovium indicates that these lining cells display an epithelial-like phenotype. In addition, the presence of alpha-sma in the synovial lining layer of RA patients and induction of fibrotic markers in healthy FLSs by SF from RA patients indicate that a regulated process comparable to EMT might cause the alteration in phenotype of RA FLSs. Therefore, BMP-7 may represent a promising agent to counteract the transition imposed on synoviocytes in the RA joint. 相似文献
138.
Antioxidant activity of coumarins and flavonols from the resinous exudate of Haplopappus multifolius
The antioxidant activity of eight coumarins and two flavonols isolated from Haplopappus multifolius was studied with the DPPH radical method. Results show that a high concentration of phenolic coumarins and the presence of quercetin and rhamnetin in the exudates could account for the protection of the plant against oxidative stress. Structures for the coumarins 6-hydroxy-7-[(E,E)-3',7'-dimethyl-2',4',7'-octatrienyloxy] coumarin and 7-[(E)-3'-methyl-4'-hydroxy-2'-butenyloxy] coumarin are proposed on the basis of spectroscopic evidence. 相似文献
139.
Advances in nanotechnology have enabled the production and characterization of magnetic particles with nanometer-sized features that can be functionalized with biological recognition elements for numerous applications in biotechnology. In the present study, the synthesis of and interactions between self-assembled monolayers (SAMs) on gold and glass surfaces and functionalized magnetic nanoparticles have been characterized. Immobilization of 10-15 nm streptavidin-functionalized nanoparticles to biotinylated gold and glass surfaces was achieved by the strong interactions between biotin and streptavidin. Fluorescent streptavidin-functionalized nanoparticles, biotinylated surfaces, and combinations of the two were characterized by Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and electron and fluorescent microscopy to confirm that little or no functionalization occurred in nonbiotinylated regions of the gold and glass surfaces compared to the biotinylated sites. Together these techniques have potential use in studying the modification and behavior of functionalized nanoparticles on surfaces in biosensing and other applications. 相似文献
140.