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101.
Kwiecień RA Rostkowski M Dybała-Defratyka A Paneth P 《Journal of inorganic biochemistry》2004,98(6):1078-1086
Several semiempirical methods (MNDO-d, PM3tm, PM3-d, PM5, PM6, and AM1-d) have been tested against experimental data and density functional theory (DFT) results in search for the best methods that can be used for quantum-mechanical-molecular mechanics (QM/MM) modeling of corrinoid systems of vitamin B(12) co-factor. It has been found that the PM6 parametrization in its present form gives results closest to hybrid DFT calculations that are most widely used thus far. In comparison with pure DFT and experimental data the best agreement is obtained for PM3tm parametrization, while PM6 yields slightly worse results. AM1-d yields bad geometry of the corrin moiety. The worst performance was observed for MNDO-d, which has severe problem with position and orientation of the alpha-ligands. 相似文献
102.
Kashyap SR Belfort R Berria R Suraamornkul S Pratipranawatr T Finlayson J Barrentine A Bajaj M Mandarino L DeFronzo R Cusi K 《American journal of physiology. Endocrinology and metabolism》2004,287(3):E537-E546
Muscle insulin resistance develops when plasma free fatty acids (FFAs) are acutely increased to supraphysiological levels (approximately 1,500-4,000 micromol/l). However, plasma FFA levels >1,000 micromol/l are rarely observed in humans under usual living conditions, and it is unknown whether insulin action may be impaired during a sustained but physiological FFA increase to levels seen in obesity and type 2 diabetes mellitus (T2DM) (approximately 600-800 micromol/l). It is also unclear whether normal glucose-tolerant subjects with a strong family history of T2DM (FH+) would respond to a low-dose lipid infusion as individuals without any family history of T2DM (CON). To examine these questions, we studied 7 FH+ and 10 CON subjects in whom we infused saline (SAL) or low-dose Liposyn (LIP) for 4 days. On day 4, a euglycemic insulin clamp with [3-3H]glucose and indirect calorimetry was performed to assess glucose turnover, combined with vastus lateralis muscle biopsies to examine insulin signaling. LIP increased plasma FFA approximately 1.5-fold, to levels seen in T2DM. Compared with CON, FH+ were markedly insulin resistant and had severely impaired insulin signaling in response to insulin stimulation. LIP in CON reduced insulin-stimulated glucose disposal (Rd) by 25%, insulin-stimulated insulin receptor tyrosine phosphorylation by 17%, phosphatidylinositol 3-kinase activity associated with insulin receptor substrate-1 by 20%, and insulin-stimulated glycogen synthase fractional velocity over baseline (44 vs. 15%; all P < 0.05). In contrast to CON, a physiological elevation in plasma FFA in FH+ led to no further deterioration in Rd or to any additional impairment of insulin signaling. In conclusion, a 4-day physiological increase in plasma FFA to levels seen in obesity and T2DM impairs insulin action/insulin signaling in CON but does not worsen insulin resistance in FH+. Whether this lack of additional deterioration in insulin signaling in FH+ is due to already well-established lipotoxicity, or to other molecular mechanisms related to insulin resistance that are nearly maximally expressed early in life, remains to be determined. 相似文献
103.
Watkins WJ Lemoine RC Chong L Cho A Renau TE Kuo B Wong V Ludwikow M Garizi N Iqbal N Barnard J Jankowska R Singh R Madsen D Lolans K Lomovskaya O Oza U Dudley MN 《Bioorganic & medicinal chemistry letters》2004,14(20):5133-5137
Structure-activity relationships of a novel series of fungal efflux pump inhibitors with respect to potentiation of the activity of fluconazole against strains of Candida albicans and Candida glabrata over-expressing ABC-type efflux pumps are systematically explored. 相似文献
104.
Heasley BH Jarosz R Carter KM Van SJ Lynch KR Macdonald TL 《Bioorganic & medicinal chemistry letters》2004,14(15):4069-4074
A recently reported dual LPA(1)/LPA(3) receptor antagonist (1) has been modified so as to modulate the basicity, sterics, and dipole moment of the 2-pyridyl moiety. Additionally, the implications of installing nonhydrolyzable phosphate head group isosteres with regard to antagonist potency and selectivity at LPA receptors is described. This study has resulted in the development of the first nonhydrolyzable and presumably phosphatase-resistant LPA(3)-selective antagonist reported to date. 相似文献
105.
Basto R Scaerou F Mische S Wojcik E Lefebvre C Gomes R Hays T Karess R 《Current biology : CB》2004,14(1):56-61
Rough Deal (Rod) and Zw10 are components of a complex required for the metazoan metaphase checkpoint and for recruitment of dynein/dynactin to the kinetochore. The Rod complex, like most classical metaphase checkpoint components, forms part of the outer domain of unattached kinetochores. Here we analyze the dynamics of a GFP-Rod chimera in living syncytial Drosophila embryos. Uniquely among checkpoint proteins, GFP-Rod robustly streams from kinetochores along microtubules, from the time of chromosome attachment until anaphase onset. Prometaphase and metaphase kinetochores continuously recruit new Rod, thus feeding the current. Rod flux from kinetochores appears to require biorientation but not tension because it continues in the presence of taxol. As with Mad2, kinetochore- and spindle-associated Rod rapidly turns over with free cytosolic Rod, both during normal mitosis and after colchicine treatment, with a t1/2 of 25-45 s. GFP-Rod coimmunoprecipitates with dynein/dynactin, and in the absence of microtubules both Rod and dynactin accumulate on kinetochores. Nevertheless, Rod and dynein/dynactin behavior are distinguishable. We propose that the Rod complex is a major component of the fibrous corona and that the recruitment of Rod during metaphase is required to replenish kinetochore dynein after checkpoint conditions have been satisfied but before anaphase onset. 相似文献
106.
Nautiloids, the externally shelled cephalopods of Cambrian origin, are the most ancient lineage among extant cephalopods. Their ancestral characters are explored based on morphological and molecular data (18S rDNA sequence) to investigate the evolution of present cephalopod lineages. Among molluscs, nautilus 18S rDNA gene is the longest reported so far, due to large nucleotidic insertions. By comparison with other 18S sequences, the complete gene of N. macromphalus helps to clarify the taxonomic status of the three universally recognised Nautilus species. The range of interspecific molecular differences supports separation of the present species into two surviving ectocochleate genera, Nautilus and Allonautilus. Nautiloid 18S is considered as corresponding to the ancestral form of 18S as is the number of chromosomes in Nautilus (52), the lowest among cephalopods. Comparison of karyological characteristics amongst cephalopods in a phylogenetic context suggests a possible correlation between duplication events and lineage divergence. 相似文献
107.
Staphylococcus aureus , a leading cause of bacterial infections in humans, is endowed with a wealth of virulence factors that contribute to the disease process. Several extracellular proteolytic enzymes, including cysteine proteinases referred to as the staphopains (staphopain A, encoded by the scpA gene, and staphopain B, encoded by sspB ), have proposed roles for staphylococcal virulence. Here we present data regarding the distribution, copy number and genetic variability of the genes encoding the staphopains in a large number of S. aureus strains. The polymorphism of the scpA and sspB genes in three laboratory strains and 126 clinical isolates was analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). Both genes were detected in all isolates by PCR amplification and, based on the PCR-RFLP patterns, classified as four types for scpA and six types for sspB . Those with the most divergent patterns were subjected to DNA sequencing and compared with genomic sequence data for the seven available strains of S. aureus . Southern blot analysis of the scpA and sspB sequences indicates that they are strongly conserved as single-copy genes in the genome of each S. aureus strain investigated. Taken together, these data suggest that the staphopains have important housekeeping and/or virulence functions, and therefore may constitute an interesting target for the development of therapeutic inhibitors for the treatment of staphylococcal diseases. 相似文献
108.
Rzychon M Filipek R Sabat A Kosowska K Dubin A Potempa J Bochtler M 《Protein science : a publication of the Protein Society》2003,12(10):2252-2256
Staphostatins are the endogenous inhibitors of the major secreted cysteine proteases of Staphylococcus aureus, the staphopains. Here, we present the 1.4 A crystal structure of staphostatin B and show that the fold can be described as a fully closed, highly sheared eight-stranded beta-barrel. Thus, staphostatin B is related to beta-barrel domains that are involved in the inhibition or regulation of proteases of various catalytic types and to the superfamily of lipocalins/cytosolic fatty acid binding proteins. Unexpectedly for a cysteine protease inhibitor, staphostatin B is not significantly similar to cystatins. 相似文献
109.
Ellerby HM Lee S Ellerby LM Chen S Kiyota T del Rio G Sugihara G Sun Y Bredesen DE Arap W Pasqualini R 《The Journal of biological chemistry》2003,278(37):35311-35316
Protein engineering is an emerging area that has expanded our understanding of protein folding and laid the groundwork for the creation of unprecedented structures with unique functions. We previously designed the first native-like pore-forming protein, small globular protein (SGP). We show here that this artificially engineered protein has membrane-disrupting properties and anti-tumor activity in several cancer animal models. We propose and validate a mechanism for the selectivity of SGP toward cell membranes in tumors. SGP is the prototype for a new class of artificial proteins designed for therapeutic applications. 相似文献
110.
Endogenous cardiotonic steroids (ECS) are putative ligands of the inhibitory binding site of the membrane sodium pump (Na+, K+-ATPase). There is growing evidence that cardiotonic steroids may promote the growth of cardiac and vascular myocytes, including evidence indicating growth stimulation at concentrations in the same range as circulating ECS concentrations. We investigated four parameters to determine whether ouabain, a proposed ECS, promotes growth of immortalized rat proximal tubule epithelial cells: cell count by hemocytometer; metabolic activity as reflected in the mitochondrial conversion of the tetrazolium salt, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, to its formazan product (MA); DNA synthesis reflected as bromodeoxyuridine incorporation (DNA); and mitosis reflected as histone phosphorylation state detected using anti-phosphohistone 3 antibody (HP). Maximum stimulatory responses were observed at 1 nm ouabain (MA, 20.3% increase, p < 0.01; DNA, 28.4% increase, p < 0.001; HP, maximum response at 0.5 h, 50% increase, p < 0.001). We observed that growth stimulation was associated with stimulation of ERK1/2 phosphorylation (ERK-P), and both growth and ERK-P could be blocked by the MEK inhibitor (U0126, 100 nm). Western blot analysis revealed that the only alpha isoform of Na+, K+-ATPase that could be detected in these cultures was the highly ouabain-resistant alpha1 isoform. Measurement of ouabain inhibition of ion transport in these cultures using 86Rb+ uptake revealed the predominance of the expected ouabain-resistant isoform (IC50 = 24 microm) and an additional minor ( approximately 15%) ouabain-sensitive inhibition with IC50 approximately 30 pm. Similar bimodal transport inhibition curves were obtained in freshly dissected rat proximal tubules. These results indicate that renal epithelial cells may be a sensitive target of the ERK1/2-activating and growth-promoting effects of ouabain even in the presence of ouabain-resistant Na+, K+-ATPase. 相似文献