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排序方式: 共有106条查询结果,搜索用时 15 毫秒
71.
Avihai Yacovan Rachel Ozeri Tzofit Kehat Sima Mirilashvili Daniel Sherman Alex Aizikovich Alina Shitrit Efrat Ben-Zeev Nili Schutz Osnat Bohana-Kashtan Alexander Konson Vered Behar Oren M. Becker 《Bioorganic & medicinal chemistry letters》2012,22(20):6460-6468
Cancer cells preferentially use glycolysis rather than oxidative phosphorylation for their rapid growth. They consume large amount of glucose to produce lactate even when oxygen is abundant, a phenomenon known as the Warburg effect. This metabolic change originates from a shift in the expression of alternative spliced isoforms of the glycolytic enzyme pyruvate kinase (PK), from PKM1 to PKM2. While PKM1 is constitutively active, PKM2 is switched from an inactive dimer form to an active tetramer form by small molecule activators. The prevalence of PKM2 in cancer cells relative to the prevalence of PKM1 in many normal cells, suggests a therapeutic strategy whereby activation of PKM2 may counter the abnormal cellular metabolism in cancer cells, and consequently decreased cellular proliferation. Herein we describe the discovery and optimization of a series of PKM2 activators derived from the 2-((2,3-dihydrobenzo[b][1,4] dioxin-6-yl)thio)-1-(2-methyl-1-(methylsulfonyl)indolin-5-yl) ethanone scaffold. The synthesis, SAR analysis, enzyme active site docking, enzymatic reaction kinetics, selectivity and pharmaceutical properties are discussed. 相似文献
72.
The number of physical activity measures and indexes used in the human literature is large and may result in some difficulty for the average investigator to choose the most appropriate measure. Accordingly, this review is intended to provide information on the utility and limitations of the various measures. Its primary focus is the objective assessment of free‐living physical activity in humans based on physiological and biomechanical methods. The physical activity measures have been classified into three categories:
- 1 . Measures based on energy expenditure or oxygen uptake, such as activity energy expenditure, activity‐related time equivalent, physical activity level, physical activity ratio, metabolic equivalent, and a new index of potential interest, daytime physical activity level.
- 2 . Measures based on heart rate monitoring, such as net heart rate, physical activity ratio heart rate, physical activity level heart rate, activity‐related time equivalent, and daytime physical activity level heart rate.
- 3 . Measures based on whole‐body accelerometry (counts/U time).
73.
Realistic studies of ion current in biologic channels present a major challenge for computer simulation approaches. All-atom molecular dynamics simulations involve serious time limitations that prevent their use in direct evaluation of ion current in channels with significant barriers. The alternative use of Brownian dynamics (BD) simulations can provide the current for simplified macroscopic models. However, the time needed for accurate calculations of electrostatic energies can make BD simulations of ion current expensive. The present work develops an approach that overcomes some of the above challenges and allows one to simulate ion currents in models of biologic channels. Our method provides a fast and reliable estimate of the energetics of the system by combining semimacroscopic calculations of the self-energy of each ion and an implicit treatment of the interactions between the ions, as well as the interactions between the ions and the protein-ionizable groups. This treatment involves the use of the semimacroscopic version of the protein dipole Langevin dipole (PDLD/S) model in its linear response approximation (LRA) implementation, which reduces the uncertainties about the value of the protein "dielectric constant." The resulting free energy surface is used to generate the forces for on-the-fly BD simulations of the corresponding ion currents. Our model is examined in a preliminary simulation of the ion current in the KcsA potassium channel. The complete free energy profile for a single ion transport reflects reasonable energetics and captures the effect of the protein-ionized groups. This calculated profile indicates that we are dealing with the channel in its closed state. Reducing the barrier at the gate region allows us to simulate the ion current in a reasonable computational time. Several limiting cases are examined, including those that reproduce the observed current, and the nature of the productive trajectories is considered. The ability to simulate the current in realistic models of ion channels should provide a powerful tool for studies of the biologic function of such systems, including the analysis of the effect of mutations, pH, and electric potentials. 相似文献
74.
Hovering aggregations of male salt marsh greenheads Tabanus nigrovittatusand the sibling species T. conterminuswere observed on marshes in southern New Jersey. T. nigrovittatusmales hovered over expanses of short marsh grasses, while T. conterminushovered over tidal creeks and near other prominent landmarks. T. nigrovittatusexhibited two distinct daily hovering periods. The timing of these periods varied daily but showed a strong negative correlation with ambient temperature. A principal-components analysis identified a combination of ambient temperature, black-body temperature, and light intensity as most predictive of hovering onset. T. conterminushovered during a time period which was generally intermediate to the two hovering periods of T. nigrovittatus.Temporal partitioning of hovering windows may represent a premating isolating mechanism. 相似文献
75.
New Alleles of the Yeast MPS1 Gene Reveal Multiple Requirements in Spindle Pole Body Duplication 总被引:1,自引:1,他引:0
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In Saccharomyces cerevisiae, the Mps1p protein kinase is critical for both spindle pole body (SPB) duplication and the mitotic spindle assembly checkpoint. The mps1–1 mutation causes failure early in SPB duplication, and because the spindle assembly checkpoint is also compromised, mps1–1 cells proceed with a monopolar mitosis and rapidly lose viability. Here we report the genetic and molecular characterization of mps1–1 and five new temperature-sensitive alleles of MPS1. Each of the six alleles contains a single point mutation in the region of the gene encoding the protein kinase domain. The mutations affect several residues conserved among protein kinases, most notably the invariant glutamate in subdomain III. In vivo and in vitro kinase activity of the six epitope-tagged mutant proteins varies widely. Only two display appreciable in vitro activity, and interestingly, this activity is not thermolabile under the assay conditions used. While five of the six alleles cause SPB duplication to fail early, yielding cells with a single SPB, mps1–737 cells proceed into SPB duplication and assemble a second SPB that is structurally defective. This phenotype, together with the observation of intragenic complementation between this unique allele and two others, suggests that Mps1p is required for multiple events in SPB duplication. 相似文献
76.
Carbohydrate recognition by proteins is a key event in many biological
processes. Concanavalin A is known to specifically recognize the
pentasaccharide core (beta-GlcNAc-(1-->2)-alpha- Man-(1-->3)-[beta-
GlcNAc-(1-->2)-alpha-Man-(1-->6)]-Man) of N-linked oligosaccharides
with a Ka of 1.41 x 10(6 )M-1. We have determined the structure of
concanavalin A bound to beta-GlcNAc-(1-->2)-alpha-Man-(1-->3)-[beta-
GlcNAc-(1-->2)-alpha-Man- (1-->6)]-Man to 2.7A. In six of eight
subunits there is clear density for all five sugar residues and a well
ordered binding site. The pentasaccharide adopts the same conformation in
all eight subunits. The binding site is a continuous extended cleft on the
surface of the protein. Van der Waals interactions and hydrogen bonds
anchor the carbohydrate to the protein. Both GlcNAc residues contact the
protein. The GlcNAc on the 1-->6 arm of the pentasaccharide makes
particularly extensive contacts and including two hydrogen bonds. The
binding site of the 1-->3 arm GlcNAc is much less extensive.
Oligosaccharide recognition by Con A occurs through specific protein
carbohydrate interactions and does not require recruitment of adventitious
water molecules. The beta-GlcNAc-(1-->2)-Man glycosidic linkage PSI
torsion angle on the 1-->6 arm is rotated by over 50 degrees from that
observed in solution. This rotation is coupled to disruption of
interactions at the monosaccharide site. We suggest destabilization of the
monosaccharide site and the conformational strain reduces the free energy
liberated by additional interactions at the 1-->6 arm GlcNAc site.
相似文献
77.
78.
Purification and properties of rat liver tryptophan oxygenase 总被引:6,自引:0,他引:6
79.
80.
Julian Weghuber Stefan Sunzenauer Mario Brameshuber Birgit Plochberger Clemens Hesch Gerhard J. Schutz 《Journal of visualized experiments : JoVE》2010,(37)
Unraveling the interaction network of molecules in-vivo is key to understanding the mechanisms that regulate cell function and metabolism. A multitude of methodological options for addressing molecular interactions in cells have been developed, but most of these methods suffer from being rather indirect and therefore hardly quantitative. On the contrary, a few high-end quantitative approaches were introduced, which however are difficult to extend to high throughput. To combine high throughput capabilities with the possibility to extract quantitative information, we recently developed a new concept for identifying protein-protein interactions (Schwarzenbacher et al., 2008). Here, we describe a detailed protocol for the design and the construction of this system which allows for analyzing interactions between a fluorophore-labeled protein ("prey") and a membrane protein ("bait") in-vivo. Cells are plated on micropatterned surfaces functionalized with antibodies against the bait exoplasmic domain. Bait-prey interactions are assayed via the redistribution of the fluorescent prey. The method is characterized by high sensitivity down to the level of single molecules, the capability to detect weak interactions, and high throughput capability, making it applicable as screening tool. 相似文献