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161.
Biochemical characterization of CA IX, one of the most active carbonic anhydrase isozymes 总被引:1,自引:0,他引:1
Hilvo M Baranauskiene L Salzano AM Scaloni A Matulis D Innocenti A Scozzafava A Monti SM Di Fiore A De Simone G Lindfors M Jänis J Valjakka J Pastoreková S Pastorek J Kulomaa MS Nordlund HR Supuran CT Parkkila S 《The Journal of biological chemistry》2008,283(41):27799-27809
Carbonic anhydrase IX (CA IX) is an exceptional member of the CA protein family; in addition to its classical role in pH regulation, it has also been proposed to participate in cell proliferation, cell adhesion, and tumorigenic processes. To characterize the biochemical properties of this membrane protein, two soluble recombinant forms were produced using the baculovirus-insect cell expression system. The recombinant proteins consisted of either the CA IX catalytic domain only (CA form) or the extracellular domain, which included both the proteoglycan and catalytic domains (PG + CA form). The produced proteins lacked the small transmembrane and intracytoplasmic regions of CA IX. Stopped-flow spectrophotometry experiments on both proteins demonstrated that in the excess of certain metal ions the PG + CA form exhibited the highest catalytic activity ever measured for any CA isozyme. Investigations on the oligomerization and stability of the enzymes revealed that both recombinant proteins form dimers that are stabilized by intermolecular disulfide bond(s). Mass spectrometry experiments showed that CA IX contains an intramolecular disulfide bridge (Cys(119)-Cys(299)) and a unique N-linked glycosylation site (Asn(309)) that bears high mannose-type glycan structures. Parallel experiments on a recombinant protein obtained by a mammalian cell expression system demonstrated the occurrence of an additional O-linked glycosylation site (Thr(78)) and characterized the nature of the oligosaccharide structures. This study provides novel information on the biochemical properties of CA IX and may help characterize the various cellular and pathophysiological processes in which this unique enzyme is involved. 相似文献
162.
Jarkko Utriainen Sari Janhunen Heljä-Sisko Helmisaari Toini Holopainen 《Trees - Structure and Function》2000,14(8):475-484
Three-year-old Scots pine (Pinus sylvestris L.) seedlings were exposed to ambient or elevated ozone (O3) (1.52ambient) and carbon dioxide (CO2) (590 µmol mol-1) concentrations during two growing seasons in open-top field chambers (OTCs). Five different treatments were applied in the chambers: filtered air, ambient air, elevated O3, elevated CO2, and elevated O3 and CO2 combined. Ambient plots outside the OTCs were also included, but the chamber ambient was used as a control in O3 and CO2 treatments due to a significant chamber effect. Increases in yellowing and chlorotic mottling of previous-year (C+1) needles and in the amount of cytoplasmic ribosomes and electron density of the chloroplast stroma in current-year (C) and C+1 needle mesophyll cells were observed in elevated O3 at both CO2 concentrations. Elevated O3 alone caused a non-significant 10.9% decrease in plant total dry mass and a significant decrease in manganese (Mn) content of C needles. CO2 enrichment caused a significant increase in needle cross-sectional width after the first year of exposure, and an accumulation of starch and slight curling and swelling of the chloroplast thylakoids in the mesophyll tissue of C needles after the second year of exposure. Calcium and Mn contents were increased and copper and nitrogen contents were decreased, significantly, in CO2-exposed needles. A non-significant 19.1% increase in plant total dry mass was measured in elevated CO2 alone, whereas a 14.8% reduction in total dry mass, together with a significant reduction in current-year main shoot length, was found in the combined treatment. Overall, in spite of decreases in O3-induced visible injuries by CO2, elevated CO2 levels were not able to counteract the impact of O3 in this experiment. 相似文献
163.
Holviala JH Sallinen JM Kraemer WJ Alen MJ Häkkinen KK 《Journal of strength and conditioning research / National Strength & Conditioning Association》2006,20(2):336-344
Progressive strength training can lead to substantial increases in maximal strength and mass of trained muscles, even in older women and men, but little information is available about the effects of strength training on functional capabilities and balance. Thus, the effects of 21 weeks of heavy resistance training--including lower loads performed with high movement velocities--twice a week on isometric maximal force (ISOmax) and force-time curve (force produced in 500 milliseconds, F0-500) and dynamic 1 repetition maximum (1RM) strength of the leg extensors, 10-m walking time (10WALK) and dynamic balance test (DYN.D) were investigated in 26 middle-aged (MI; 52.8 +/- 2.4 years) and 22 older women (O; 63.8 +/- 3.8 years). 1RM, ISOmax, and F0-500 increased significantly in MI by 28 +/- 10%, 20 +/- 19%, 31 +/- 34%, and in O by 27 +/- 8%, 20 +/- 16%, 18 +/- 45%, respectively. 10WALK (MI and O, p < 0.001) shortened and DYN.D improved (MI and O, p < 0.001). The present strength-training protocol led to large increases in maximal and explosive strength characteristics of leg extensors and in walking speed, as well to an improvement in the present dynamic balance test performance in both age groups. Although training-induced increase in explosive strength is an important factor for aging women, there are other factors that contribute to improvements in dynamic balance capacity. This study indicates that total body heavy resistance training, including explosive dynamic training, may be applied in rehabilitation or preventive exercise protocols in aging women to improve dynamic balance capabilities. 相似文献
164.
165.
Karvinen J Hurskainen P Gopalakrishnan S Burns D Warrior U Hemmilä I 《Journal of biomolecular screening》2002,7(3):223-231
In addition to kinases and G protein-coupled receptors, proteases are one of the main targets in modern drug discovery. Caspases and viral proteases, for instance, are potential targets for new drugs. To satisfy the current need for fast and sensitive high-throughput screening for inhibitors, new homogeneous protease assays are needed. We used a caspase-3 assay as a model to develop a homogeneous time-resolved fluorescence quenching assay technology. The assay utilizes a peptide labeled with both a luminescent europium chelate and a quencher. Cleavage of the peptide by caspase-3 separates the quencher from the chelate and thus recovers europium fluorescence. The sensitivity of the assay was 1 pg/microl for active caspase-3 and 200 pM for the substrate. We evaluated the assay for high-throughput usage by screening 9600 small-molecule compounds. We also evaluated this format for absorption/distribution/metabolism/excretion assays with cell lysates. Additionally, the assay was compared to a commercial fluorescence caspase-3 assay. 相似文献
166.
167.
Nikki A. Thiele Jussi Kärkkäinen Kenneth B. Sloan Jarkko Rautio Kristiina M. Huttunen 《Bioorganic & medicinal chemistry letters》2018,28(17):2856-2860
To achieve the sustained release of dopamine in the brain for the symptomatic treatment of Parkinson’s disease, dopamine was conjugated to l-tyrosine, an l-type amino acid transporter 1 (LAT1)-targeting vector, using a secondary carbamate linker. The resulting prodrug, dopa-CBT, inhibited the uptake of the LAT1 substrate [14C]-l-leucine in LAT1-expressing MCF-7 cells with an IC50 value of 28?µM, which was 3.5-times lower than that of the gold standard for dopamine replacement therapy, l-dopa (IC50 ca. 100?µM). Despite its high affinity for LAT1, dopa-CBT was transported via LAT1 into MCF-7 cells 850-times more slowly (Vmax?<?3?pmol/min/mg) than l-dopa (Vmax 2.6?nmol/min/mg), most likely due to its large size compared to l-dopa. However, dopa-CBT was significantly more stable in 10% rat liver homogenate than l-dopa, releasing dopamine and l-tyrosine, an endogenous dopamine precursor, slowly, which indicates that it may serve as a dual carrier of dopamine across the blood-brain barrier selectively expressing LAT1. 相似文献
168.
The role of epistatic interactions underpinning resistance to parasitic Varroa mites in haploid honey bee (Apis mellifera) drones 下载免费PDF全文
Benjamin H. Conlon Eva Frey Peter Rosenkranz Barbara Locke Robin F. A. Moritz Jarkko Routtu 《Journal of evolutionary biology》2018,31(6):801-809
The Red Queen hypothesis predicts that host–parasite coevolutionary dynamics can select for host resistance through increased genetic diversity, recombination and evolutionary rates. However, in haplodiploid organisms such as the honeybee (Apis mellifera), models suggest the selective pressure is weaker than in diploids. Haplodiploid sex determination, found in A. mellifera, can allow deleterious recessive alleles to persist in the population through the diploid sex with negative effects predominantly expressed in the haploid sex. To overcome these negative effects in haploid genomes, epistatic interactions have been hypothesized to play an important role. Here, we use the interaction between A. mellifera and the parasitic mite Varroa destructor to test epistasis in the expression of resistance, through the inhibition of parasite reproduction, in haploid drones. We find novel loci on three chromosomes which explain over 45% of the resistance phenotype. Two of these loci interact only additively, suggesting their expression is independent of each other, but both loci interact epistatically with the third locus. With drone offspring inheriting only one copy of the queen's chromosomes, the drones will only possess one of two queen alleles throughout the years‐long lifetime of the honeybee colony. Varroa, in comparison, completes its highly inbred reproductive cycle in a matter of weeks, allowing it to rapidly evolve resistance. Faced with the rapidly evolving Varroa, a diversity of pathways and epistatic interactions for the inhibition of Varroa reproduction could therefore provide a selective advantage to the high levels of recombination seen in A. mellifera. This allows for the remixing of phenotypes despite a fixed queen genotype. 相似文献
169.
Hannu Peltoniemi Suvi Natunen Ilja Ritamo Leena Valmu Jarkko Räbinä 《Glycoconjugate journal》2013,30(2):159-170
Despite recent technical advances in glycan analysis, the rapidly growing field of glycomics still lacks methods that are high throughput and robust, and yet allow detailed and reliable identification of different glycans. LC-MS-MS2 methods have a large potential for glycan analysis as they enable separation and identification of different glycans, including structural isomers. The major drawback is the complexity of the data with different charge states and adduct combinations. In practice, manual data analysis, still largely used for MALDI-TOF data, is no more achievable for LC-MS-MS2 data. To solve the problem, we developed a glycan analysis software GlycanID for the analysis of LC-MS-MS2 data to identify and profile glycan compositions in combination with existing proteomic software. IgG was used as an example of an individual glycoprotein and extracted cell surface proteins of human fibroblasts as a more complex sample to demonstrate the power of the novel data analysis approach. N-glycans were isolated from the samples and analyzed as permethylated sugar alditols by LC-MS-MS2, permitting semiquantitative glycan profiling. The data analysis consisted of five steps: 1) extraction of LC-MS features and MS2 spectra, 2) mapping potential glycans based on feature distribution, 3) matching the feature masses with a glycan composition database and de novo generated compositions, 4) scoring MS2 spectra with theoretical glycan fragments, and 5) composing the glycan profile for the identified glycan compositions. The resulting N-glycan profile of IgG revealed 28 glycan compositions and was in good correlation with the published IgG profile. More than 50 glycan compositions were reliably identified from the cell surface N-glycan profile of human fibroblasts. Use of the GlycanID software made relatively rapid analysis of complex glycan LC-MS-MS2 data feasible. The results demonstrate that the complexity of glycan LC-MS-MS2 data can be used as an asset to increase the reliability of the identifications. 相似文献
170.