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101.
102.
Mutations in ACY1, the gene encoding aminoacylase 1, cause a novel inborn error of metabolism
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Sass JO Mohr V Olbrich H Engelke U Horvath J Fliegauf M Loges NT Schweitzer-Krantz S Moebus R Weiler P Kispert A Superti-Furga A Wevers RA Omran H 《American journal of human genetics》2006,78(3):401-409
N-terminal acetylation of proteins is a widespread and highly conserved process. Aminoacylase 1 (ACY1; EC 3.5.14) is the most abundant of the aminoacylases, a class of enzymes involved in hydrolysis of N-acetylated proteins. Here, we present four children with genetic deficiency of ACY1. They were identified through organic acid analyses using gas chromatography-mass spectrometry, revealing increased urinary excretion of several N-acetylated amino acids, including the derivatives of methionine, glutamic acid, alanine, leucine, glycine, valine, and isoleucine. Nuclear magnetic resonance spectroscopy analysis of urine samples detected a distinct pattern of N-acetylated metabolites, consistent with ACY1 dysfunction. Functional analyses of patients' lymphoblasts demonstrated ACY1 deficiency. Mutation analysis uncovered recessive loss-of-function or missense ACY1 mutations in all four individuals affected. We conclude that ACY1 mutations in these children led to functional ACY1 deficiency and excretion of N-acetylated amino acids. Questions remain, however, as to the clinical significance of ACY1 deficiency. The ACY1-deficient individuals were ascertained through urine metabolic screening because of unspecific psychomotor delay (one subject), psychomotor delay with atrophy of the vermis and syringomyelia (one subject), marked muscular hypotonia (one subject), and follow-up for early treated biotinidase deficiency and normal clinical findings (one subject). Because ACY1 is evolutionarily conserved in fish, frog, mouse, and human and is expressed in the central nervous system (CNS) in human, a role in CNS function or development is conceivable but has yet to be demonstrated. Thus, at this point, we cannot state whether ACY1 deficiency has pathogenic significance with pleiotropic clinical expression or is simply a biochemical variant. Awareness of this new genetic entity may help both in delineating its clinical significance and in avoiding erroneous diagnoses. 相似文献
103.
Harris TD Kalogeropoulos S Nguyen T Dwyer G Edwards DS Liu S Bartis J Ellars C Onthank D Yalamanchili P Heminway S Robinson S Lazewatsky J Barrett J 《Bioconjugate chemistry》2006,17(5):1294-1313
The integrin receptor alpha(v)beta(3) is overexpressed on the endothelial cells of growing tumors and on some tumor cells themselves. Radiolabeled alpha(v)beta(3) antagonists have demonstrated potential application as tumor imaging agents and as radiotherapeutic agents. This report describes the total synthesis of eight new HYNIC and DOTA conjugates of receptor alpha(v)beta(3) antagonists belonging to the quinolin-4-one class of peptidomimetics, and their radiolabeling with (99m)Tc (for HYNIC) and (111)In (for DOTA). Tethering of the radionuclide-chelator complexes was achieved at two different sites on the quinolin-4-one molecule. All such derivatives maintained high affinity for receptor alpha(v)beta(3) and high selectivity versus receptors alpha(IIb)beta(3), alpha(v)beta(5), alpha(5)beta(1). Biodistribution of the radiolabeled compounds was evaluated in the c-neu Oncomouse mammary adenocarcinoma model. DOTA conjugate (111)In-TA138 presented the best biodistribution profile. Tumor uptake at 2 h postinjection was 9.39% of injected dose/g of tissue (%ID/g). Activity levels in selected organs was as follows: blood, 0.54% ID/g; liver, 1.94% ID/g; kidney, 2.33% ID/g; lung, 2.74% ID/g; bone, 1.56% ID/g. A complete biodistribution analysis of (111)In-TA138 and the other radiolabeled compounds of this study are presented and discussed. A scintigraphic imaging study with (111)In-TA138 showed a clear delineation of the tumors and rapid clearance of activity from nontarget tissues. 相似文献
104.
Haas W Faherty BK Gerber SA Elias JE Beausoleil SA Bakalarski CE Li X Villén J Gygi SP 《Molecular & cellular proteomics : MCP》2006,5(7):1326-1337
Mass spectrometers that provide high mass accuracy such as FT-ICR instruments are increasingly used in proteomic studies. Although the importance of accurately determined molecular masses for the identification of biomolecules is generally accepted, its role in the analysis of shotgun proteomic data has not been thoroughly studied. To gain insight into this role, we used a hybrid linear quadrupole ion trap/FT-ICR (LTQ FT) mass spectrometer for LC-MS/MS analysis of a highly complex peptide mixture derived from a fraction of the yeast proteome. We applied three data-dependent MS/MS acquisition methods. The FT-ICR part of the hybrid mass spectrometer was either not exploited, used only for survey MS scans, or also used for acquiring selected ion monitoring scans to optimize mass accuracy. MS/MS data were assigned with the SEQUEST algorithm, and peptide identifications were validated by estimating the number of incorrect assignments using the composite target/decoy database search strategy. We developed a simple mass calibration strategy exploiting polydimethylcyclosiloxane background ions as calibrant ions. This strategy allowed us to substantially improve mass accuracy without reducing the number of MS/MS spectra acquired in an LC-MS/MS run. The benefits of high mass accuracy were greatest for assigning MS/MS spectra with low signal-to-noise ratios and for assigning phosphopeptides. Confident peptide identification rates from these data sets could be doubled by the use of mass accuracy information. It was also shown that improving mass accuracy at a cost to the MS/MS acquisition rate substantially lowered the sensitivity of LC-MS/MS analyses. The use of FT-ICR selected ion monitoring scans to maximize mass accuracy reduced the number of protein identifications by 40%. 相似文献
105.
Natália T?kési Attila Lehotzky István Horváth Bálint Szabó Judit Oláh Pierre Lau Judit Ovádi 《The Journal of biological chemistry》2010,285(23):17896-17906
TPPP/p25 (tubulin polymerization-promoting protein/p25) is an unstructured protein that induces microtubule polymerization in vitro and is aligned along the microtubule network in transfected mammalian cells. In normal human brain, TPPP/p25 is expressed predominantly in oligodendrocytes, where its expression is proved to be crucial for their differentiation process. Here we demonstrated that the expression of TPPP/p25 in HeLa cells, in doxycycline-inducible CHO10 cells, and in the oligodendrocyte CG-4 cells promoted the acetylation of α-tubulin at residue Lys-40, whereas its down-regulation by specific small interfering RNA in CG-4 cells or by the withdrawal of doxycycline from CHO10 cells decreased the acetylation level of α-tubulin. Our results indicate that TPPP/p25 binds to HDAC6 (histone deacetylase 6), an enzyme responsible for tubulin deacetylation. Moreover, we demonstrated that the direct interaction of these two proteins resulted in the inhibition of the deacetylase activity of HDAC6. The measurement of HDAC6 activity showed that TPPP/p25 is able to induce almost complete (90%) inhibition at 3 μm concentration. In addition, treatment of the cells with nocodazole, vinblastine, or cold exposure revealed that microtubule acetylation induced by trichostatin A, a well known HDAC6 inhibitor, does not cause microtubule stabilization. In contrast, the microtubule bundling activity of TPPP/p25 was able to protect the microtubules from depolymerization. Finally, we demonstrated that, similarly to other HDAC6 inhibitors, TPPP/p25 influences the microtubule dynamics by decreasing the growth velocity of the microtubule plus ends and also affects cell motility as demonstrated by time lapse video experiments. Thus, we suggest that TPPP/p25 is a multiple effector of the microtubule organization. 相似文献
106.
Judit Padisák Éva Hajnal Lothar Krienitz József Lakner Viktória Üveges 《Hydrobiologia》2010,653(1):45-64
In this article, we attempt to estimate the contemporary phytoplankton species pool of a particular lake, by assessing the
rate of floral change over a period of 15 years. Phytoplankton time series data from Lake Stechlin, an oligo-mesotrophic lake
in the Baltic Lake District (Germany) were used. Of the 254 algal species recorded during the 15-year of studies with roughly
biweekly sampling, 212 species were planktonic. In the individual plankton years, the recorded total number of species changed
between 97 and 122, of which the number of dominants (>1% contribution to the annual average of total biomass) was only 10–19.
The 15-year cumulative number of species exhibited an almost linear increase after an initial saturation phase. This increase
was attributed to two reasons: increase of sample size and immigration of species new to the flora. Based on a probabilistic
model developed in this study, we estimated the number of co-existing planktonic species of the lake as some 180, and the
rate of floral change as 1–2 species per year. Of these co-existing species, only few maintain the matter–energy processing
ecosystem functions in any particular plankton year. Selection of these dominants is probably driven by mesoclimatic cycles,
coupled with human-induced forcing, like eutrophication. All others are hiding as an ecological memory, in the sense of the
capacity or experiences of past states to influence present or future responses of the community. Data analyses suggest that
selection of the ‘memory species’ that show temporary abundance increases over shorter (several years) periods are largely
dependent upon the dominants. These results show that interspecific interactions and the particular autecological features
of the dominants, together with their effects on the whole ecosystem, act as a major organizing force. Some phytoplankton
species, like Planktothrix rubescens, are efficient ecosystem engineers with cascading effects of both a top-down and bottom-up nature. Historical scientific
data on Planktothrix blooms in Lake Stechlin suggest cyclic patterns in long-term development of phytoplankton which, as the legend of the Red
Cock suggests, dates back much further than scientific archives. 相似文献
107.
108.
The effects of training and detraining on memory, neurotrophins and oxidative stress markers in rat brain 总被引:8,自引:0,他引:8
Radak Z Toldy A Szabo Z Siamilis S Nyakas C Silye G Jakus J Goto S 《Neurochemistry international》2006,49(4):387-392
In the current investigation we tested how swimming training (T) (8 week, 5 times/week, 2 h/day), and detraining (DT) affects brain functions and oxidative stress markers in rat brain. The free radical concentration, measured by electron paramagnetic resonance, decreased in brain of T and DT rats compared to controls (C). The level of brain-derived neurotrophic factor (BDNF) increased as a result of training, but decreased below the control level after 6 weeks of detraining. In addition, the concentration of nerve growth factor (NGF) also declined with DT. The passive avoidance test was used to assess the memory of rats, and training-induced improvement was observed but the enhancement disappeared with detraining. When the content of mitochondrial electron transport complexes, as a potent free radical generator, was evaluated by the blue native gel method, no significant alterations were observed. The repair of nuclear and mitochondrial 8-oxodeoxyguanosine, as measured by the activity of OGG1, showed no significant difference. Therefore, the results suggest that regular exercise training improves memory, decreases the level of reactive oxygen species, and increase the production of BDNF and NGF. On the other hand, it appears that the beneficial effects of training are reversible in the brain, since detraining down-regulates the neurotrophin level, and memory. It is suggested that exercise training is more likely to beneficially effect the production of reactive oxygen species and the related oxidative damage. 相似文献
109.
Genescà A Martín M Latre L Soler D Pampalona J Tusell L 《BioEssays : news and reviews in molecular, cellular and developmental biology》2006,28(12):1172-1180
Human individuals often exhibit important differences in their sensitivity to ionising radiation. Extensive literature links radiation sensitivity with impaired DNA repair which is due to a lack of correct functioning in many proteins involved in DNA-repair pathways and/or in DNA-damage checkpoint responses. Given that ionising radiation is an important and widespread diagnostic and therapeutic tool, it is important to investigate further those factors and mechanisms that underlie individual radiosensitivity. Recently, evidence is accumulating that telomere function may well be involved in cellular and organism responses to ionising radiation, broadening still further the currently complex and challenging scenario. 相似文献
110.
Horseradish peroxidase C is a class III peroxidase whose structure is stabilized by the presence of two endogenous calcium atoms. Calcium removal has been shown to decrease the enzymatic activity of the enzyme and significantly affect the spectroscopically detectable properties of the heme, such as the spin state of the iron, heme normal modes, and distortions from planarity. In this work, we report on normal mode analysis (NMA) performed on models subjected to 2 ns of molecular dynamics simulations to describe the effect of calcium removal on protein collective motions and to investigate the correlation between active site (heme) and protein matrix fluctuations. We show that in the native peroxidase model, heme fluctuations are correlated to matrix fluctuations while they are not in the calcium-depleted model. 相似文献