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991.
Susan Adel Katharina Hofheinz Dagmar Heydeck Hartmut Kuhn Ann-Kathrin Häfner 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2014,1841(10):1460-1466
5-Lipoxygenase (ALOX5) plays a key role in the biosynthesis of pro-inflammatory leukotrienes whereas 15-lipoxygenases (ALOX15) have been implicated in the formation of pro-resolving eicosanoids (lipoxins, resolvins). Recently, it has been suggested that a phosphorylation mimicking mutant (Ser663Asp) of a stabilized variant of human ALOX5 exhibits dominant arachidonic acid 15-lipoxygenase activity (> 95%). To test whether similar alterations in the reaction specificity can also be observed for ALOX5 orthologs of other species we expressed wildtype and phosphorylation mimicking mutants (Ser271Asp, Ser523Asp, Ser663Asp, Ser663Glu) of human, mouse and zebrafish ALOX5 in pro- and eukaryotic overexpression systems and characterized their reaction specificities. We found that neither of the phosphorylation mimicking mutants produced significant amounts of 15-hydroperoxyeicosatetraenoic acid and the 5-lipoxygenation/15-lipoxygenation ratio for all wildtype and mutant enzyme species was lower than 100:2. Taken together, this data suggest that phosphorylation of native ALOX5 orthologs of different vertebrates may not induce major alterations in the reaction specificity and thus may not inverse their biological activity. 相似文献
992.
Lee JH Kang GB Lim HH Jin KS Kim SH Ree M Park CS Kim SJ Eom SH 《Journal of molecular biology》2008,376(2):308-316
GluR0 from Nostoc punctiforme (NpGluR0) is a bacterial homologue of the ionotropic glutamate receptor (iGluR). We have solved the crystal structure of the ligand-binding core of NpGluR0 in complex with l-glutamate at a resolution of 2.1 Å. The structure exhibits a noncanonical ligand interaction and two distinct subunit interfaces. The side-chain guanidium group of Arg80 forms a salt bridge with the γ-carboxyl group of bound l-glutamate: in GluR0 from Synechocystis (SGluR0) and other iGluRs, the equivalent residues are Asn or Thr, which cannot form a similar interaction. We suggest that the local positively charged environment and the steric constraint created by Arg80 mediate the selectivity of l-glutamate binding by preventing the binding of positively charged and hydrophobic amino acids. In addition, the NpGluR0 ligand-binding core forms a new subunit interface in which the two protomers are arranged differently than the known iGluR and SGluR0 dimer interfaces. The significance of there being two different dimer interfaces was investigated using analytical ultracentrifugation analysis. 相似文献
993.
Collapsin response mediator protein-2 hyperphosphorylation is an early event in Alzheimer's disease progression 总被引:1,自引:0,他引:1
Cole AR Noble W van Aalten L Plattner F Meimaridou R Hogan D Taylor M LaFrancois J Gunn-Moore F Verkhratsky A Oddo S LaFerla F Giese KP Dineley KT Duff K Richardson JC Yan SD Hanger DP Allan SM Sutherland C 《Journal of neurochemistry》2007,103(3):1132-1144
Collapsin response mediator protein 2 (CRMP2) is an abundant brain-enriched protein that can regulate microtubule assembly in neurons. This function of CRMP2 is regulated by phosphorylation by glycogen synthase kinase 3 (GSK3) and cyclin-dependent kinase 5 (Cdk5). Here, using novel phosphospecific antibodies, we demonstrate that phosphorylation of CRMP2 at Ser522 (Cdk5-mediated) is increased in Alzheimer's disease (AD) brain, while CRMP2 expression and phosphorylation of the closely related isoform CRMP4 are not altered. In addition, CRMP2 phosphorylation at the Cdk5 and GSK3 sites is increased in cortex and hippocampus of the triple transgenic mouse [presenilin-1 (PS1)(M146V)KI; Thy1.2-amyloid precursor protein (APP)(swe); Thy1.2tau(P301L)] that develops AD-like plaques and tangles, as well as the double (PS1(M146V)KI; Thy1.2-APP(swe)) transgenic mouse. The hyperphosphorylation is similar in magnitude to that in human AD and is evident by 2 months of age, ahead of plaque or tangle formation. Meanwhile, there is no change in CRMP2 phosphorylation in two other transgenic mouse lines that display elevated amyloid beta peptide levels (Tg2576 and APP/amyloid beta-binding alcohol dehydrogenase). Similarly, CRMP2 phosphorylation is normal in hippocampus and cortex of Tau(P301L) mice that develop tangles but not plaques. These observations implicate hyperphosphorylation of CRMP2 as an early event in the development of AD and suggest that it can be induced by a severe APP over-expression and/or processing defect. 相似文献
994.
《Cell cycle (Georgetown, Tex.)》2013,12(18):3345-3346
Comment on: Maiti A, et al. Proc Natl Acad Sci USA 2012; 109:8091-6. 相似文献
995.
Hisako Hirayama Hideto Takami Akira Inoue Koki Horikoshi 《FEMS microbiology letters》1998,169(2):219-225
Two toluene-sensitive mutants were generated from Pseudomonas putida IH-2000, the first known toluene-tolerant isolate, by Tn5 transposon mutagenesis. These mutants were unable to grow in the presence of toluene (log Pow 2.8) but they could grow in medium overlaid with organic solvents having a log Pow value higher than that of toluene such as p-xylene (log Pow 3.1), cyclohexane (log Pow 3.4) and n-hexane (log Pow 3.9). The Tn5 transposable element knocked out a cyoB-like gene in one mutant and a cyoC-like gene in the other mutant. Seven open reading frames were found in a 5.5-kb region containing the cyoB- and cyoC-like genes of strain IH-2000. ORFs 3–7 showed significant identity to the cyoABCDE gene products of Escherichia coli, but ORFs 1 and 2 showed no significant homology to any protein reported so far. The growth patterns of the Tn5 mutants with the inactivated cyo-like gene were similar to that of the wild-type strain in the absence of organic solvents, although the doubling times were slightly longer than that of the wild-type strain. Our findings indicate that cyo is an important gene for toluene tolerance, although its role is still unclear. 相似文献
996.
Sara Violante Lodewijk IJlst Heleen te Brinke Janet Koster Isabel Tavares de Almeida Ronald J.A. Wanders Fátima V. Ventura Sander M. Houten 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2013,1831(9):1467-1474
Fatty acid β-oxidation may occur in both mitochondria and peroxisomes. While peroxisomes oxidize specific carboxylic acids such as very long-chain fatty acids, branched-chain fatty acids, bile acids, and fatty dicarboxylic acids, mitochondria oxidize long-, medium-, and short-chain fatty acids. Oxidation of long-chain substrates requires the carnitine shuttle for mitochondrial access but medium-chain fatty acid oxidation is generally considered carnitine-independent. Using control and carnitine palmitoyltransferase 2 (CPT2)- and carnitine/acylcarnitine translocase (CACT)-deficient human fibroblasts, we investigated the oxidation of lauric acid (C12:0). Measurement of the acylcarnitine profile in the extracellular medium revealed significantly elevated levels of extracellular C10- and C12-carnitine in CPT2- and CACT-deficient fibroblasts. The accumulation of C12-carnitine indicates that lauric acid also uses the carnitine shuttle to access mitochondria. Moreover, the accumulation of extracellular C10-carnitine in CPT2- and CACT-deficient cells suggests an extramitochondrial pathway for the oxidation of lauric acid. Indeed, in the absence of peroxisomes C10-carnitine is not produced, proving that this intermediate is a product of peroxisomal β-oxidation. In conclusion, when the carnitine shuttle is impaired lauric acid is partly oxidized in peroxisomes. This peroxisomal oxidation could be a compensatory mechanism to metabolize straight medium- and long-chain fatty acids, especially in cases of mitochondrial fatty acid β-oxidation deficiency or overload. 相似文献
997.
998.
Van B. Lu S. Balasubramanyan J. E. Biggs M. J. Stebbing S. L. Gustafson K. Todd A. Lai D. Dawbarn W. F. Colmers K. Ballanyi P. A. Smith 《Neurophysiology》2007,39(4-5):272-283
Chronic constriction injury (CCI) of the rat sciatic nerve increases the dorsal horn excitability. This “central sensitization”
leads to behavioral manifestations analogous to those related to human neuropathic pain. We found, using whole-cell recording
from acutely isolated spinal cord slices, that 7-to 10-day-long CCI increases excitatory synaptic drive to putative excitatory
“delay”-firing neurons in the substantia gelatinosa but attenuates that to putative inhibitory “tonic”-firing neurons. A defined-medium organotypic culture (DMOTC) system was
used to investigate the long-term actions of brain-derived neurotrophic factor (BDNF) as a possible instigator of these changes.
When all five neuronal types found in the substantia gelatinosa were considered, BDNF and CCI produced similar patterns, or “footprints,” of changes across the whole population. This pattern
was not seen with another putative “pain mediator,” interleukin 1β. Thus, BDNF decreased synaptic drive to “tonic” neurons
and increased synaptic drive to “delay” neurons. Actions of BDNF on “delay” neurons were presynaptic and involved increased
mEPSC frequency and amplitude without changes in the function of postsynaptic AMPA receptors. By contrast, BDNF exerted both
pre-and post-synaptic actions on “ tonic” cells to reduce the mEPSC frequency and amplitude. These differential actions of
BDNF on excitatory and inhibitory neurons contributed to a global increase in the dorsal horn network excitability as assessed
by the amplitude of depolarization-induced increases in the intracellular [Ca2+]. Experiments with the BDNF-binding protein TrkB-d5 provided additional evidence for BDNF as a harbinger of neuropathic pain.
Thus, the cellular processes altered by BDNF likely contribute to “central sensitization” and hence to the onset of neuropathic
pain.
Neirofiziologiya/Neurophysiology, Vol. 39, Nos. 4/5, pp. 315–326, July–October, 2007. 相似文献
999.
Mechanism of antiviral activity of 1-β-d -arabinofuranosyl-E-5-(2-bromovinyl)uracil (BV-araU) against the YSR strain of varicella-zoster virus (VZV), which is a mutant derived from the wild YS strain and is completely deficient in viral thymidine kinase (TK), was searched in comparison with antiviral activity of other thymidine analogues, guanosine analogue and thymidylate synthase (TS) inhibitor in human embryo lung fibroblast cells. Thymidine analogues, such as BV-araU, 5-iododeoxyuridine (IUDR), 1-β-d -arabinofuranosylthymine (araT), and guanosine analogue, such as 9-(2-hydroxyethoxymethyl)guanine (ACV), showed higher antiviral activity to the YS strain than to the YSR strain. Though, BV-araU also had the antiviral activity of a microgram level against the YSR strain. In contrast to these results, TS inhibitor, 5-fluorodeoxyuridine (FUDR), had higher antiviral activity to the YSR strain than to the YS strain. Highly synergistic antiviral activities of FUDR to the YS strain and the YSR strain were observed in combination with IUDR, araT, or ACV. However, weakly synergistic or additive inhibition to the YSR strain was shown in combination of BV-araU and FUDR, in spite of highly synergistic effect of this combination to the YS strain. The viral and cellular TS activity was partially inhibited by BV-araU monophosphate, but not by BV-araU. These results indicate that BV-araU is converted into BV-araU monophosphate by cellular TK, and the inhibition of TS activity by BV-araU monophosphate in the YSR strain-infected cells results in the suppression of viral replication. 相似文献
1000.
Jürgen Bajorath 《Journal of molecular modeling》1998,4(7):239-249
Modeling and structure-function studies on two cell surface proteins are presented, which are implicated in the regulation of immune responses and cell adhesion. In the first part, model building of RANK, a new member of the tumor necrosis factor receptor (TNFR) superfamily (TNFRSF), is reported. The model is analyzed in light of structural studies on the TNFR-ligand complex and molecular model-based mutagenesis analyses of CD40-ligand and Fas-ligand interactions. The study makes it possible to predict residues important for ligand binding to RANK and further rationalizes differences in specificity between TNFR-like cell surface receptors. In the second part, recent investigations on the structure and carbohydrate binding site of CD44, a member of the link protein family, are discussed. The binding site in CD44 is compared to calcium-dependent (C-type) lectins, which include the selectins, another family of cell adhesion molecules. The studies on TNFRSF members and link proteins reported herein complement a recent review article in this journal, which focused on modeling and binding site analysis of immune cell surface proteins.Electronic Supplementary Material available. 相似文献