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101.
Dourlat J Valentin B Liu WQ Garbay C 《Bioorganic & medicinal chemistry letters》2007,17(14):3943-3946
Investigation within the pTyr-binding pocket of the STAT3 SH2 domain led us to develop a novel synthesis of two pTyr mimetics, l-tetrazolylmethylphenylalanine (l-Tmp) and l-O-malonyltyrosine (l-OMT), that were next incorporated in a high affinity ligand of STAT3 SH2 domain. Biological evaluation of peptidomimetics on STAT3 dimerization identified l-OMT as the first non-phosphorus pTyr mimetic so far reported against STAT3 SH2 domain, harboring an activity similar to that of the Pmp-containing reference peptidomimetic. 相似文献
102.
UmuD and RecA directly modulate the mutagenic potential of the Y family DNA polymerase DinB 总被引:3,自引:0,他引:3
DinB is the only translesion Y family DNA polymerase conserved among bacteria, archaea, and eukaryotes. DinB and its orthologs possess a specialized lesion bypass function but also display potentially deleterious -1 frameshift mutagenic phenotypes when overproduced. We show that the DNA damage-inducible proteins UmuD(2) and RecA act in concert to modulate this mutagenic activity. Structural modeling suggests that the relatively open active site of DinB is enclosed by interaction with these proteins, thereby preventing the template bulging responsible for -1 frameshift mutagenesis. Intriguingly, residues that define the UmuD(2)-interacting surface on DinB statistically covary throughout evolution, suggesting a driving force for the maintenance of a regulatory protein-protein interaction at this site. Together, these observations indicate that proteins like RecA and UmuD(2) may be responsible for managing the mutagenic potential of DinB orthologs throughout evolution. 相似文献
103.
Garavito G Bertani S Rincon J Maurel S Monje MC Landau I Valentin A Deharo E 《Parasite (Paris, France)》2007,14(2):135-140
Methylene blue (MB) is the oldest synthetic antimalarial. It is not used anymore as antimalarial but should be reconsidered. For this purpose we have measured its impact on both chloroquine sensitive and resistant Plasmodium strains. We showed that around 5 nM of MB were able to inhibit 50% of the parasite growth in vitro and that late rings and early trophozoites were the most sensitive stages; while early rings, late trophozoites and schizonts were less sensitive. Drug interaction study following fractional inhibitory concentrations (FIC) method showed antagonism with amodiaquine, atovaquone, doxycycline, pyrimethamine; additivity with artemether, chloroquine, mefloquine, primaquine and synergy with quinine. These results confirmed the interest of MB that could be integrated in a new low cost antimalarial combination therapy. 相似文献
104.
Rassoulzadegan M Grandjean V Gounon P Cuzin F 《Journal de la Société de Biologie》2007,201(4):397-399
By contrast with a wide definition of the 'epigenetic variation', including all changes in gene expression that do not result from alteration of the gene structure, a more restricted class had been defined, initially in plants, under the name 'paramutation'. It corresponds to epigenetic modifications distinct from the regulatory interactions of the cell differentiation pathways, mitotically stable and sexually transmitted with non-Mendelian patterns. This class of epigenetic changes appeared for some time restricted to the plant world, but examples progressively accumulated of epigenetic inheritance in organisms ranging from mice to humans. Occurrence of paramutation in the mouse and possible mechanisms were then established in the paradigmatic case of a mutant phenotype maintained and hereditarily transmitted by wild type homozygotes. Together with recent findings in plants indicative of a necessary step of RNA amplification in the reference maize paramutation, the mouse studies point to a new role of RNA, as an inducer and hereditary determinant of epigenetic variation. Given the known presence of a wide range of RNAs in human spermatozoa, as well as a number of unexplained cases of familial disease predisposition and transgenerational maintenance, speculations can be extended to possible roles of RNA-mediated inheritance in human biology and pathology.La paramutation est une modification épigénétique héréditaire, découverte chez des plantes et récemment, chez la souris. C'est un changement héréditaire du phénotype associé avec un allèle sauvage à la suite de son passage dans une structure hétérozygote avec un allèle mutant (phénomène quelquefois appelé "conversation interchromosomique"). Souvent il est considéré comme une exception à la base de lois de Mendel, "les allèles sont retrouvés inchangés lors des ségrégations au cours des croisements". Au contraire la paramutation observée chez la souris résulte d'une modification de l'allèle sauvage du gène Kit après transmission à partir d'un hétérozygote avec un allèle mutant "insertion". Le phénotype des taches blanches visibles aisément par la couleur du pelage est transmis en absence de l'allèle inducteur sur plusieurs générations. Il est corrélé avec une diminution du niveau d'ARNm de Kit et une accumulation d'ARN de taille variable de Kit dans les spermatozo?des des souris paramutantes. La micro-injection de l'ARN de l'hétérozygote, ou de l'ARN et des microARN spécifiques de Kit dans l'oeuf fécondé induit le phénotype "taches blanches". Le r?le de l'ARN dans l'établissement et le maintien d'un état épigénétique héréditaire est proposé et discuté. 相似文献
105.
Enhanced suicidal death of erythrocytes from gene-targeted mice lacking the Cl-/HCO(3)(-) exchanger AE1 总被引:2,自引:0,他引:2
Akel A Wagner CA Kovacikova J Kasinathan RS Kiedaisch V Koka S Alper SL Bernhardt I Wieder T Huber SM Lang F 《American journal of physiology. Cell physiology》2007,292(5):C1759-C1767
Genetic defects of anion exchanger 1 (AE1) may lead to spherocytic erythrocyte morphology, severe hemolytic anemia, and/or cation leak. In normal erythrocytes, osmotic shock, Cl removal, and energy depletion activate Ca2+-permeable cation channels with Ca2+-induced suicidal erythrocyte death, i.e., surface exposure of phosphatidylserine, cell shrinkage, and membrane blebbing, all features typical for apoptosis of nucleated cells. The present experiments explored whether AE1 deficiency favors suicidal erythrocyte death. Peripheral blood erythrocyte numbers were significantly smaller in gene-targeted mice lacking AE1 (AE1/ mice) than in their wild-type littermates (AE1+/+ mice) despite increased percentages of reticulocytes (AE1/: 49%, AE1+/+: 2%), an indicator of enhanced erythropoiesis. Annexin binding, reflecting phosphatidylserine exposure, was significantly larger in AE1/erythrocytes/reticulocytes (10%) than in AE1+/+ erythrocytes (1%). Osmotic shock (addition of 400 mM sucrose), Cl removal (replacement with gluconate), or energy depletion (removal of glucose) led to significantly stronger annexin binding in AE1/ erythrocytes/reticulocytes than in AE1+/+ erythrocytes. The increase of annexin binding following exposure to the Ca2+ ionophore ionomycin (1 µM) was, however, similar in AE1/ and in AE1+/+ erythrocytes. Fluo3 fluorescence revealed markedly increased cytosolic Ca2+ permeability in AE1/ erythrocytes/reticulocytes. Clearance of carboxyfluorescein diacetate succinimidyl ester-labeled erythrocytes/reticulocytes from circulating blood was more rapid in AE1/ mice than in AE1+/+ mice and was accelerated by ionomycin treatment in both genotypes. In conclusion, lack of AE1 is associated with enhanced Ca2+ entry and subsequent scrambling of cell membrane phospholipids. annexin; cell volume; osmolarity; phosphatidylserine; energy depletion 相似文献
106.
107.
Diabetes is chronic disease that is accompanied by a rapid thymus involution. To investigate the factors responsible for thymic involution in a model of STZ-induced diabetes, mice were injected with STZ alone or in combination with the cyclooxygenase 2 inhibitor indomethacin (INDO). Thymus weight, glycemia and serum corticosterone were measured, and apoptosis in thymus and thymocyte cultures was analyzed by flow cytometry. Although earlier studies report that streptozotocin (STZ) is toxic to lymphoid tissues, in our experiments even massive doses of STZ did not negatively affect thymocyte cultures. Cultured thymocytes also seemed unaffected by high glucose concentrations, even after 24 h of exposure. Administration of INDO concomitantly with STZ reduced thymic involution but did not prevent the onset of hyperglycemia or reduce established hyperglycemia. When INDO was given before STZ, the same degree of thymic involution occurred; however, hyperglycemia was reduced, although normoglycemia was not restored. INDO also reduced serum corticosterone. Because thymocytes are known to be sensitive to glucocorticoids, this finding suggests that cyclooxygenase 2 inhibition may retard thymic involution by reducing serum glucocorticoids. In conclusion, our results show that STZ and hyperglycemia are not toxic to thymocytes and that cyclooxygenase 2-mediated mechanisms are involved in thymic involution during diabetes. 相似文献
108.
Vezenkov Lyubomir T. Danalev Dancho L. Iwanov Iwan Lozanov Valentin Atanasov Atanas Todorova Rumyana Vassilev Nikolay Karadjova Veronika 《Amino acids》2022,54(6):897-910
Amino Acids - The Alzheimer’s disease leads to neurodegenerative processes and affecting negatively million people worldwide. The treatment of the disease is still difficult and incomplete in... 相似文献
109.
110.
Kenichi Kitanishi Valentin Cracan Ruma Banerjee 《The Journal of biological chemistry》2015,290(33):20466-20476
Adenosylcobalamin-dependent isomerases catalyze carbon skeleton rearrangements using radical chemistry. We have recently demonstrated that an isobutyryl-CoA mutase variant, IcmF, a member of this enzyme family that catalyzes the interconversion of isobutyryl-CoA and n-butyryl-CoA also catalyzes the interconversion between isovaleryl-CoA and pivalyl-CoA, albeit with low efficiency and high susceptibility to inactivation. Given the biotechnological potential of the isovaleryl-CoA/pivalyl-CoA mutase (PCM) reaction, we initially attempted to engineer IcmF to be a more proficient PCM by targeting two active site residues predicted based on sequence alignments and crystal structures, to be key to substrate selectivity. Of the eight mutants tested, the F598A mutation was the most robust, resulting in an ∼17-fold increase in the catalytic efficiency of the PCM activity and a concomitant ∼240-fold decrease in the isobutyryl-CoA mutase activity compared with wild-type IcmF. Hence, mutation of a single residue in IcmF tuned substrate specificity yielding an ∼4000-fold increase in the specificity for an unnatural substrate. However, the F598A mutant was even more susceptible to inactivation than wild-type IcmF. To circumvent this limitation, we used bioinformatics analysis to identify an authentic PCM in genomic databases. Cloning and expression of the putative AdoCbl-dependent PCM with an α2β2 heterotetrameric organization similar to that of isobutyryl-CoA mutase and a recently characterized archaeal methylmalonyl-CoA mutase, allowed demonstration of its robust PCM activity. To simplify kinetic analysis and handling, a variant PCM-F was generated in which the αβ subunits were fused into a single polypeptide via a short 11-amino acid linker. The fusion protein, PCM-F, retained high PCM activity and like PCM, was resistant to inactivation. Neither PCM nor PCM-F displayed detectable isobutyryl-CoA mutase activity, demonstrating that PCM represents a novel 5′-deoxyadenosylcobalamin-dependent acyl-CoA mutase. The newly discovered PCM and the derivative PCM-F, have potential applications in bioremediation of pivalic acid found in sludge, in stereospecific synthesis of C5 carboxylic acids and alcohols, and in the production of potential commodity and specialty chemicals. 相似文献