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Adenine
Terms modified by Adenine Selected AbstractsSyntheses and Coordination Chemistry of Aminomethylphosphine Derivatives of AdenineEUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 13 2003Qingzhi Zhang Abstract Two aminomethylphosphane derivatives of adenine 9-(2-{bis[(diphenylphosphanyl)methyl]amino}ethyl)adenine (La) and 9-(3-{bis[(diphenylphosphanyl)methyl]amino}propyl)adenine (Lb) were synthesised. Oxidation of La and Lb with H2O2, elemental sulfur or elemental selenium led to the corresponding oxidized products 4a/b,6a/b. Both La and Lb behave as didentate ligands towards late transition metals. Reaction of La or Lb with [MX2(cod)] (M = Pd, Pt; X = Cl, Me) gave chelate complexes 7a/b,10a/b. Reaction of La or Lb with [AuCl(tht)] or [{RuCl(,-Cl)(p -MeC6H4iPr)}2] gave the didentate bridging complexes 11a/b and 12a. All compounds have been fully characterised by microanalysis, IR, 1H and 31P{1H} NMR spectroscopy, and EI/CI/FAB mass spectrometry. 1H{31P} NMR and 1H- 13C correlation experiments were used to confirm the spectral assignments where necessary. Two compounds were structurally characterised by X-ray crystallographic analysis. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003) [source] Synthesis and Structural Properties of New Oligodeoxynucleotide Analogues Containing a 2,,5,-Internucleotidic Squaryldiamide Linkage Capable of Formation of a Watson,Crick Base Pair with Adenine and a Wobble Base Pair with Guanine at the 3,-Downstream Junction SiteEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 10 2004Kousuke Sato Abstract A TpT dimer analogue (U2,sq5,T), in which the 3,-5, phosphodiester linkage was replaced by a 2,-5, squaryldiamide linkage and the 5,-upstream T was replaced by a 3,-deoxyuridine, was synthesized in almost quantitative yield from diethyl squarate. This new dimer structural motif was designed to eliminate the squaryldiamide skeleton-induced overall strain in T3,sq5,T, previously incorporated into DNA fragments as a new TpT mimic, through the change in the connection mode from the 3,-5, linkage to a 2,-5, linkage. Spectral analyses of U2,sq5,T suggest that the overall structure of this dimer mimic is basically similar to that of TpT. A DNA 10mer 5,-d(CGCAU2,sq5,TAGCC)-3, incorporating this dimer was synthesized. From the CD analysis, it turned out that the overall structure of a DNA duplex of 5,-d(CGCAU2,sq5,TAGCC)-3,/3,-d(GCGTAATCGG)-5, is closer to that of the unmodified duplex than the DNA duplex of 5,-d(CGCAT3,sq5,TAGCC)-3,/3,-d(GCGTAATCGG)-5,. Interestingly, extensive Tm experiments suggest that d(CGCAU2,sq5,TAGCC)-3, exhibits intriguing inherent hybridization affinity not only for the completely complementary oligodeoxynucleotide 3,-d(GCGAATCGG)-5,, but also for 3,-d(GCGTAGTCGG)-5,, with a mismatched dG. The unique property of the 3,-downstream dT moiety of U2,sq5,T , the ability to recognize both dA and dG , was also supported by more detailed computational analysis of U2,sq5,T and TpT. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004) [source] Caffeine mimics adenine and 2,-deoxyadenosine, both of which inhibit the guanine-nucleotide exchange activity of RCC1 and the kinase activity of ATRGENES TO CELLS, Issue 5 2003Hitoshi Nishijima Background: Both caffeine and the inactivation of RCC1, the guanine-nucleotide exchange factor (GEF) of Ran, induce premature chromatin condensation (PCC) in hamster BHK21 cells arrested in the S-phase, suggesting that RCC1 is a target for caffeine. Results: Caffeine inhibited the Ran-GEF activity of RCC1 by preventing the binary complex formation of Ran-RCC1. Inhibition of the Ran-GEF activity of RCC1 by caffeine and its derivatives was correlated with their ability to induce PCC. Since caffeine is a derivative of xanthine, the bases and nucleosides were screened for their ability to inhibit RCC1. Adenine, adenosine, and all of the 2,-deoxynucleosides inhibited the Ran-GEF activity of RCC1; however, only adenine and 2,-deoxyadenosine (2,-dA) induced PCC. A factor(s) other than RCC1, should therefore be involved in PCC-induction. We found that both adenine and 2,-dA, but none of the other 2,-deoxynucleosides, inhibited the kinase activity of ATR, similar to that of caffeine. The ATR pathway was also abrogated by the inactivation of RCC1 in tsBN2 cells. Conclusion: The effect of caffeine on cell-cycle control mimics the biological effect of adenine and 2,-dA, both of which inhibit ATR. dATP, a final metabolite of adenine and 2,-dA, is suggested to inhibit ATR, resulting in PCC. [source] A single nucleotide polymorphism at the splice donor site of the human MYH base excision repair gene results in reduced translation efficiency of its transcriptsGENES TO CELLS, Issue 5 2002Satoru Yamaguchi Background: Adenine paired with 8-hydroxyguanine, a major oxidatively damaged DNA lesion, is excised by mutY homologue (MYH) base excision repair protein in human cells. Since genetic polymorphisms of DNA repair genes associated with the activities and the expression levels of their products may modulate cancer susceptibility of individuals, we investigated the effect of a single nucleotide polymorphism (SNP) in the MYH gene on the difference in the expression levels of its products. Results: An aberrant size of the , type nuclear form transcript was detected in a lung cancer cell line, VMRC-LCD, by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. The transcript contained the intron 1 sequence, and it was due to alternative splicing resulting from IVS1+5G/C SNP. The presence of the upstream open reading frame (ORF) on the 5,-side of the native ORF in the , type transcript from the IVS1+5C allele could reduce the translation efficiency of the transcript into the nuclear form protein. Thus, expression vectors bearing the 5,-untranslated region sequence of either the IVS1+5G or 5C allele were constructed. In vitro translation analysis, as well as Western blot and quantitative RT-PCR analyses of the H1299 lung cancer cell line transfected with these vectors, revealed that the translation efficiency of the IVS1+5C transcript into MYH protein was much lower (, 30%) than that of the IVS1+5G transcript. Conclusions: The SNP at the splice donor site of the MYH gene resulted in reduced translation efficiency of its transcripts. This is the fourth case of single nucleotide variations that cause alterations in translation initiation sites and translation efficiencies in human cells. [source] Constitutional Self-Organization of Adenine,Uracil-Derived Hybrid MaterialsCHEMISTRY - A EUROPEAN JOURNAL, Issue 24 2007Carole Arnal-Hérault Dr. Abstract The alkoxysilane nucleobase adenine (A) and uracil (U) precursors described in this paper generate in solution a complex library of hydrogen-bonded aggregates, which can be expressed in the solid state as discrete higher oligomers. The different interconverting outputs that nucleobases may form by oligomerization define a dynamic polyfunctional diversity that may be "extracted selectively" in solid state by sol,gel transcription, under the intrinsic stability of the system. After the sol,gel process, unique constitutional preference for specific geometries in hybrid materials is consistent with a preferential arrangement of nucleobase systems, favoring the self-assembly by the Hoogsteen geometry. FTIR and NMR spectroscopy and X-ray powder diffraction experiments demonstrate the formation of self-organized hybrid supramolecular materials. Electron microscopy reveals the micrometric platelike morphology of the hybrid materials. The MA,U hybrid material is nanostructured in ordered circular domains of 5,nm in diameter of alternative light and dark rows with an one-dimensional periodicity of 3.5,Å. [source] Mechanism of Charge Separation in DNA by Hole Transfer through Consecutive AdeninesCHEMISTRY - A EUROPEAN JOURNAL, Issue 12 2008Kiyohiko Kawai Prof. Abstract To investigate the mechanism of charge separation in DNA with consecutive adenines adjacent to a photosensitizer (Sens), a series of naphthalimide (NI) and 5-bromouracil (brU)-modified DNAs were prepared, and the quantum yields of formation of the charge-separated states (,) upon photo-excitation of the Sens NI in DNA were measured. The , was modulated by the incorporation site of brU, which changes the oxidation potential of its complementary A through hydrogen bonding and the hole-transfer rates between adenines. The results were interpreted as charge separation by means of the initial charge transfer between NI in the singlet excited state and the second- and third-nearest adenine to the NI. In addition, the oxidation of the A nearest to NI leads to the rapid charge recombination within a contact ion pair. This suggests that the charge-separation process can be refined to maximize the , by putting a redox-inactive spacer base pair between a photosensitizer and an A,T stretch. [source] Bioisosterism, enantioselectivity, and molecular modeling of new effective N6 - and/or N(9)-substituted 2-phenyl adenines and 8-aza analogs: Different binding modes to A1 adenosine receptorsDRUG DEVELOPMENT RESEARCH, Issue 2 2001A. Maria Bianucci Abstract Bioisosterism of the adenine and 8-azaadenine nuclei was demonstrated by comparison of A1 adenosine receptor binding affinity of 2-phenyl N6 -substituted adenines and the corresponding 8-azaadenines. Some of these new compounds are very potent A1 adenosine receptor antagonists. This work also describes the synthesis and A1 adenosine receptor binding of the enantiomers of some 2-phenyladenines substituted with a 1-phenylethyl chiral group in N6 and N(9) positions. Biological results, showing the same stereoselectivity for all the couples of enantiomers, may supply proof for the hypothesis of a possible double arrangement of 2-phenylsubstituted adenines inside A1 adenosine receptors. Theoretical studies, based on an improved A1 adenosine receptor model and consisting of evaluation and comparison of interaction energies in complexes involving some selected chiral ligands, support the above hypothesis. Drug Dev. Res. 54:52,65, 2001. © 2001 Wiley-Liss, Inc. [source] Redox Couple of DNA on Multiwalled Carbon Nanotube Modified ElectrodeELECTROANALYSIS, Issue 14 2009Hongxia Luo Abstract It has been envisioned that carbon nanotubes could promote electron-transfer reactions when used as electrode materials in electrochemical cells. In the present study, calf thymus DNA was electrochemically oxidized at an electrode modified with multiwalled carbon nanotubes. The potentials for DNA oxidation at pH,7.0 were found to be 0.71 and 0.81,V versus SCE, corresponding to the oxidation of guanine and adenine residues, respectively. An initial oxidation of adenine was observed in the first scan, which was followed by a quasi-reversible redox process of the oxidation product in the subsequent scans. [source] Square-Wave Voltammetry as a Tool for Investigation of Doxorubicin Interactions with DNA Isolated from Neuroblastoma CellsELECTROANALYSIS, Issue 3-5 2009Dalibor Huska Abstract We investigated ethidium bromide intercalation into DNA molecule as a model system to test square-wave voltammetry (SWV) as a suitable method for this purpose We found that 0.13,,g EtBr intercalates into 1,,g dsDNA in average. Further, SWV was utilized for investigation of doxorubicin-DNA interactions. Intercalated doxorubicin reduced observed dsDNA cytosine and adenine (CA) signal, but also provided new signal called DOXO at ,0.35,V. This phenomenon was observed at both single and double stranded DNA standards. We also employed adsorptive transfer stripping technique coupled with SWV for study of doxorubicin-DNA interactions. Doxorubicin intercalation into dsDNA molecule adsorbed onto working electrode was fast, because we observed considerable changes in CA and DOXO signals after 360,s. Finally, we detected doxorubicin-DNA adducts formed in doxorubicin treated neuroblastoma cells. [source] Fabrication and Application of a Novel Modified Electrode Based on Multiwalled Nanotubes/Cerium(III) 12-Tungstophosphoric Acid NanocompositeELECTROANALYSIS, Issue 11 2008Bin Fang Abstract A novel multiwalled nanotubes (MWNTs)/Cerium(III) 12 - tungstophosphoric acid (CePW) nanocomposite film glassy carbon electrode was prepared in this paper. Electrochemical behaviors of the CePW/MWNTs modified electrode were investigated by electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV). This modified electrode brought new capabilities for electrochemical devices by combining the advantages of carbon nanotubes, rare-earth, and heteropoly-acids. The results demonstrated that the CePW/MWNTs modified electrode exhibited enhanced electrocatalytic behavior and good stability for the detection of guanine and adenine in 0.1,M PBS (pH,7.0). The experimental parameters were optimized and a direct electrochemical method for the simultaneous determination of guanine and adenine was proposed. The detection limit (S/N=3) for guanine and adenine was 2.0×10,8,M and 3.0×10,8,M, respectively. Further, the acid-denatured calf thymus DNA was also detected and the result was satisfied. [source] Working Electrodes from Amalgam Paste for Electrochemical MeasurementsELECTROANALYSIS, Issue 4 2008Bogdan Yosypchuk Abstract Paste electrode with paste amalgam as an active electrode material is described here for the first time. Designed electrode from silver paste amalgam (AgA-PE) is solely metallic and does not contain any organic binder. Mechanical surface regeneration of AgA-PE is performed in the same way as for classical carbon paste electrodes and reproducibility of such regeneration is about 10%. Electrochemical surface regeneration appeared very efficient for most measurements. In dependence on paste metal content, the electrode surface can be liquid (resembling a film) or rather solid. The hydrogen overvoltage on AgA-PE is high, and the electrode allows measurements at highly negative potentials. AgA-PE is well suited for study of reduction or oxidation processes without an accumulation step. Anodic stripping voltammetry of some metals tested on the electrode is influenced by formation of intermetallic compounds. The measurement based on cathodic stripping voltammetry (adenine, cysteine) and on catalytic processes from adsorbed state (complex of osmium tetroxide with 2,2,-bipyridine) can be performed on AgA-PE practically under the same conditions as found earlier for HMDE and for silver solid amalgam electrode. The working electrode from paste amalgam combines the advantages of paste and metal electrodes. [source] DNA Determination in the Presence of Copper in Diluted Alkaline Electrolyte by Adsorptive Stripping Voltammetry at the Mercury Film ElectrodeELECTROANALYSIS, Issue 11 2007Augusto, Mardini Farias, Percio Abstract A stripping method for the determination of single-stranded DNA in presence of copper at the submicromolar concentration levels is described. The method is based on controlled adsorptive accumulation of adenine (from acid-treated DNA) at thin-film mercury electrode followed by linear scan voltammetry measurement of the surface species. Optimum experimental conditions were found to be the use of a 5.0×10,3,M NaOH solution, an accumulation potential of ,0.40,V and a scan rate of 200,mV s,1. The response of adenine,copper is linear over the concentration range 50,250,ppb. For an accumulation time of 15,minutes, the detection limit was found to be 4,ppb. The more convenient relation to measuring the ssDNA in presence of metals and nitrogenated bases were also investigated. The utility of the method is demonstrated by the presence of adenosine-triphosphate (ATP) and amino acids. [source] Label-Free and Label Based Electrochemical Detection of Hybridization by Using Methylene Blue and Peptide Nucleic Acid Probes at Chitosan Modified Carbon Paste ElectrodesELECTROANALYSIS, Issue 24 2002Pinar Kara Abstract A chitosan modified carbon paste electrode (ChiCPE) based DNA biosensor for the recognition of calf thymus double stranded DNA (dsDNA), single stranded DNA (ssDNA) and hybridization detection between complementary DNA oligonucleotides is presented. DNA and oligonucleotides were electrostatically attached by using chitosan onto CPE. The amino groups of chitosan formed a strong complex with the phosphate backbone of DNA. The immobilized probe could selectively hybridize with the target DNA to form hybrid on the CPE surface. The detection of hybridization was observed by using the label-free and label based protocols. The oxidation signals of guanine and adenine greatly decreased when a hybrid was formed on the ChiCPE surface. The changes in the peak currents of methylene blue (MB), an electroactive label, were observed upon hybridization of probe with target. The signals of MB were investigated at dsDNA modified ChiCPE and ssDNA modified ChiCPE and the increased peak currents were observed, in respect to the order of electrodes. The hybridization of peptide nucleic acid (PNA) probes with the DNA target sequences at ChiCPE was also investigated. Performance characteristics of the sensor were described, along with future prospects. [source] Enhanced separation of purine and pyrimidine bases using carboxylic multiwalled carbon nanotubes as additive in capillary zone electrophoresisELECTROPHORESIS, Issue 16 2006Xin Xiong Abstract This paper describes the enhanced separation of adenine (A), hypoxanthine (HX), 8-azaadenine (8-AA), thymine (T), cytosine (C), uracil (U) and guanine (G) by CZE dispersing carboxylic multiwalled carbon nanotubes (c-MWNTs) into the running buffer. The effect of important factors such as c-MWNT nanoparticle concentration, the acidity and concentration of running buffer, and separation voltage were investigated to acquire the optimum conditions. The seven purine and pyrimidine bases could be well separated within 16,min in a 35,cm effective length fused-silica capillary at a separation voltage of +8.0,kV in a 23,mM tetraborate buffer (pH,9.2) containing 8.0×10,5,g/mL c-MWNTs. Under the optimal conditions, the linear ranges were of 2,250,,g/mL for A (R2,=,0.995), 3,200,,g/mL for U (R2,=,0.990) and G (R2,=,0.992), 3,250,,g/mL for T (R2,=,0.998), 2,200,,g/mL for C (R2,=,0.985) and 4,200,,g/mL for HX (R2,=,0.988) and 8-AA (R2,=,0.990). The detection limits were 0.9,,g/mL for A (S/N,=,3), 2.4,,g/mL for U, 2.0,,g/mL for T, 1.5,,g/mL for C, 2.5,,g/mL for G and 3.0,,g/mL for HX and 8-AA. The proposed method was successfully applied for determining five purine and pyrimidine bases in yeast RNA. [source] Enhancement of the NAD(P)(H) Pool in Saccharomyces cerevisiaeENGINEERING IN LIFE SCIENCES (ELECTRONIC), Issue 4 2008A. Knepper Abstract Asymmetric biosyntheses allow for an efficient production of chiral building blocks. The application of whole cells as biocatalysts for asymmetric syntheses is advantageous because they already contain the essential coenzymes NAD(H) or NADP(H), which additionally can be regenerated in the cells. Unfortunately, reduced catalytic activity compared to the oxidoreductase activity is observed in many cases during whole-cell biotransformation. This may be caused by low intracellular coenzyme pool sizes and/or a decline in intracellular coenzyme concentrations. To enhance the intracellular coenzyme pool sizes, the effects of the precursor metabolites adenine and nicotinic acid on the intracellular accumulation of NAD(H) and NADP(H) were studied in Saccharomyces cerevisiae. Based on the results of simple batch experiments with different precursor additions, fed-batch processes for the production of yeast cells with enhanced NAD(H) or enhanced NADP(H) pool sizes were developed. Supplementation of the feed medium with 95,mM adenine and 9.5,mM nicotinic acid resulted in an increase of the intracellular NAD(H) concentration by a factor of 10 at the end of the fed-batch process compared to the reference process. The final NAD(H) concentration remains unchanged if the feed medium was solely supplemented with 95,mM adenine, but intracellular NADP(H) was increased by a factor of 4. The effects of NADP(H) pool sizes on the asymmetric reduction of ethyl-4-chloro acetoacetate (CAAE) to the corresponding (S)-4-chloro-3-hydroxybutanoate (S-CHBE) was evaluated with S.,cerevisiae,FasB,His6 as an example. An intracellular threshold concentration above 0.07,mM NADP(H) was sufficient to increase the biocatalytic S-CHBE productivity by 25,% compared to lower intracellular NADP(H) concentrations. [source] Syntheses and Coordination Chemistry of Aminomethylphosphine Derivatives of AdenineEUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 13 2003Qingzhi Zhang Abstract Two aminomethylphosphane derivatives of adenine 9-(2-{bis[(diphenylphosphanyl)methyl]amino}ethyl)adenine (La) and 9-(3-{bis[(diphenylphosphanyl)methyl]amino}propyl)adenine (Lb) were synthesised. Oxidation of La and Lb with H2O2, elemental sulfur or elemental selenium led to the corresponding oxidized products 4a/b,6a/b. Both La and Lb behave as didentate ligands towards late transition metals. Reaction of La or Lb with [MX2(cod)] (M = Pd, Pt; X = Cl, Me) gave chelate complexes 7a/b,10a/b. Reaction of La or Lb with [AuCl(tht)] or [{RuCl(,-Cl)(p -MeC6H4iPr)}2] gave the didentate bridging complexes 11a/b and 12a. All compounds have been fully characterised by microanalysis, IR, 1H and 31P{1H} NMR spectroscopy, and EI/CI/FAB mass spectrometry. 1H{31P} NMR and 1H- 13C correlation experiments were used to confirm the spectral assignments where necessary. Two compounds were structurally characterised by X-ray crystallographic analysis. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003) [source] Coordination Modes of 9-Methyladenine in cis -Platinum(II) Complexes with Dimethyl(phenyl)phosphanes as Ancillary Ligands , Synthesis and Characterization of cis -[PtL2(9-MeAd)2](NO3)2, cis -[PtL2{9-MeAd(,H)}]3(NO3)3, and cis -[L2Pt{9-MeAd(,H)}PtL2](NO3)3EUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 1 2003Bruno Longato Abstract Treatment of 9-methyladenine (9-MeAd) with cis -[PtL2(NO3)2] (1) (L = PMe2Ph) in a 2:1 molar ratio generated the bis(adduct) cis -[PtL2(9-MeAd)2](NO3)2 (2), which was isolated and fully characterized by multinuclear (1H, 31P, 13C, 195Pt and 15N) NMR analysis, which showed that the two nucleobases are selectively coordinated through the N1 atom. Small amounts of a mono(adduct) cis -[PtL2(S)(9-MeAd)]2+ (3) (S = solvent) and of a diplatinated species cis -[L2Pt(S){9-MeAd(,H)}PtL2]3+ (4) are formed in DMSO solution when 9-MeAd is present in smaller quantities than 1. Complex 3 is platinated at N1, with a solvent molecule representing the fourth ligand around the metal center. Complex 4 contains an adenine molecule deprotonated and platinated at N1,N6,N7, with two cis -L2Pt units bonded to nitrogen atom N1 and to nitrogen atoms N6 and N7, respectively. With increasing relative concentration of the nucleobase, both complexes 3 and 4 progressively convert into the bis(adduct) 2, the only species detectable in solution when the Ad/Pt molar ratio is 2:1. The trinuclear compound cis -[L2Pt{9-MeAd(,H)}]3(NO3)3 (5) (L = PMe2Ph), containing an NH2 -deprotonated nucleobase bridging the metal centers through the N1 and N6 atoms, is quantitatively formed when the dinuclear hydroxo complex cis -[Pt(,-OH)L2]2(NO3)2 (6) reacts with 9-MeAd in CH3CN solution. The isolated complex was fully characterized by multinuclear NMR spectroscopy and mass spectrometry. It appears to be stable in solution in CH3CN and chlorinated solvents, whereas in DMSO it partially converts into a new species, probably the dinuclear analog cis -[PtL2{9-MeAd(,H)}]2(NO3)2, in which the adenine maintains its coordination mode. At equilibrium the trinuclear/dinuclear species molar ratio is 20:1. Through the addition of a stoichiometric amount of nitrate 1 to a DMSO solution of 5 we were able to generate the diplatinated compound 4 in high yield. Complex 4 displays a new coordination mode for the adeninate ion, with N1 bonded to one platinum atom whereas N6 and N7 are chelated to a second one. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003) [source] Mechanisms of neurodegeneration in Huntington's diseaseEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2008Joana M. Gil Abstract Huntington's disease (HD) is caused by an expansion of cytosine,adenine,guanine (CAG) repeats in the huntingtin gene, which leads to neuronal loss in the striatum and cortex and to the appearance of neuronal intranuclear inclusions of mutant huntingtin. Huntingtin plays a role in protein trafficking, vesicle transport, postsynaptic signaling, transcriptional regulation, and apoptosis. Thus, a loss of function of the normal protein and a toxic gain of function of the mutant huntingtin contribute to the disruption of multiple intracellular pathways. Furthermore, excitotoxicity, dopamine toxicity, metabolic impairment, mitochondrial dysfunction, oxidative stress, apoptosis, and autophagy have been implicated in the progressive degeneration observed in HD. Nevertheless, despite the efforts of a multidisciplinary scientific community, there is no cure for this devastating neurodegenerative disorder. This review presents an overview of the mechanisms that may contribute for HD pathogenesis. Ultimately, a better understanding of these mechanisms will lead to the development of more effective therapeutic targets. [source] NMR Quantification of Tautomeric Populations in Biogenic Purine BasesEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 9 2009Bartl Abstract Purine bases such as purine, adenine, hypoxanthine, and mercaptopurine are known to exist in several tautomeric forms. Characterization of their tautomeric equilibria is important not only for predicting the regioselectivity of their N -alkylation reactions, but also for gaining knowledge of the patterns with which these compounds of significant biological activity form hydrogen bonds with their biological targets. The tautomeric equilibria of purine and some purine derivatives in methanol and N,N -dimethylformamide solutions were investigated by low-temperature 1H and 13C NMR spectroscopy. The N(7)H and N(9)H tautomeric forms were quantified by integrating the individual 1H NMR signals at low temperatures. The Gibbs free energy differences were calculated and the effects of substitution on the N(7)H/N(9)H ratio discussed. A previously published theoretically predicted mechanism of the tautomeric exchange is compared with our measurements in deuteriated solvents. The influence of concentration on the temperature of coalescence indicates that supramolecular clusters play a significant role in this proton transfer process. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009) [source] XNA, (xylo Nucleic Acid): A Summary and New DerivativesEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 11 2005B. Ravindra Babu Abstract Fully modified homopyrimidine 2'-deoxy- xylo nucleic acid (dXNA) form triple helixes with complementary DNA/RNA with thermal stabilities comparable to those of the corresponding DNA:DNA and DNA:RNA duplexes. However, a single or few insertions of dXNA monomers in a DNA strand significantly lower duplex stabilities. The dXNA monomers are known to adopt predominantly an N -type furanose conformation in solution. With a desire to increase the binding affinity, seven sugar-modified XNA monomers (H, F, N, M, K, P and Q) have been synthesised and their effect on hybridization towards DNA and RNA complements studied. The introduction of 2'-fluoro and 2'-hydroxy substituents was expected to induce conformational restriction towards C3'- endo -type furanose conformation of monomer F derived from 1-(2'-deoxy-2'-fluoro-,- D -xylofuranosyl)thymine and monomer H derived from 1-(,- D -xylofuranosyl)thymine. The presence of functionalites facing the minor groove as in 1-(2'-amino-2'-deoxy-2'- N,4'- C -methylene-,- D -xylofuranosyl)thymine (monomer N), 1-[4- C -(N -methylpiperazinyl)methyl-,- D -xylofuranosyl]thymine (monomer P), 1-(4- C -piperazinylmethyl-,- D -xylofuranosyl)thymine (monomer Q), 1-(4- C -hydroxymethyl-,- D -xylofuranosyl)thymine (monomer M) and 9-(4- C -hydroxymethyl-,- D -xylofuranosyl)adenine (monomer K) was studied, with monomer N being locked in an N -type furanose conformation. Besides, an efficient synthesis of known xylo -LNA phosphoramidite 19, required for the incorporation of 1-(2'- O,4'- C -methylene-,- D -xylofuranosyl)thymine (monomer L) is described. For comparison, hydridization data of various XNAs reported in the literature are included in the discussion section. The thermal denaturation studies show that XNAs containing conformationally locked monomers (N and L) display improved binding affinity, and that partially modified DNA/XNA chimera, or fully modified XNA display preferential hybridization towards RNA complements. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005) [source] Synthesis of Novel Nucleo-,-Amino Acids and Nucleobase-Functionalized ,-PeptidesEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 18 2003Arndt M. Brückner Abstract Four novel ,-amino acids bearing the canonical nucleobases guanine, cytosine, adenine, and thymine in the side chain, are synthesized starting from Boc- L -aspartic acid 4-benzyl ester. The syntheses are accomplished in six steps by the nucleophilic substitution of (S)-,-(tert -butoxycarbonylamino)-,-bromopentanoic acid benzyl ester with the corresponding nucleobase derivative as the key step. The guaninyl and cytosinyl ,-amino acids were built into ,-peptides that were studied by temperature-dependent CD and UV spectroscopy. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003) [source] Kinetic mechanism for p38 MAP kinase ,FEBS JOURNAL, Issue 18 2005A partial rapid-equilibrium random-order ternary-complex mechanism for the phosphorylation of a protein substrate p38 Mitogen-activated protein kinase alpha (p38 MAPK,) is a member of the MAPK family. It is activated by cellular stresses and has a number of cellular substrates whose coordinated regulation mediates inflammatory responses. In addition, it is a useful anti-inflammatory drug target that has a high specificity for Ser-Pro or Thr-Pro motifs in proteins and contains a number of transcription factors as well as protein kinases in its catalog of known substrates. Fundamental to signal transduction research is the understanding of the kinetic mechanisms of protein kinases and other protein modifying enzymes. To achieve this end, because peptides often make only a subset of the full range of interactions made by proteins, protein substrates must be utilized to fully elucidate kinetic mechanisms. We show using an untagged highly active form of p38 MAPK,, expressed and purified from Escherichia coli[Szafranska AE, Luo X & Dalby KN (2005) Anal Biochem336, 1,10) that at pH 7.5, 10 mm Mg2+ and 27 °C p38 MAPK, phosphorylates ATF2,115 through a partial rapid-equilibrium random-order ternary-complex mechanism. This mechanism is supported by a combination of steady-state substrate and inhibition kinetics, as well as microcalorimetry and published structural studies. The steady-state kinetic experiments suggest that magnesium adenosine triphosphate (MgATP), adenylyl (,,,-methylene) diphosphonic acid (MgAMP-PCP) and magnesium adenosine diphosphate (MgADP) bind p38 MAPK, with dissociation constants of KA = 360 µm, KI = 240 µm, and KI > 2000 µm, respectively. Calorimetry experiments suggest that MgAMP-PCP and MgADP bind the p38 MAPK,,ATF2,115 binary complex slightly more tightly than they do the free enzyme, with a dissociation constant of Kd , 70 µm. Interestingly, MgAMP-PCP exhibits a mixed inhibition pattern with respect to ATF2,115, whereas MgADP exhibits an uncompetitive-like pattern. This discrepancy occurs because MgADP, unlike MgAMP-PCP, binds the free enzyme weakly. Intriguingly, no inhibition by 2 mm adenine or 2 mm MgAMP was detected, suggesting that the presence of a ,-phosphate is essential for significant binding of an ATP analog to the enzyme. Surprisingly, we found that inhibition by the well-known p38 MAPK, inhibitor SB 203580 does not follow classical linear inhibition kinetics at concentrations >,100 nm, as previously suggested, demonstrating that caution must be used when interpreting kinetic experiments using this inhibitor. [source] Visualization of the interaction between archaeal DNA polymerase and uracil-containing DNA by atomic force microscopyGENES TO CELLS, Issue 1 2006Yasuo Asami Deamination of cytosine to uracil is a hydrolytic reaction that is greatly accelerated at high temperatures. The resulting uracil pairs with adenine during DNA replication, thereby inducing G:C to A:T transitions in the progeny. Interestingly, B-family DNA polymerases from hyperthermophilic Archaea recognize the presence of uracil in DNA and stall DNA synthesis. To better understand the recognition mechanism, the binding modes of DNA polymerase B1 of Sulfolobus solfataricus (Pol B1) to uracil-containing DNA were examined by gel mobility shift assays and atomic force microscopy. Although PolB1 per se specifically binds to uracil-containing single-stranded DNA, the binding efficiency was substantially enhanced by the initiation of DNA synthesis. Analysis by the atomic force microscopy showed a number of double-stranded DNA (dsDNA) in the products of DNA synthesis. The generation of ds DNA was significantly inhibited, however, by the presence of template uracil, and intermediates where monomeric forms of Pol B1 appeared to bind to uracil-containing DNA were observed. These results suggest that Pol B1 more efficiently recognizes uracil in DNA during DNA synthesis rather than during random diffusion in solution, and that single molecules of Pol B1 bind to template uracil and stall DNA synthesis. [source] Caffeine mimics adenine and 2,-deoxyadenosine, both of which inhibit the guanine-nucleotide exchange activity of RCC1 and the kinase activity of ATRGENES TO CELLS, Issue 5 2003Hitoshi Nishijima Background: Both caffeine and the inactivation of RCC1, the guanine-nucleotide exchange factor (GEF) of Ran, induce premature chromatin condensation (PCC) in hamster BHK21 cells arrested in the S-phase, suggesting that RCC1 is a target for caffeine. Results: Caffeine inhibited the Ran-GEF activity of RCC1 by preventing the binary complex formation of Ran-RCC1. Inhibition of the Ran-GEF activity of RCC1 by caffeine and its derivatives was correlated with their ability to induce PCC. Since caffeine is a derivative of xanthine, the bases and nucleosides were screened for their ability to inhibit RCC1. Adenine, adenosine, and all of the 2,-deoxynucleosides inhibited the Ran-GEF activity of RCC1; however, only adenine and 2,-deoxyadenosine (2,-dA) induced PCC. A factor(s) other than RCC1, should therefore be involved in PCC-induction. We found that both adenine and 2,-dA, but none of the other 2,-deoxynucleosides, inhibited the kinase activity of ATR, similar to that of caffeine. The ATR pathway was also abrogated by the inactivation of RCC1 in tsBN2 cells. Conclusion: The effect of caffeine on cell-cycle control mimics the biological effect of adenine and 2,-dA, both of which inhibit ATR. dATP, a final metabolite of adenine and 2,-dA, is suggested to inhibit ATR, resulting in PCC. [source] New Long-Chain Esters and Adenine Analogs from the Leaves of Formosan Bridelia balansaeHELVETICA CHIMICA ACTA, Issue 7 2003Yeh-Hsin Tsai Six new compounds, including the two long-chain esters balansenate I (=6,8,11-trimethyldodecanoic acid (2E)-3-methylhexadec-2-enyl ester; 1) and balansenate II (=10,12,15-trimethylhexadedecanoic acid (2E)-3-methylhexadec-2-enyl ester; 2), the eburicane-like triterpenoid bridelone (=hexadecahydro-4,4,10,13,14-pentamethyl-17-(5-methyl-1,4-dimethylenehexyl)-3H -cyclopenta[a]phenanthren-3-one; 3), the ,deimino-xanthine', bridelonine (=5-(3-methylbut-2-enyl)pyrrolo[3,4- d]imidazole-4,6(1H,5H)-dione; 6), and the two adenine analogs 9-(3-methylbut-2-enyl)adenine (7) and 1-(3-methylbut-2-enyl)adenine (8), besides three known compounds, i.e., N6 -(3-methylbut-2-enyl)adenine (4), 3-(3-methylbut-2-enyl)adenine (5), and adenine (9), were isolated from the leaves of Formosan Bridelia balansae. The novel skeleton of 6 consists of a fused pyrrolidine-2,5-dione and imidazole moiety. The already known adenines 7 and 8 were isolated for the first time from a plant. The structures of the isolated compounds were elucidated by spectroscopic analyses. [source] Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitisHEPATOLOGY, Issue 1 2000Kosh Agarwal Genetic susceptibility to type 1 autoimmune hepatitis is indicated by a preponderance of female subjects and strong associations with human leukocyte antigens (HLA) DRB1*0301 and DRB1*0401. The gene encoding cytotoxic T-lymphocyte antigen-4 (CTLA-4) on chromosome 2q33 may also influence autoimmunity. To determine the frequency and significance of the exon 1 adenine (A)-guanine (G) base-exchange polymorphism for CTLA-4 in patients with type 1 autoimmune hepatitis, 155 northern European Caucasoid patients and 102 ethnically-matched control subjects were tested by polymerase chain reaction. The genotype distribution was significantly different in patients compared to controls (AA = 50/155 patients vs. 51/102 controls; AG = 84/155 patients vs. 38/102 controls; GG = 21/155 patients vs. 13/102 controls, ,2 = 8.94, P = .011). This difference was caused by a significant over-representation of the G allele in patients compared to controls (105/155 patients vs. 51/102 controls, ,2 = 8.34, P = .004, odds ratio = 2.12). The GG genotype was associated with a significantly higher mean serum aspartate transaminase level (P = .03), greater frequency of antibodies to thyroid microsomal antigens (P = .004) and was found more commonly in patients with HLADRB1*0301 (P = .02). Treatment outcomes, however, were not affected by the genotype. The CTLA-4 G allele is more common in patients with type 1 autoimmune hepatitis and may represent a second susceptibility allele. Furthermore, there may be synergy between the HLA-DRB1*0301 and the GG genotype in terms of disease risk. [source] Sequence and organization of the mitochondrial genome of the Chagas disease vector, Triatoma dimidiataINSECT MOLECULAR BIOLOGY, Issue 3 2001E. M. Dotson Abstract The 17 019 bp mitochondrial genome of Triatoma dimidiata is composed of thirteen protein coding sequences, twenty-two tRNAs, small and large ribosomal units, and a control region. The gene order and orientation are identical to that of Drosophila yakuba. The nucleotide composition is biased toward adenine and thymine (69.5% A + T). The 2.1 kb putative control region, known as the A + T rich region in most insects, has an A + T bias of 66%, but contains a 400 bp sequence that is 77.5% A + T and two other distinct regions: (1) one with a lower A + T bias (60.1%) and (2) a region of eight tandem repeat units. The identified 1.4 kb nuclear copy of mitochondrial sequences encompasses the string of Gs and the beginning of the cytochrome c oxidase 1 gene but lacks the 1.8 kb region spanning the eight tandem repeats and the 5, end of the NADH dehydrogenase subunit II gene. [source] Tautomeric forms of adenine: Vertical ionization energies and Dyson orbitalsINTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 10 2010Raman K. Singh Abstract For the MP2/6-311++g(2df,p) optimized geometry of all the 14 adenine tautomers, the first three vertical ionization energies have been calculated using several electron propagator decouplings. The corresponding Dyson orbitals provide detailed insight into the role of structural variations in different adenine tautomers. Changes in the electron binding energies and the corresponding Dyson orbital amplitudes have been correlated with tautomeric proton shifts and changes in conjugation patterns. © 2009 Wiley Periodicals, Inc. Int J Quantum Chem, 2010 [source] ONIOM quantum chemistry study of cyclic nucleotide recognition in phosphodiesterase 5INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 12 2007Kerrie A. O'Brien Abstract Cyclic nucleotide phosphodiesterases (PDEs) are enzymes that contribute to the regulation of cyclic nucleotides in the cell by catalyzing the hydrolysis reaction of the O3,-phosphorous bond, yielding the noncyclic nucleotide as the product. The principal substrates are cyclic 3,,5,-adenosine and -guanosine monophosphate (cAMP and cGMP). PDE5, an important target of drug inhibition, is known to be highly selective for hydrolysis of cGMP. We use all-quantum hybrid calculations to accurately describe the binding interactions between PDE5 and cAMP/cGMP for the first time. The main reasons for cGMP preference in PDE5 are found to be to the fixed orientation of a conserved glutamine residue (Gln 817) together with the fixed orientation of a nonconserved glutamine residue (Gln 775). We report ONIOM(B3LYP/6-31g(d):PM3MM) binding energies, which reflect favorable guanine alignment with Gln 817 and steric crowding of adenine by Gln 775. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2007 [source] Sex Steroid Level, Androgen Receptor Polymorphism, and Depressive Symptoms in Healthy Elderly MenJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 4 2005Guy G. T'Sjoen MD Objectives: To determine the prevalence of depression in a cohort of elderly men as assessed using a 30-item Geriatric Depression Scale (GDS) score and to describe the association between this score and sex steroids, androgen receptor (AR) polymorphism, and general health status. Design: Observational study on the relationship between sex steroid status and health-related parameters. Setting: Community-based. Participants: Ambulatory men (n=236 in 1997, n=192 in 2000) aged 70 and older at inclusion in 1996, interviewed in 1997 and 2000. Measurements: Serum levels of testosterone, estradiol, sex hormone binding globulin (SHBG), dehydroepiandrosterone-sulfate (DHEAS), cortisol, and the AR gene cytosine, adenine, guanine (CAG)-repeat length polymorphism were determined. Free testosterone and free estradiol were calculated. Questionnaires included GDS, 36-item Short Form, and Rapid Disability Rating Scale,2. Results: Median age was 75.3 years (interquartile range=73.5,78.5). A GDS score of 11 or greater was found in 30 (12.7%) men. Age and GDS score were significantly interrelated (P<.01), as were all health-assessment scores. GDS scores were not related to (free) testosterone or AR polymorphism in 1997 or 2000. In 1997 only (n=236), higher GDS scores were related to higher estradiol, free estradiol, and DHEAS levels. Conclusion: The data did not support a role for testosterone in depression in elderly community-based men as assessed using the GDS. [source] | |||||||||||||||||||||||||||||||||||||||||||