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Guanine
Terms modified by Guanine Selected AbstractsSynthesis 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] Guanine-Based Biogenic Photonic-Crystal Arrays in Fish and SpidersADVANCED FUNCTIONAL MATERIALS, Issue 2 2010Avital Levy-Lior Abstract Biological photonic systems composed of anhydrous guanine crystals evolved separately in several taxonomic groups. Here, two such systems found in fish and spiders, both of which make use of anhydrous guanine crystal plates to produce structural colors, are examined. Measurements of the photonic-crystal structures using cryo-SEM show that the crystal plates in both fish skin and spider integument are ,20-nm thick. The reflective unit in the fish comprises stacks of single plates alternating with ,230-nm-thick cytoplasm layers. In the spiders the plates are formed as doublet crystals, cemented by 30-nm layers of amorphous guanine, and are stacked with ,200,nm of cytoplasm between crystal doublets. They achieve light reflective properties through the control of crystal morphology and stack dimensions, reaching similar efficiencies of light reflectivity in both fish skin and spider integument. The structure of guanine plates in spiders are compared with the more common situation in which guanine occurs in the form of relatively unorganized prismatic crystals, yielding a matt white coloration. [source] The CBS subdomain of inosine 5,-monophosphate dehydrogenase regulates purine nucleotide turnoverMOLECULAR MICROBIOLOGY, Issue 2 2008Maxim Pimkin Summary Inosine 5,-monophosphate dehydrogenase (IMPDH) catalyses the rate-limiting step in guanine nucleotide biosynthesis. IMPDH has an evolutionary conserved CBS subdomain of unknown function. The subdomain can be deleted without impairing the in vitro IMPDH catalytic activity and is the site for mutations associated with human retinitis pigmentosa. A guanine-prototrophic Escherichia coli strain, MP101, was constructed with the subdomain sequence deleted from the chromosomal gene for IMPDH. The ATP content was substantially elevated in MP101 whereas the GTP content was slighty reduced. The activities of IMPDH, adenylosuccinate synthetase and GMP reductase were two to threefold lower in MP101 crude extracts compared with the BW25113 wild-type strain. Guanine induced a threefold reduction in the MP101 ATP pool and a fourfold increase in the GTP pool within 10 min of addition to growing cells; this response does not result from the reduced IMPDH activity or starvation for guanylates. In vivo kinetic analysis using 14-C tracers and 33-P pulse-chasing revealed mutation-associated changes in purine nucleotide fluxes and turnover rates. We conclude that the CBS subdomain of IMPDH may coordinate the activities of the enzymes of purine nucleotide metabolism and is essential for maintaining the normal ATP and GTP pool sizes in E. coli. [source] Rotational Spectral Signatures of Four Tautomers of Guanine,ANGEWANDTE CHEMIE, Issue 33 2009Ultraschnell: Das Rotationsspektrum von Guanin wurde mithilfe der Laserabtragungs-Molekularstrahl-Fourier-Transformations-Mikrowellen(LA-MB-FTMW)-Spektroskopie untersucht. Die N7H-Keto-, N9H-Keto-, N9H-Enol- trans - und N9H-Enol- cis -Formen (siehe Strukturen) wurden zweifelsfrei in der Überschallexpansion anhand der experimentellen Werte der Rotationskonstanten identifiziert. [source] Low-Energy-Barrier Proton Transfer Induced by Electron Attachment to the Guanine,,,Cytosine Base PairCHEMPHYSCHEM, Issue 4 2010Anna Szyperska Abstract The photoelectron spectrum of the anion of the guanine,,,cytosine base apair (GC)., is recorded for the first time. The observed variation in the spectral peak-height ratios with the source conditions suggests the presence of two or more anionic isomers. Two maxima of the broad bands in the photoelectron spectrum were measured at about 1.9 and about 2.6 eV. These values are very well reproduced by the vertical detachment energies of the B3LYP/6-31++G(d,p) calculated low-energy anionic structures, which are 1) the Watson,Crick base-pair anion with proton transferred from N1 of guanine to N3 of cytosine, 2) its analogue in which the proton is transferred from N9 of guanine to N7 of guanine, and 3) the global minimum geometry, which is formed from the latter anion by rotation of guanine about the axis approximately defined by C2 of guanine and C4 of cytosine. Furthermore, a minor difference in the stabilities of the two lowest energy anions explains the experimentally observed source (temperature) dependence of the PES spectrum. A rational procedure, based on the chemistry involved in the formation of anionic dimers, which enables the low-energy anions populated in the photoelectron spectrum to be identified is proposed. In contrast to the alternative combinatorial approach, which in the studied case would lead to carrying out quantum chemical calculations for 2000,2500 structures, the procedure described here reduces the computational problem to only 15 geometries. [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] 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] Zinc Oxide/Zinc Hexacyanoferrate Hybrid Film-Modified Electrodes for Guanine DetectionELECTROANALYSIS, Issue 18 2007Hung-Wei Chu Abstract An electroactive polynuclear hybrid films of zinc oxide and zinc hexacyanoferrate (ZnO/ZnHCF) have been deposited on electrode surfaces from H2SO4 solution containing Zn(NO3)2 and K3[Fe(CN)6] by repetitive potential cycling method. Simultaneous cyclic voltammetry and electrochemical quartz crystal microbalance (EQCM) measurements demonstrate the steady growth of hybrid film. There are two redox couples present in the voltammograms of hybrid film and it is obvious in the case of pH,2. Surface morphology of hybrid film was investigated using scanning electron microscopy (SEM) and atomic force microscopy (AFM). Energy dispersive spectrometer (EDS) data confirm existence of zinc oxide in the hybrid film. The effect of type of monovalent cations on the redox behavior of resulting film was investigated. In pure supporting electrolyte, electrochemical responses of modified electrode resemble with that of a surface immobilized redox couple. The electrocatalytic activity of ZnO/ZnHCF hybrid film was investigated towards guanine using cyclic voltammetry and rotating disc electrode (RDE) techniques. Finally, feasibility of using ZnO/ZnHCF hybrid film-coated electrodes for guanine estimation in flow injection analysis (FIA) was also investigated. [source] Electrochemical Biosensor for the Detection of Interaction Between Arsenic Trioxide and DNA Based on Guanine SignalELECTROANALYSIS, Issue 7 2003Mehmet Ozsoz Abstract The interaction of arsenic trioxide (As2O3) with calf thymus double-stranded DNA (dsDNA), calf thymus single-stranded DNA (ssDNA) and also 17-mer short oligonucleotide (Probe,A) was studied electrochemically by using differential pulse voltammetry (DPV) with carbon paste electrode (CPE) at the surface and also in solution. Potentiometric stripping analysis (PSA) was employed to monitor the interaction of As2O3 with dsDNA in solution phase by using a renewable pencil graphite electrode (PGE). The changes in the experimental parameters such as the concentration of As2O3, and the accumulation time of As2O3 were studied by using DPV; in addition, the reproducibility data for the interaction between DNA and As2O3 was determined by using both electrochemical techniques. After the interaction of As2O3 with dsDNA, the DPV signal of guanine was found to be decreasing when the accumulation time and the concentration of As2O3 were increased. Similar DPV results were also found with ssDNA and oligonucleotide. PSA results observed at a low DNA concentration such as 1,ppm and a different working electrode such as PGE showed that there could be damage to guanine bases. The partition coefficients of As2O3 after interaction with dsDNA and ssDNA in solution by using CPE were calculated. Similarly, the partition coefficients (PC) of As2O3 after interaction with dsDNA in solution was also calculated by PSA at PGE. The features of this proposed method for the detection of DNA damage by As2O3 are discussed and compared with those methods previously reported for the other type of DNA targeted agents in the literature. [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] A novel approach for analysis of oligonucleotide,cisplatin interactions by continuous elution gel electrophoresis coupled to isotope dilution inductively coupled plasma mass spectrometry and matrix-assisted laser desorption/ionization mass spectrometryELECTROPHORESIS, Issue 7 2008Wolfram Brüchert Abstract In this work we present a novel approach for in vitro studies of cisplatin interactions with 8-mer oligonucleotides. The approach is based on the recently developed coupling of continuous elution gel electrophoresis (GE) to an inductively coupled plasma-sector field mass spectrometer (ICP-SFMS) with the aim of monitoring the interaction process between this cytostatic drug and the nucleotides. In contrast to existing methods, the electrophoretic separation conditions used here allow both the determination of the reaction kinetics in more detail as well as the observation of dominant intermediates. Two different nucleotides sequences have been investigated for comparison purposes, one containing two adjacent guanines (5,-TCCGGTCC-3,) and one with a combination of thymine and guanine (5,-TCCTGTCC-3,), respectively. In order to gain further structural information, MALDI-TOF MS measurements have been performed after fraction collection. This allows for identification of the intermediates and the final products and confirms the stepwise coordination of cisplatin via monoadduct to bisadduct formation. Furthermore, the ICP-MS results were quantitatively evaluated in order to calculate the kinetics of the entire process. [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] Novel DNA repair alkyltransferase from Caenorhabditis elegansENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 2-3 2001Sreenivas Kanugula Abstract O6 -Alkylguanine DNA-alkyltransferase (AGT) is a widely distributed DNA repair protein that protects living organisms from endogenous and exogenous alkylation damage to DNA at the O6 -position of guanine. The search of the C. elegans genome database for an AGT protein revealed the presence of a protein (cAGT-2) with some similarity to known AGTs in addition to the easily recognized cAGT-1 protein. The predicted protein sequence of cAGT-2 contains the amino acid sequence ,ProCysHisPro, at the presumed active site of the protein, whereas all other known AGTs have ,ProCysHisArg,. A truncated version of the cAGT-2 protein was expressed in E. coli. This purified recombinant protein was able to repair O6 -methylguanine and O4 -methylthymine adducts in DNA in vitro and also reacted with the bulky benzyl adduct in O6 -benzylguanine. This fragment of cAGT-2 (104 amino acids) is the smallest protein possessing AGT activity yet described. The full-length cAGT-2 protein (274 amino acids) totally lacks the N-terminal domain present in all other known AGTs but has a long C-terminal extension that has significant homology to histone 1C. Expression of cAGT-2 in an E. coli strain lacking endogenous AGT activity provided modest but statistically significant resistance to the toxicity of N -methyl- N,-nitro- N -nitrosoguanidine, confirming that cAGT-2 is an alkyltransferase. Environ. Mol. Mutagen. 38:235,243, 2001. © 2001 Wiley-Liss, Inc. [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] 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] Guanine-Based Biogenic Photonic-Crystal Arrays in Fish and SpidersADVANCED FUNCTIONAL MATERIALS, Issue 2 2010Avital Levy-Lior Abstract Biological photonic systems composed of anhydrous guanine crystals evolved separately in several taxonomic groups. Here, two such systems found in fish and spiders, both of which make use of anhydrous guanine crystal plates to produce structural colors, are examined. Measurements of the photonic-crystal structures using cryo-SEM show that the crystal plates in both fish skin and spider integument are ,20-nm thick. The reflective unit in the fish comprises stacks of single plates alternating with ,230-nm-thick cytoplasm layers. In the spiders the plates are formed as doublet crystals, cemented by 30-nm layers of amorphous guanine, and are stacked with ,200,nm of cytoplasm between crystal doublets. They achieve light reflective properties through the control of crystal morphology and stack dimensions, reaching similar efficiencies of light reflectivity in both fish skin and spider integument. The structure of guanine plates in spiders are compared with the more common situation in which guanine occurs in the form of relatively unorganized prismatic crystals, yielding a matt white coloration. [source] Crystal structure of human Rad GTPase of the RGK-familyGENES TO CELLS, Issue 8 2006Arry Yanuar Rad (Ras associated with diabetes) is an RGK-family small GTPase that is over-expressed in the skeletal muscle of humans with type II diabetes. Unlike other small GTPases, RGK family members including Rad lack several conserved residues in the GTPase domain. Here, we report the crystal structure of the GTPase domain of human Rad in the GDP-bound form at 1.8 Å resolution. The structure revealed unexpected disordered structures of both switches I and II. We showed that the conformational flexibility of both switches is caused by non-conservative substitutions in the G2 and G3 motifs forming the switch cores together with other substitutions in the structural elements interacting with the switches. Glycine-rich sequences of the switches would also contribute to the flexibility. Switch I lacks the conserved phenylalanine that makes non-polar interactions with the guanine base in H-Ras. Instead, water-mediated hydrogen bonding interactions were observed in Rad. The GDP molecule is located at the same position as in H-Ras and adopts a similar conformation as that bound in H-Ras. This similarity seems to be endowed by the conserved hydrogen bonding interactions with the guanine base-recognition loops and the magnesium ion that has a typical octahedral coordination shell identical to that in H-Ras. [source] Deficiency in OGG1 Protects against Inflammation and Mutagenic Effects Associated with H. pylori Infection in MouseHELICOBACTER, Issue 5 2006Eliette Touati Abstract Background:,Helicobacter pylori infection is associated with gastric cancer. Study with the Big Blue mouse model has reported a mutagenic effect associated with the H. pylori infection, as a result in part of oxidative DNA damage. The present work investigates the consequences of a deficiency in the OGG1 DNA glycosylase, responsible for the excision of 8-oxo guanine, on the inflammatory and genotoxic host response to the infection. Materials and Methods:, Big Blue Ogg1,/, C57BL/6 mice were orally inoculated with H. pylori strain SS1 or vehicle only, and sacrificed after 1, 3, or 6 months. The serologic response, histologic lesions, mutant frequency, and spectra of mutations were assessed in the stomach and compared to what observed in the wild-type (Wt) context. Results:, Inflammatory lesions induced in the gastric mucosa of H. pylori -infected mice, corresponding to a moderate gastritis, were less severe in Ogg1,/, than in Wt Big Blue mice. Analysis of antimicrobial humoral immunity exhibited a lower IgG2a serum level (Th1 response) after 6 months of infection in Ogg1,/, than in the Wt mice. In these conditions, the H. pylori -SS1 infection in the Ogg1,/, mice did not induce a mutagenic effect at the gastric epithelial cells level, either after 3 or 6 months. Conclusions:, The inactivation of the OGG1 DNA glycosylase in mouse leads to less severe inflammatory lesions and abolished the mutagenic effect at the gastric epithelial cells level, induced by the H. pylori infection. These data suggest for the OGG1deficiency a protective role against inflammation and genotoxicity associated to the H. pylori infection. [source] An Efficient Synthesis of 3,-Amino-3,-deoxyguanosine from GuanosineHELVETICA CHIMICA ACTA, Issue 3 2003Lei Zhang 3,-Amino-3,-deoxyguanosine was synthesized from guanosine in eight steps and 58% overall yield. The 2,,3,-diol of 5,- O -[(tert -butyl)diphenylsilyl]-2- N -[(dimethylamino)methylidene]guanosine was reacted with , -acetoxyisobutyryl bromide and treated with 0.5n NH3 in MeOH to yield 9-{2,- O -acetyl-3,-bromo-5,- O -[(tert -butyl)diphenylsilyl]-3,-deoxy- , - D -xylofuranosyl]-2- N -[(dimethylamino)methylidene]guanine, which was reacted with benzyl isocyanate, NaH, and then 3.0n NaOH, and finally with Pd/C (10%) and HCO2NH4 in EtOH/AcOH to afford 3,-amino-3,-deoxyguanosine. [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-dependent proton-transfer reaction in stacked GC pair III: The influence of proton transfer to conductivityINTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 12 2010Yasuyuki Nakanishi Abstract We have computed current,voltage character of natural DNA and its proton-transferred structure by scattering theory based on density functional theory. The current is not observed if the electron path contains only hydrogen bonding such as one base pair. The current becomes larger if the electron path contains ,,, stacking molecule such as two base pairs. We also found that the conductivity of pseudo-ion pair (C+G,/G,C+), which is derived from proton-transfer reaction in CG/GC, differs from that of the original structure. On the other hand, the current changes dramatically if the electrode connects to guanine or cytosine, which can be explained by the difference of electron affinities. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2010 [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] High levels of MMP-1 expression in the absence of the 2G single nucleotide polymorphism is mediated by p38 and ERK1/2 mitogen-activated protein kinases in VMM5 melanoma cellsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2002Ulrike Benbow Abstract Matrix metalloproteinase-1 (MMP-1) is one of only a few enzymes with the ability to degrade the stromal collagens (types I and III) at neutral pH, and high expression of MMP-1 has been associated with aggressive and invasive cancers. We recently reported a single nucleotide insertion/deletion polymorphism (SNP) in the collagenase-1 (MMP-1) promoter (Rutter et al. [1998] Can. Res. 58:5321,5325), where the insertion of an extra guanine (G) at ,1607 bp creates the sequence, 5,-GGAA-3 (2G allele), compared to the sequence 5,-GAA-3, (1G allele). The presence of 2G constitutes a binding site for the ETS family of transcription factors, and increases MMP-1 transcription in fibroblasts and A2058 melanoma cells cultured in vitro. In addition, the presence of the 2G allele has been linked to several aggressive malignancies as well as to enhanced expression of MMP-1. In this study, we describe a melanoma cell line, VMM5, that is 1G homozygous, but that is invasive and expresses high levels of MMP-1 constitutively. The high level of MMP-1 expression in VMM5 cells is due to the utilization of both the p38 and ERK1/2 transduction pathways. In contrast, in the A2058 cell line, which also expresses MMP-1 constitutively and which is 2G homozygous, only the ERK pathway is activated. Thus, our data suggest that in the absence of 2G allele and in the presence of the appropriate transcription factors, tumor cells may use alternative signal/transduction pathways and cis-acting sequences to achieve high levels of MMP-1 expression, which contribute to the ability of tumor cells to invade, regardless of their genotype. © 2002 Wiley-Liss, Inc. [source] Coarse-grained model of nucleic acid basesJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 8 2010Maciej Maciejczyk Abstract Atomistic simulations of nucleic acids are prohibitively expensive and, consequently, reduced models of these compounds are of great interest in the field. In this work, we propose a physics-based coarse-grained model of nucleic-acid bases in which each base is represented by several (3,5) interaction centers. van der Waals interactions are modeled by Lennard-Jones spheres with a 12,6 potential energy function. The charge distribution is modeled by a set of electric dipole moments located at the centers of the Lennard-Jones spheres. The method for computing the Lennard-Jones parameters, electric dipole moments (their magnitude and orientation) and positions of the interaction centers is described. Several models with different numbers of interaction centers were tested. The model with three-center cytosine, four-center guanine, four-center thymine, and five-center adenine satisfactorily reproduces the canonical Watson,Crick hydrogen bonding and stacking interaction energies of the all-atom AMBER model. The computation time with the coarse-grained model is reduced seven times compared with that of the all-atom model. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010 [source] QM/MM calculation of solvent effects on absorption spectra of guanineJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 1 2010Maja Parac Abstract Electronic spectra of guanine in the gas phase and in water were studied by quantum mechanical/molecular mechanical (QM/MM) methods. Geometries for the excited-state calculations were extracted from ground-state molecular dynamics (MD) simulations using the self-consistent-charge density functional tight binding (SCC-DFTB) method for the QM region and the TIP3P force field for the water environment. Theoretical absorption spectra were generated from excitation energies and oscillator strengths calculated for 50 to 500 MD snapshots of guanine in the gas phase (QM) and in solution (QM/MM). The excited-state calculations used time-dependent density functional theory (TDDFT) and the DFT-based multireference configuration interaction (DFT/MRCI) method of Grimme and Waletzke, in combination with two basis sets. Our investigation covered keto-N7H and keto-N9H guanine, with particular focus on solvent effects in the low-energy spectrum of the keto-N9H tautomer. When compared with the vertical excitation energies of gas-phase guanine at the optimized DFT (B3LYP/TZVP) geometry, the maxima in the computed solution spectra are shifted by several tenths of an eV. Three effects contribute: the use of SCC-DFTB-based rather than B3LYP-based geometries in the MD snapshots (red shift of ca. 0.1 eV), explicit inclusion of nuclear motion through the MD snapshots (red shift of ca. 0.1 eV), and intrinsic solvent effects (differences in the absorption maxima in the computed gas-phase and solution spectra, typically ca. 0.1,0.3 eV). A detailed analysis of the results indicates that the intrinsic solvent effects arise both from solvent-induced structural changes and from electrostatic solute,solvent interactions, the latter being dominant. © 2009 Wiley Periodicals, Inc. J Comput Chem 2010 [source] Interactions of the "piano-stool" [ruthenium(II) (,6 -arene)(en)CL]+ complexes with water and nucleobases; ab initio and DFT studyJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 12 2009k Futera Abstract Piano stool ruthenium complexes of the composition [Ru(II)(,6 -arene)(en)Cl]+/2+ (en = ethylenediamine) represent an emerging class of cisplatin-analogue anticancer drug candidates. In this study, we use computational quantum chemistry to characterize the structure, stability and reactivity of these compounds. All these structures were optimized at DFT(B3LYP)/6-31G(d) level and their single point properties were determined by the MP2/6-31++G(2df,2pd) method. Thermodynamic parameters and rate constants were determined for the aquation process, as a replacement of the initial chloro ligand by water and subsequent exchange reaction of aqua ligand by nucleobases. The computations were carried out at several levels of DFT and ab initio theories (B3LYP, MP2 and CCSD) utilizing a range of bases sets (from 6-31G(d) to aug-cc-pVQZ). Excellent agreement with experimental results for aquation process was obtained at the CCSD level and reasonable match was achieved also with the B3LYP/6-31++G(2df,2pd) method. This level was used also for nucleobase-water exchange reaction where a smaller rate constant for guanine exchange was found in comparison with adenine. Although adenine follows a simple replacement mechanism, guanine complex passes by a two-step mechanism. At first, Ru-O6(G) adduct is formed, which is transformed through a chelate TS2 to the Ru-N7(G) final complex. In case of guanine, the exchange reaction is more favorable thermodynamically (releasing in total by about 8 kcal/mol) but according to our results, the rate constant for guanine substitution is slightly smaller than the analogous constant in adenine case when reaction course from local minimum is considered. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2009 [source] Formation of 8-nitroguanine and 8-oxoguanine due to reactions of peroxynitrite with guanineJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 8 2007N. R. Jena Abstract Reactions of peroxynitrite with guanine were investigated using density functional theory (B3LYP) employing 6-31G** and AUG-cc-pVDZ basis sets. Single point energy calculations were performed at the MP2/AUG-cc-pVDZ level. Genuineness of the calculated transition states (TS) was tested by visually examining the vibrational modes corresponding to the imaginary vibrational frequencies and applying the criterion that the TS properly connected the reactant and product complexes (PC). Genuineness of all the calculated TS was further ensured by intrinsic reaction coordinate (IRC) calculations. Effects of aqueous media were investigated by solvating all the species involved in the reactions using the polarizable continuum model (PCM). The calculations reveal that the most stable nitro-product complex involving the anion of 8-nitroguanine and a water molecule i.e. 8NO2G, + H2O can be formed according to one reaction mechanism while there are two possible reaction mechanisms for the formation of the oxo-product complex involving 8-oxoguanine and anion of the NO2 group i.e. 8OG + NO2,. The calculated relative stabilities of the PC, barrier energies of the reactions and the corresponding enthalpy changes suggest that formation of the complex 8OG + NO2, would be somewhat preferred over that of the complex 8NO2G, + H2O. The possible biological implications of this result are discussed. © 2007 Wiley Periodicals, Inc. J Comput Chem 2007 [source] Activation barriers for DNA alkylation by carcinogenic methane diazonium ionsJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 3 2006Kaushalya S. Ekanayake Abstract Methylation reactions of the DNA bases with the methane diazonium ion, which is the reactive intermediate formed from several carcinogenic methylating agents, were examined. The SN2 transition states of the methylation reactions at N7, N3, and O6 of guanine; N7, N3, and N1 of adenine; N3 and O2 of cytosine; and O2 and O4 of thymine were calculated using the B3LYP density functional method. Solvation effects were examined using the conductor-like polarizable continuum method and the combined discrete/SCRF method. The transition states for reactions at guanine N3, adenine N7, and adenine N1 are influenced by steric interactions between the methane diazonium ion and exocyclic amino groups. Both in the gas phase and in aqueous solution, the methylation reactions at N atoms have transition states that are looser, and generally occur earlier along the reaction pathways than reactions at O atoms. The forming bonds in the transition states in water are 0.03 to 0.13 Å shorter than those observed in the gas phase, and the activation energies are 13 to 35 kcal/mol higher. The combined discrete/SCRF solvation energy calculations using base-water complexes with three water molecules yield base solvation energies that are larger than those obtained from the CPCM continuum method, especially for cytosine. Reactivities calculated using barriers obtained with the discrete/SCRF method are consistent with the experimentally observed high reactivity at N7 of guanine. © 2005 Wiley Periodicals, Inc. J Comput Chem 27: 277,286, 2006 [source] TDDFT investigation on nucleic acid bases: Comparison with experiments and standard approachJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 5 2004M.K. Shukla Abstract A comprehensive theoretical study of electronic transitions of canonical nucleic acid bases, namely guanine, adenine, cytosine, uracil, and thymine, was performed. Ground state geometries were optimized at the MP2/6-311G(d,p) level. The nature of respective potential energy surfaces was determined using the harmonic vibrational frequency analysis. The MP2 optimized geometries were used to compute electronic vertical singlet transition energies at the time-dependent density functional theory (TDDFT) level using the B3LYP functional. The 6-311++G(d,p), 6-311(2+,2+)G(d,p), 6-311(3+,3+)G(df,pd), and 6-311(5+,5+)G(df,pd) basis sets were used for the transition energy calculations. Computed transition energies were found in good agreement with the corresponding experimental data. However, in higher transitions, the Rydberg contaminations were also obtained. The existence of ,,* type Rydberg transition was found near the lowest singlet ,,* state of all bases, which may be responsible for the ultrafast deactivation process in nucleic acid bases. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 768,778, 2004 [source] Systematic quantum chemical study of DNA-base tautomersJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 1 2004M. Piacenza Abstract The relative energies of the energetically low-lying tautomers of pyridone, cytosine, uracil, thymine, guanine, and iso-cytosine are studied by a variety of different quantum chemical methods. In particular, we employ density functional theory (DFT) using the six functionals HCTH407, PBE, BP86, B-LYP, B3-LYP, and BH-LYP, and the ab initio methods Hartree-Fock (HF), standard second-order Møller-Plesset perturbation theory (MP2), an improved version of it (SCS-MP2), and quadratic configuration interaction including single and double excitations (QCISD) and perturbative triple corrections [QCISD(T)]. A detailed basis set study is performed for the formamide/formamidic acid tautomeric pair. In general, large AO basis sets of at least valence triple-, quality including f-functions (TZV) are employed, which are found to be necessary for an accurate energetic description of the various structures. The performance of the more approximate methods is evaluated with QCISD(T)/TZV(2df,2dp) data taken as reference. In general it is found that DFT is not an appropriate method for the problem. For the tautomers of pyridone and cytosine, most density functionals, including the popular B3-LYP hybrid, predict a wrong energetic order, and only for guanine, the correct sequence of tautomers is obtained with all functionals. Out of the density functionals tested, BH-LYP, which includes a rather large fraction of HF exchange, performs best. A consistent description of the nonaromatic versus aromatic tautomers seems to be a general problem especially for pure, nonhybrid functionals. Tentatively, this could be assigned to the exchange potentials used while the functional itself, including the correlation part, seems to be appropriate. Out of the ab initio methods tested, the new SCS-MP2 approach seems to perform best because it effectively reduces some outliers obtained with standard MP2. It outperforms the much more costly QCISD method and seems to be a very good compromise between computational effort and accuracy. © 2003 Wiley Periodicals, Inc. J Comput Chem 1: 83,98, 2004 [source] | |||||||||||||||||||||||||||||||||||||