Thymine kinase 2 (TK2) is a mitochondrial matrix protein encoded in nuclear DNA and phosphorylates the pyrimidine nucleosides: thymidine and deoxycytidine. Autosomal recessiveTK2mutations cause a spectrum of disease from infantile onset to adult onset manifesting primarily as myopathy.
Diamond-anvil cell, pressure-tuning infrared (IR), and Raman microspectroscopic measurements have been undertaken to examine the effects of high pressures up to about 45 kbar on the vibrational spectra of the four DNA bases, adenine, cytosine, guanine, and thymine. Small structural changes were evident for all the four bases, viz., for adenine and cytosine at 28-31 kbar; for guanine at 16-19 kbar; and for thymine at 25-26 kbar. These changes are most likely associated with alterations in the intermolecular hydrogen-bonding interactions. The pressure dependences of the main peaks observed in the IR spectra of the two phases of guanine lie in the -0.07-0.66 (low-pressure phase) and 0.06-0.91 (high-pressure phase) cm(-1)/kbar ranges. Also, in the Raman spectra of this nucleoside base, the dν/dP values range from -0.07-0.31 (low-pressure phase) to 0.08-0.50 (high-pressure phase) cm(-1)/kbar. Similar ranges of dν/dP values were obtained for the other three nucleoside bases.
Tautomerization processes of amino-imino adenine isomer (A → A1) in five different environments are studied by the density functional theory (B3LYP) method. The five environments are metal ion (M, M = K(+), Na(+), Cu(+), Zn(+), Ca(2+), Mg(2+), Cu(2+), Zn(2+)) coordinated bidentate system, either monowater (W) or monoammonia (N) attached system, both metal ion and monowater cooperative system (M-W), and both metal ion and monoammonia cooperative system (M-N). Results show that the complexes formed by noncanonical rare imino form A1 are more stable than those formed by the canonical amino one in most of these environments. The tautomerization of A → A1 becomes quite easy in either M-W or M-N system. It is noteworthy that under divalent M-N environment the A → A1 process meets with particularly lower and even free energy barrier, indicating the instability of the amino adenine isomer and probable existence of more stable imino adenine isomer. Expanding studies for the microhydration at the metal ion of the M-N system predict the required number (n) of water molecules to remain the amino adenine isomer A (AMNnW) stable. The number of n is 2, 3, 3, and 4 for M = Ca(2+), Zn(2+), Cu(2+), and Mg(2+), respectively. The present study provides further understanding for the amino-imino tautomerization behavior of the most stable adenine under the influence of several related closely factors, and is useful for rational design of these different environments for the purposes of prevention and control of pyrimidines mispairing, which is responsible for the mutagenic properties of the nucleic acid bases.
DNA and RNA oxidation have been linked to diseases such as cancer, arteriosclerosis, neurodegeneration and diabetes. The prototype base modification studied is the 8-hydroxylation of guanine. DNA integrity is maintained by elaborate repair systems, RNA integrity is less studied but relies mainly on degradation.
We provide theoretical predictions of the intrinsic stability of different arrangements of guanine quadruplex (G-DNA) stems. Most computational studies of nucleic acids have applied Molecular Mechanics (MM) approaches using simple pairwise-additive force fields. The principle limitation of such calculations is the highly approximate nature of the force fields. In this study we for the first time apply accurate QM computations (DFT-D3 with large atomic orbital basis sets) to essentially complete DNA building blocks, namely, seven different folds of the cation-stabilized 2-quartet G-DNA stem, each having more than 250 atoms. The solvent effects are approximated by COSMO continuum solvent. We reveal sizeable differences between MM and QM descriptions of relative energies of different G-DNA stems, which apparently reflect approximations of the DNA force field. Using the QM energy data, we propose correction to earlier free energy estimates of relative stabilities of different parallel, hybrid and antiparallel G-stem folds based on classical simulations. The new energy ranking visibly improves the agreement between theory and experiment. We predict the 5'-anti-anti-3' GpG dinucleotide step to be the most stable one, closely followed by the 5'-syn-anti-3' step. The results are in good agreement with known experimental structures of 2, 3 and 4-quartet G-DNA stems. Besides providing specific results for G-DNA, our study highlights basic limitations of force field modeling of nucleic acids. Although QM computations have their own limitations, mainly the lack of conformational sampling and the approximate description of the solvent, they can substantially improve quality of calculations currently relying exclusively on force fields.
G-quadruplexes, whose building blocks are guanine tetrads, encounter increasing interest with respect to their potential applications in the field of molecular electronics. Here we study how the size of these nanostructures affects their fluorescence. We compare the properties of thymine capped G-quadruplexes, formed by association of four single DNA strands d(TG3T), d(TG4T) and d(TG5T) and stabilized by K(+) ions. We show that an increase in the number of tetrads induces a narrowing of the fluorescence spectrum, an increase in the fluorescence quantum yield, a lengthening of fluorescence lifetime and a decrease of the anisotropy detected on the femtosecond time-scale. The in-plane depolarization of the fluorescence, occurring in less than 1 ps, is attributed to population of Franck-Condon exciton states and ultrafast intraband scattering, leading to energy transfer. The persistence of excitons with partial J-aggregate character on the picosecond time-scale increases with the G-quadruplex size, which enhances the stiffness of the system.
In this study, a simple, rapid, efficient analytical method was established for the qualification and quantification of 16 nucleosides and nucleobases in Euryale ferox Salisb. by using liquid chromatography coupled with electrospray ionization tandem triple quadrupole mass spectrometry (HPLC-ESI-TQ-MS/MS) in multiple-reaction monitoring (MRM) mode. Ideal separation of 16 target compounds was achieved on Xbridge Amide HILIC column (4.6 × 150 mm, 3.5 μm) with gradient elution in 11 min by optimized conditions. Variations of nucleosides and nucleobase in samples from different cultivation regions ranging from 190.50 to 1594.30 μg/g were obvious. The total nucleoside contents were higher than total nucleobases, especially in the compositions of guanosine, cytidine and 2'-deoxyguanosine. Samples 1-18 with dense thorns were better characters than samples 19-26 without thorns in terms of nucleosides and nucleobases concentrations in general. The limits of detection (LODs) and quantification (LOQs) for 16 analytical substances were investigated to be 0.11-6.33 ng/mL and 0.35-21.1 ng/mL, respectively. And the method was first applied to large aquatic plants with good linearity, precision, repeatability and accuracy. All present information provided a scientific and rational reference for quality assessment and control of Euryale ferox Salisb.
Phenylnitrenium ion (PhNH(+)) may bind to nucleophiles through nitrogen as well as through C2 or C4 carbons. However, only adducts of the former type have been hitherto reported after its reaction with purine nucleosides. In this study, reactions of N-acetoxyaniline (PhNHOAc), a precursor to PhNH(+), with 2'-deoxyadenosine (dA), 2'-deoxyguanosine (dG) and with DNA in vitro at physiological conditions are described. The reaction of PhNHOAc with dA followed by a hydrolytic deribosylation afforded 8-phenylaminoadenine (C8-PhNHA) together with a smaller amount of N(6)-(4-aminophenyl)adenine (N(6)-4APA). Similar reaction with dG afforded 8-phenylaminoguanine (C8-PhNHG) together with traces of 7-(4-aminophenyl)guanine (N7-4APG). The same adducts were found also in the DNA treated with PhNHOAc and all of them were identified by comparison of their HPLC retention times and MS2 spectra with a set of synthesized authentic adenine adducts at C2, C8, N7 and N6 position and guanine adducts at C8, N7 and N2 position. Newly identified minor adduct N7-4APG represents the first proof of an arylnitrenium adduction at N7 position of dG, which is the prominent site of attack by most C-electrophiles.
Synthesis, Antibacterial Activity, Interaction with Nucleobase and Molecular Docking Studies of 4-Formylbenzoic Acid Based Thiazoles
- Medicinal chemistry (Shariqah (United Arab Emirates))
- Published over 3 years ago
Background Synthesis, characterization and investigation of antibacterial activity of ten novel Schiff base derivatives of 4-formylbenzoic acid is presented. Their structures were determined using 1H and 13C NMR, EI(+)-MS and elemental analyses. Additionally, DFT calculations of interaction energies in complexes of the novel drugs and DNA bases are carried out Objective Design and synthesis of thiazole derivatives with benzoic acid scaffold to obtain compounds with an improved antibacterial activity. Method The examined compounds were screened in vitro for antibacterial activity using the broth microdilution method. Geometrical parameters of the investigated complexes were optimized within the Density Functional Theory (DFT) approximation using the B3LYP functional and the 6-311G** basis set. The docking simulations were performed using the FlexX docking module. Results Among the derivatives, compound 4b showed very strong bacterial activity against staphylococci, MIC 1.95-3.91 µg/ml, micrococci, MIC 0.98 µg/ml, and Bacillus spp., MIC 7.81-15.62 µg/ml. The compounds 4c, 4d, 4e and 4j also showed high bioactivity against staphylococci, MIC 3.91-31.25 µg/ml, and micrococci, MIC 0.98-15.62 µg/ml. Interaction energy values for investigated guanine complexes are about 2 kcal/mol lower than for the corresponding cytosine complexes. Molecular docking studies of all compounds on the active sites of bacterial enzymes indicated gyrase B as possible target. Conclusion To conclude, an efficient and economic method for the synthesis of thiazoles containing benzoic acid moiety has been developed. The results of antibacterial screenings reveal that some obtained compounds show high to very strong antibacterial activity. The DFT calculations showed that interaction of the obtained drugs with guanine is stronger than with cytosine. Molecular docking studies of all compounds on the active sites of bacterial enzymes indicated gyrase B as possible target.
- Radiation physics and chemistry (Oxford, England : 1993)
- Published almost 3 years ago
Nucleobase radicals are major products of the reactions between nucleic acids and hydroxyl radical, which is produced via the indirect effect of ionizing radiation. The nucleobase radicals also result from hydration of cation radicals that are produced via the direct effect of ionizing radiation. The role that nucleobase radicals play in strand scission has been investigated indirectly using ionizing radiation to generate them. More recently, the reactivity of nucleobase radicals resulting from formal hydrogen atom or hydroxyl radical addition to pyrimidines has been studied by independently generating the reactive intermediates via UV-photolysis of synthetic precursors. This approach has provided control over where the reactive intermediates are produced within biopolymers and facilitated studying their reactivity. The contributions to our understanding of pyrimidine nucleobase radical reactivity by this approach are summarized.