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At least 145 records · Page 8Linked to original sources
PubMed2006

Novel drug discovery and molecular biological methods, via DNA, RNA and protein changes using structure-function transitions: Transitional structural chemogenomics, transitional structural chemoproteomics and novel multi-stranded nucleic acid microarray.

Nucleic acids and proteins are dynamic molecules that undergo structural changes which control gene expression. The authors have developed two novel techniques, viz., transitional structural chemogenomics and transitional structural chemoproteomics. Transitional structural chemogenomics is used to regulate gene expression, employing ultrasensitive small-molecule drugs targeted toward nucleic acids. Gene expression can be regulated by using chemicals to target transitional changes in the helical conformations of single-stranded (ss-) and double-stranded (ds-) DNA (e.g., B- to Z-DNA), and RNA (e.g., A- to Z-RNA). This method also targets alternative types of ds- and ss-DNA and RNA (e.g., cruciform DNA), and other multi-stranded nucleic acids (e.g., triplex-DNA). Our second technique, transitional structural chemoproteomics, targets a protein before, during or after post-translational modifications which alters its structure and function. Both a proteins' structured and unstructured regions are targeted. These two novel methods represent the next step in the evolution of chemical genomics and chemical proteomics. They allow for two approaches to regulate gene expression, viz., turning genes "on", "off" or variable control (e.g., dimmer switch). This article also discusses the confusion that exists between the term chemical genomics and other related subdisciplines, such as chemical proteomics. Additionally, we have developed a novel multi-stranded DNA, RNA and plasmid microarray which immobilizes intact nondenatured ds-DNA, alternative, and other multiple-stranded nucleic acids onto a substrate surface. This technique represents the next generation of nucleic acid microarrays, which will enhance the characterization of nucleic acids and the drug discovery process. These three novel techniques allow for a multifaceted approach that will greatly enhance the success of molecular biology, the "omics" and drug discovery. They represent the next era of gene expression tools.

Base Sequence↗
PubMed2004

The interaction of poly(ethylenimine) with nucleic acids and its use in determination of nucleic acids based on light scattering.

For the first time, poly(ethylenimine) (PEI) was used to determine nucleic acids with a light scattering technique using a common spectrofluorometer. The interaction of PEI with DNA results in greatly enhanced intensity of light scattering at 300 nm, which is caused by the formation of the big particles between DNA and PEI. Based on this, a new quantitative method for nucleic acid determination in aqueous solutions has been developed. Under the optimum conditions, the enhanced intensity of light scattering is proportional to the concentration of nucleic acid in the range of 0.01-10.0 microg ml(-1) for herring sperm DNA (hsDNA), 0.02-10.0 microg ml(-1) for calf thymus DNA (ctDNA), 0.02-20.0 microg ml(-1) for yeast RNA (yRNA). The detection limits are 5.3, 9.9, and 13.7 ng ml(-1), respectively. Synthetic samples were determined satisfactorily. At the same time, the light scattering technique has been successfully used to obtain the information on the effects of pH and ionic strength on the formation and the stability of the DNA/PEI complex, which is important in some fields such as genetic engineering and gene transfer. Using ethidium bromide (EB) as a fluorescent probe, the binding of PEI with hsDNA was studied. Both the binding constant of EB with DNA and the number of binding sites per nucleotide decrease with increasing concentration of PEI, indicating noncompetitive inhibition of EB binding to DNA in the presence of PEI. And the association constant of PEI to DNA obtained is 1.2 x 10(5) M(-1). IR-spectra show that PEI interacts with DNA through both the phosphate groups and the bases of DNA and the formation of DNA/PEI complex may cause the change of the conformation of the DNA secondary structure, which is also proved by UV-spectra.

Buffers↗
PubMedDate not supplied

An efficient, convenient solid-phase synthesis of amino acid-modified peptide nucleic acid monomers and oligomers.

An efficient and highly versatile method for the synthesis of amino acid-modified peptide nucleic acid (PNA) monomers is described. By using solid-phase Fmoc techniques, such monomers can be assembled readily in a stepwise manner and obtained in high yield with minimal purification. Protected neutral hydrophilic, acidic, and basic amino acids were coupled to 2-chlorotrityl chloride resin. Following Fmoc removal, innovative conditions for the key step, reductive alkylation with N-Fmoc-aminoacetaldehyde, were developed to circumvent problems encountered with previously reported methods. Activation and coupling of pyrimidine and purine nucleobases to the resulting secondary amines afforded amino acid-modified PNA monomers. The mild reaction conditions utilized were compatible with sensitive and labile functional groups, such as tert-butyl ethers and tert-butyl esters. PNA monomers were obtained in 36-42% overall yield and very high purity, after cleavage and purification. Using standard solid-phase Fmoc chemistry, two of these monomers were incorporated with high coupling efficiency into a variety of modified PNA oligomers, including four tetradecamers designed to target bcl-2 mRNA. Such modified oligomers have the potential to enhance water solubility and cell portability, while maintaining hybridization affinity and promoting favorable biodistribution properties.

Amino Acids↗
PubMed2006

Rapid kinetics of protein-nucleic acid interaction is a major component of HIV-1 nucleocapsid protein's nucleic acid chaperone function.

The nucleic acid chaperone activity of the human immunodeficiency virus type-1 (HIV-1) nucleocapsid protein (NC) plays an important role in the retroviral life cycle, in part, by facilitating numerous nucleic acid rearrangements throughout the reverse transcription process. Recent studies have identified duplex destabilization and nucleic acid aggregation as the two major components of NC's chaperone activity. In order to better understand the contribution of the functional domains of NC to these two activities, we used optical tweezers to stretch single lambda DNA molecules through the helix-coil transition in the presence of wild-type or mutant HIV-1 NC. Protein-induced duplex destabilization was measured directly as an average decrease of the force-induced melting free energy, while NC's ability to facilitate strand annealing was determined by the amount of hysteresis in the DNA stretch-relax cycle. By studying zinc-free variants of full-length and truncated NC, the relative contributions of NC's zinc fingers and N-terminal basic domain to the two major components of chaperone activity were elucidated. In addition, examination of NC variants containing mutations affecting one or both zinc finger motifs showed that effective strand annealing activity is correlated with NC's ability to rapidly bind and dissociate from nucleic acids. NC variants with slow on/off rates are inefficient in strand annealing, even though they may still be capable of high affinity nucleic acid binding, duplex destabilization, and/or nucleic acid aggregation. Taken together, these observations establish the rapid kinetics of protein-nucleic acid interaction as another major component of NC's chaperone function.

Amino Acid Sequence↗
PubMed1995

A yeast gene product, G4p2, with a specific affinity for quadruplex nucleic acids.

G4 nucleic acids are quadruplex structures involving guanine-rich sequences that form in vitro under moderate conditions. Experimental evidence exists supporting biological functions for these elements; however, direct demonstration of G4 nucleic acids in vivo has not yet been achieved. Here we purify and characterize a yeast protein, G4p2, which has a specific affinity for G4 nucleic acids. G4p2 binds equivalently to RNA and DNA in G4 form. The Keq for G4p2 binding to a G4 DNA oligomer is 2.2 x 10(8) M-1 under near physiological conditions. We have cloned and sequenced the gene encoding G4p2 and have shown it to be identical to MPT4 and STO1. MPT4 was isolated in a screen for multicopy suppressors of staurosporine sensitivity in POP2 cells. Pop2 is a complex regulatory factor that participates, in part, in the repression of certain genes in the absence of glucose (Sakai, A., Chibazakura, T., Shimizu, Y., and Hishinuma, F. (1992) Nucleic Acids Res. 20, 6227-6233). STO1 was isolated as a multicopy suppressor of TOM1, an uncharacterized mutation that leads to temperature-sensitive cell cycle arrest at the G2/M boundary. Suppression of these mutations by G4p2 indicate this G4 nucleic acid binding protein may function in signal transduction pathways regulated by protein kinases, which control carbon source utilization, and in cell cycle progression.

Amino Acid Sequence↗
PubMed1982

Free-radical damage to lipids, amino acids, carbohydrates and nucleic acids determined by thiobarbituric acid reactivity.

1. The thiobarbituric acid (TBA) reaction, widely applied to the detection of autoxidation in polyunsaturated fatty acids, can be used to measure free-radical damage to amino acids, carbohydrates and nucleic acids. 2. In all of these systems malondialdehyde (MDA) is predominately formed from intermediate precursor molecules which break down during the acid-heating stage of the TBA test. 3. The acid reagent used to bring about these decompositions appears to be critical.

Amino Acids↗
PubMed2004

Cell-surface-bound nucleic acids: Free and cell-surface-bound nucleic acids in blood of healthy donors and breast cancer patients.

Concentrations of extracellular DNA and RNA in the blood of healthy donors and patients with malignant and nonmalignant breast tumors were investigated. Cell-surface-bound extracellular DNA and RNA were detached by PBS-EDTA treatment or mild trypsin treatment of erythrocytes and leukocytes. In healthy donors, almost all extracellular nucleic acids (98%) are bound at the surface of blood cells. In the blood of cancer patients, extracellular nucleic acids were found in plasma and not at the cell surface. In patients with nonmalignant breast tumors, extracellular nucleic acids were found both at the surface of blood cells and in plasma. In healthy donors, the cell-surface-bound DNA is represented by 20-kbp DNA fragments and smaller fragments that varied in amounts in different fractions.

Breast Neoplasms↗
PubMed1986

Conformational studies of nucleic acids: III. Empirical multiple correlation functions for nucleic acid torsion angles.

There are seven significantly variable torsion angles in each monomer unit of a polynucleotide. Because of this, it is computationally infeasible to consider the energetics of all conformations available to a nucleic acid without the use of simplifications. In this paper, we develop functions suggested by and regression fit to crystallographic data which allow three of these torsion angles, alpha (O3'-P-O5'-C5'), delta (C5'-C4'-C3'-O3') and epsilon (C4'-C3'-O3'-P), to be calculated as dependent variables of those remaining. Using these functions, the seven independent torsions are reduced to four, a reduction in complexity sufficient to allow an examination of the global conformational energetics of a nucleic acid for the remaining independent torsion angles. These functions are the first to quantitatively relate a dependent nucleic acid torsion angle to several different independent angles. In all three cases the data are fit reasonably well, and in one case, alpha, the fit is exceptionally good, lending support for the suitability of the functions in conformational searches. In addition, an examination of the most significant terms in each of the correlation functions allows insight into the physical basis for the correlations.

Base Sequence↗
PubMedDate not supplied

[Charge transfer complexes of nucleic acid purine bases with benzoquinone. Evidence that nucleic acid components are pi-donors].

The absorption bands of the charge transfer complexes between nucleic acid, purine components and some of their derivatives (9CH3--Ade, Ado, dAdo, pA, App, Guo, Gpp, Gppp, Cof, Hyp) as electron donors and p-benzoquinone as the acceptor were obtained by the differential method in water solution at 293 K. These bands lie in the range 330--430 nm and have all characteristic properties of the charge transfer bands. All points of the relationships between the energy corresponding to the charge transfer band maximum (hvct) and the donor ionization potential (Id) for the nucleic acid components and their derivatives fall on the same straight line for the pi-donors (the aromatic molecules), known from literature data, which differ markedly from the same straight line for n-donors (the alifatic amines), obtained in this work. It shows that the investigated nucleic acid components and their derivatives are the pi-donors in the charge transfer complexes with p-benzoquinone.

Adenine↗
PubMed1979

Models of interaction between nucleic acids and proteins. Hydrogen bonding of arginine with nucleic acid bases, phosphate groups and carboxylic acids.

Complex formation between the side chain of arginine and nucleic acid bases has been investigated by proton magnetic resonance in dimethylsulfoxide. Simultaneous formation of two hydrogen bonds leads to a selectivity of arginine interaction towards cytosine and guanine. A comparison is made of the interaction of arginine side chain with nucleic acid bases, phosphate and carboxylate anions. It is shown that interaction between carboxylate and arginine is stronger than between phosphate and arginine. These results are discussed with respect to the selective recognition of nucleic acid bases by arginine side chains and by the arginyl-glutamyl ion pair which could form in proteins interacting with nucleic acids.

Arginine↗