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S S Skuratovskii IYaHasnain D G Alexeev G P Diakun L I Volkova 《Journal of inorganic biochemistry》1987,29(4):249-257
Preliminary EXAFS experiments were carried out on film of the Ca salts of the synthetic polynucleotide polydA:polydT at 95%, 81%, and 76% relative humidity (r.h.) and for the Ca salt of chicken erythrocyte DNA at 81% r.h. (approximately 43% GC pairs). Detailed analysis of EXAFS data shows that the Ca2+ ion is in fairly close proximity (within 4 A) to a number of phosphorous atoms. This is in contradiction with the recently proposed model, which assumes a close coordination between the cations and the purine and pyrimidine bases deep inside the polynucleotide molecule, so that the distance to the nearest phosphorous atoms must not be less than 5 A. Instead, the EXAFS results suggest that the Ca2+ ions are, for the most part, located at the periphery of individual polydA:polydT (or DNA) molecules, possibly serving as intermolecular links. 相似文献
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Oligonucleotide-directed mutagenesis and targeted gene correction: a mechanistic point of view 总被引:3,自引:0,他引:3
Within the last decade, a number of nucleic acid-based gene targeting strategies have been developed with the ultimate goal to cure human genetic disorders caused by mutations. Thus far, site-directed gene targeting is the only procedure that can make predefined alterations in the genome. The advantage of this approach is that expression of the corrected gene is regulated in the same way as a normal gene. In addition, targeted specific mutations can be made in the genome for functional analysis of proteins. Several approaches, including chimeric RNA-DNA oligonucleotides, short single-stranded oligonucleotides, small fragment homologous replacements, and triple-helix-forming oligonucleotides have been used for targeted modification of the genome. Due to the absence of standardized assays and mechanistic studies in the early developmental stages of oligonucleotide-directed gene alteration, it has been difficult to explain the large variations and discrepancies reported. Here, we evaluate the progress in the field, summarize the achievements in understanding the molecular mechanism, and outline the perspective for the future development. This review will emphasize the importance of reliable, sensitive and standardized assays to measure frequencies of gene repair and the use of these assays in mechanistic studies. Such studies have become critical for understanding the gene repair process and setting realistic expectations on the capability of this technology. The conventionally accepted but unproven dogmas of the mechanism of gene repair are challenged and alternative points of view are presented. Another important focus of this review is the development of general selection procedures that are required for practical application of this technology. 相似文献
5.
Homologous recombination is important for the repair of double-stranded DNA breaks in all organisms. Rad51 and Rad54 proteins are two key components of the homologous recombination machinery in eukaryotes. In vitro, Rad51 protein assembles with single-stranded DNA to form the helical nucleoprotein filament that promotes DNA strand exchange, a basic step of homologous recombination. Rad54 protein interacts with this Rad51 nucleoprotein filament and stimulates its DNA pairing activity, suggesting that Rad54 protein is a component of the nucleoprotein complex involved in the DNA homology search. Here, using physical criteria, we demonstrate directly the formation of Rad54-Rad51-DNA nucleoprotein co-complexes that contain equimolar amounts of each protein. The binding of Rad54 protein significantly stabilizes the Rad51 nucleoprotein filament formed on either single-stranded DNA or double-stranded DNA. The Rad54-stabilized nucleoprotein filament is more competent in DNA strand exchange and acts over a broader range of solution conditions. Thus, the co-assembly of an interacting partner with the Rad51 nucleoprotein filament represents a novel means of stabilizing the biochemical entity central to homologous recombination, and reveals a new function of Rad54 protein. 相似文献
6.
Alexeev EI Krasnov IB 《Journal of gravitational physiology : a journal of the International Society for Gravitational Physiology》2002,9(1):P303-P304
The pancreas of the rats exposed to primary and repeated prolonged hypergravity was studied by means of cytological methods. The rats were rotated on centrifuge at 2 G for 19 days and then after 30-day adaptation to 1 G were repeatedly exposed to 2 G for 5 days simultaneously with the rats first subjected to 5-day 2 G. After 5-day and 19-day hypergravity in pancreatic beta-cells the signs of decrease in insulin production were found. Adaptation of rats to 1 G for 30 days restored this process. Repeated 2 G for 5 days induced in beta-cells the changes of structure and hormonal product content indicating the pronounced increase in insulin synthesis and secretion. Response of alpha-cells to repeated 5-day 2 G was in parallel with beta-cell reactions. 相似文献
7.
Geinguenaud F Liquier J Brevnov MG Petrauskene OV Alexeev YI Gromova ES Taillandier E 《Biochemistry》2000,39(41):12650-12658
Oligonucleotides of nonregular heteropyrimidine sequences incorporating or not incorporating purine residues 5'-d(ACTCCCTTCTCCTCTCTA), 5'-d(ACTCCCTGGTCCTCTCTA), 5'-d(TCTCTCCTGGTCCCTCC), and 5'-d(TCTCTCCTCTTCCCTCC) can form self-associated parallel-stranded (ps) structures at pH 4-5.5. The ps structures were identified by studying at neutral and acidic pH UV melting transitions, FTIR spectra, and fluorescence of pyrene-labeled oligonucleotides as well as by chemical joining of 5'-phosphorylated oligonucleotides. A gel electrophoresis run for oligonucleotides 5'-d(TCTCTCCTCTTCCCTCC) and 5'-d(ACTCCCTTCTCCTCTCTA) has shown the formation of homoduplexes at low DNA strand concentrations. Ps structures are held by C-C(+) base pairs and have N- and S-types of sugar puckering as detected by FTIR spectroscopy in the millimolar concentration range. Guanine inserts as well as thymine and purine inserts into an oligomeric cytosine sequence make the formation of the tetraplex i-motif unfavorable. MvaI restriction endonuclease, which recognizes the CCT/AGG sequence in DNA, does not cleave parallel pseudosubstrates. 相似文献
8.
Webster SP Alexeev D Campopiano DJ Watt RM Alexeeva M Sawyer L Baxter RL 《Biochemistry》2000,39(3):516-528
8-Amino-7-oxononanoate synthase (also known as 7-keto-8-aminopelargonate synthase, EC 2.3.1.47) is a pyridoxal 5'-phosphate-dependent enzyme which catalyzes the decarboxylative condensation of L-alanine with pimeloyl-CoA in a stereospecific manner to form 8(S)-amino-7-oxononanoate. This is the first committed step in biotin biosynthesis. The mechanism of Escherichia coli AONS has been investigated by spectroscopic, kinetic, and crystallographic techniques. The X-ray structure of the holoenzyme has been refined at a resolution of 1.7 A (R = 18.6%, R(free) = 21. 2%) and shows that the plane of the imine bond of the internal aldimine deviates from the pyridine plane. The structure of the enzyme-product external aldimine complex has been refined at a resolution of 2.0 A (R = 21.2%, R(free) = 27.8%) and shows a rotation of the pyridine ring with respect to that in the internal aldimine, together with a significant conformational change of the C-terminal domain and subtle rearrangement of the active site hydrogen bonding. The first step in the reaction, L-alanine external aldimine formation, is rapid (k(1) = 2 x 10(4) M(-)(1) s(-)(1)). Formation of an external aldimine with D-alanine, which is not a substrate, is significantly slower (k(1) = 125 M(-)(1) s(-)(1)). Binding of D-alanine to AONS is enhanced approximately 2-fold in the presence of pimeloyl-CoA. Significant substrate quinonoid formation only occurs upon addition of pimeloyl-CoA to the preformed L-alanine external aldimine complex and is preceded by a distinct lag phase ( approximately 30 ms) which suggests that binding of the pimeloyl-CoA causes a conformational transition of the enzyme external aldimine complex. This transition, which is inferred by modeling to require a rotation around the Calpha-N bond of the external aldimine complex, promotes abstraction of the Calpha proton by Lys236. These results have been combined to form a detailed mechanistic pathway for AONS catalysis which may be applied to the other members of the alpha-oxoamine synthase subfamily. 相似文献
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Panova N. G. Shcheveleva E. V. Alexeev C. S. Mukhortov V. G. Zuev A. N. Mikhailov S. N. Esipov R. S. Chuvikovsky D. V. Miroshnikov A. I. 《Molecular Biology》2004,38(5):770-776
The new substrates 4-thiouridine and 4-thiothymidine were proposed for spectrophotometric measurement of the activity of uridine (UP) and thymidine (TP) phosphorylases. At pH 7.5, 4-thiouridine has an absorbance maximum at 330 nm, and the difference in extinction coefficient () between 4-thiouridine and 4-thiouracil is 3000 –1cm–1. 4-Thiouridine proved to be a good substrate for UP: the Michaelis (
) and catalytic (k
cat) constants were estimated respectively at 130 M and 49 s–1 at 25°C. Even a greater (5000 M–1cm–1 at 336 nm) was observed for the 4-thiothymidine/4-thiothymine pair. 相似文献