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Dyguda-Kazimierowicz E Sokalski WA Leszczyński J 《Journal of molecular modeling》2007,13(6-7):839-849
The subject of this study was an analysis of the role of active site residues in the phosphoryl transfer reaction catalyzed
by 4-methyl-5-β-hydroxyethylthiazole kinase (ThiK). The ThiK-catalyzed reaction is of special interest due to the lack of
a highly conserved aspartate residue serving as a catalytic base. ONIOM(B3LYP:PM3) models of stationary points along the reaction
pathway consisted of reactants, two magnesium ions and several highly conserved ThiK active site residues. The results indicate
that an SN2-like mechanism of ThiK, with γ-phosphate acting as an alcohol-activating base is reasonable. Geometries of substrates, transition
state and products were utilized in the non-empirical analysis of the physical nature of catalytic interactions taking place
in the ThiK active site. The role of particular residues was investigated in terms of their ability to preferentially stabilize
the transition state relative to substrates (differential transition state stabilization, DTSS) or products (differential
product stabilization, DPS). It seems that Mg2, Glu126 and Cys198 play a major catalytic role, whereas Mg1 and the same Cys198
are responsible for product release. It is remarkable that no dominant role of an electrostatic term in the interactions involved
in catalytic activity is observed for product release. Determination of catalytic fields expressing differential electrostatic
potential of the transition state with respect to substrates revealed the optimal electrostatic features of an ideal catalyst
for the studied reaction. The predicted catalytic environment is in agreement with experimental data showing increased catalytic
activity of ThiK upon mutation of Cys198 to aspartate.
Figure Catalytic fields for ThiK-catalyzed reaction juxtaposed with the positions of active site residues of a model system. Magnesium
ions are considered part of the transition state/reactants. The surface of constant electronic density is colored according
to differential electrostatic potential of transition state with respect to reactants. The sign of the differential potential
reflects the electrostatic properties of a complementary molecular environment. Red (green) color denotes regions where a negative (positive) charge would be optimal for catalytic activity 相似文献
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Osiadacz J Majka J Czarnecki K Peczyńska-Czoch W Zakrzewska-Czerwińska J Kaczmarek L Sokalski WA 《Bioorganic & medicinal chemistry》2000,8(5):937-943
Indolo[2,3-b]quinolines are a new family of the DNA intercalators showing significant cytotoxic activity. The mechanism of their action is based on the inhibition of DNA topoisomerase II activity. It depends on their ability to induce and stabilize drug-topII-DNA cleavable complexes. Site-specific intercalation of 5,11-dimethyl-5H-indolo[2,3-b]quinoline (DiMIQ) was analyzed in vitro by DNaseI footprinting and by molecular modeling. To model the DNA-intercalator complex, use was made of the CVFF and ESFF force fields implemented in Insight 97.0 software. Experimental results were verified using a simple statistical model. The DiMIQ molecule was found to bind preferentially to the pBR322 DNA plasmid in the 5'-TGCTAACGC-3' region between adjacent adenine bases. 相似文献
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Chiu Wan-Ling Johnson Ellen M. Kaplan Sara A. Blasko Kimberly Sokalski Mary B. Wolfson Ruth Sears Barbara B. 《Molecular genetics and genomics : MGG》1990,221(1):59-64
Molecular Genetics and Genomics - Oenothera plants homozygous for a recessive allele at the plastome mutator (pm) locus show non-Mendelian mutation frequencies that are 1000-fold higher than... 相似文献
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Summary
Oenothera plants homozygous for a recessive plastome mutator allele (pm) showed spontaneous mutation frequencies for plastome genes that are 200-fold higher than spontaneous levels. Mutations occurred at high frequencies in plants grown in the field, in a glass-house, or as leaf tip cultures under fluorescent light, indicating that the plastome mutator activity is UV-independent. However, the chlorotic sectors became visible at an earlier stage of development when seedlings were irradiated, compared to seedlings that were not exposed to UV. These results imply that the rate of sorting-out was increased by the irradiation treatment, possibly due to a decrease in the effective number of multiplication-competent plastids, or a reduction in the extent of cytoplasmic mixing. Nitroso-methyl urea treatment of seeds had a dramatic effect on mutation frequency in both wild-type and plastome mutator samples. When the background mutation rates were low, the combination of the plastome mutator nucleus and the chemical mutagenesis treatment resulted in a synergistic effect, suggesting that the plastome mutator may involve a cpDNA repair pathway. 相似文献
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Kaczmarek L Peczyńska-Czoch W Osiadacz J Mordarski M Sokalski WA Boratyński J Marcinkowska E Glazman-Kuśnierczyk H Radzikowski C 《Bioorganic & medicinal chemistry》1999,7(11):2457-2464
A series of new 5H-indolo[2,3-b]quinoline derivatives bearing methoxy and methyl groups at C-2 and C-9 was synthesized (according to the modified Graebe-Ullmann reaction). These compounds were evaluated for their antimicrobial and cytotoxic activity and tested as inhibitors of DNA topoisomerase II. Lipophilic and calf thymus DNA binding properties of these compounds were also established. In the SAR studies we used quantum-mechanical methodology to analyze the molecular properties of the drugs. All of the 5H-indolo[2,3-b]quinolines tested were found to inhibit the growth of gram-positive bacteria and pathogenic fungi at MIC ranging between 2.0 and 6.0 microM. They showed also cytotoxic activity in vitro against several human cancer cell lines of different origin (ID50 varied from 0.6 to 1.4 microM), and stimulated the formation of topoisomerase-II-mediated pSP65 DNA cleavage at concentration between 0.2 and 0.5 microM. The most active indolo[2,3-b]quinolines which had the greatest contribution to the increase in the Tm of DNA displayed also the highest DNA binding constants and the highest cytotoxic activity. The differences in DNA binding properties and cytotoxic activity seem to be more related to steric than electrostatic effects. 相似文献
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