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11.
Algirdas Mikalkėnas Bazilė Ravoitytė Daiva Tauraitė Elena Servienė Rolandas Meškys 《Journal of enzyme inhibition and medicinal chemistry》2018,33(1):384-389
Small molecule inhibitors have a powerful blocking action on viral polymerases. The bioavailability of the inhibitor, nevertheless, often raise a significant selectivity constraint and may substantially limit the efficacy of therapy. Phosphonoacetic acid has long been known to possess a restricted potential to block DNA biosynthesis. In order to achieve a better affinity, this compound has been linked with natural nucleotide at different positions. The structural context of the resulted conjugates has been found to be crucial for the acquisition by DNA polymerases. We show that nucleobase-conjugated phosphonoacetic acid is being accepted, but this alters the processivity of DNA polymerases. The data presented here not only provide a mechanistic rationale for a switch in the mode of DNA synthesis, but also highlight the nucleobase-targeted nucleotide functionalization as a route for enhancing the specificity of small molecule inhibitors. 相似文献
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15.
Jaroslav Votruba Jarmila Pazlarová Milada Dvořáková Kalju Vanatalu Libuše Váchová Marie Strnadová Helena Kučerová Jiří Chaloupka 《Applied microbiology and biotechnology》1987,26(4):373-377
Summary A mathematical model was formulated to describe the kinetics and stoichiometry of growth and proteinase production in Bacillus megaterium. Synthesis of the extracellular proteinase in a batch culture is repressed by amino acids. The specific rate of formation of the enzyme (r
E) can be described by the formula {ie373-1}, where k
2 and k
3 stand for the non-repressible and repressible part of enzyme synthesis respectively, k
S
2 is a repression coefficient and S
2 indicates the concentration of amono acids; the values of k
2 and k
S
2 depend on the composition of the mixture of amino acids. Even in a high concentration, a single amino acid is less effective than a mixture of amino acids. The dependence of the proteinase repression on the concentration of an external amino acid (leucine) follows the same course as its rate of incorporation into proteins, approaching saturation at concentrations higher than 50 M (half saturation approximately 10 M). However, the total uptake of leucine did not exhibit any saturation even at 500 M external concentration.Symbols
X
biomass concentration, g/l
-
E
proteinase concentration, unit/l
-
t
time, h
-
S
1
concentration of glucose, g/l
-
S
2
concentration of amino acids, g/l
-
specific growth rate, l/h
-
rE
specific rate of enzyme production, unit/g/h
-
k
1
growth kinetic constant, l/h
-
k
2
product formation kinetic constant (for non-repressible part of enzyme synthesis), unit/g
-
k
3
product formation kinetic constant (for repressible portion of enzyme synthesis), unit/g
-
k
S
1
saturation constant, g/l
-
k
S
2
repression coefficient for a certain amino acid or amino acids mixture, g/l 相似文献
16.
17.
Dario Cremaschi Giuliano Meyer Guido Bottà Carlo Rossetti 《The Journal of membrane biology》1987,95(3):219-228
Summary In the epithelium of rabbit gallbladder, in the nominal absence of bicarbonate, intracellular Cl– activity is about 25mm, about 4 times higher than intracellular Cl– activity at the electrochemical equilibrium. It is essentially not affected by 10–4
m acetazolamide and 10–4
m 4-acetamido-4-isothiocyanostilbene-2,2-disulfonate (SITS) even during prolonged exposures; it falls to the equilibrium value by removal of Na+ from the lumen without significant changes of the apical membrane potential difference. Both intracellular Cl– and Na+ activities are decreased by luminal treatment with 25mm SCN–; the initial rates of change are not significantly different. In addition, the initial rates of change of intracellular Cl– activity are not significantly different upon Na+ or Cl– entry block by the appropriate reduction of the concentration of either ion in the luminal solution. Luminal K+ removal or 10–5
m bumetanide do not affect intracellular Cl– and Na+ activities or Cl– influx through the apical membrane. It is concluded that in the absence of bicarbonate NaCl entry is entirely due to a Na+–Cl– symport on a single carrier which, at least under the conditions tested, does not cotransport K+. 相似文献
18.
Dario Cremaschi Giuliano Meyer Carlo Rossetti Guido Bottà Paola Palestini 《The Journal of membrane biology》1987,95(3):209-218
Summary Cl– influx at the luminal border of the epithelium of rabbit gallbladder was measured by 45-sec exposures to36Cl– and3H-sucrose (as extracellular marker). Its paracellular component was evaluated by the use of 25mm SCN– which immediately and completely inhibits Cl– entry into the cell. Cellular influx was equal to 16.7eq cm–2 hr–1 and decreased to 8.5eq cm–2 hr–1 upon removal of HCO
3
–
from the bathing media and by bubbling 100% O2 for 45 min. When HCO
3
–
was present, cellular influx was again about halved by the action of 10–4
m acetazolamide, 10–5 to 10–4
m furosemide, 10–5 to 10–4
m 4-acetamido-4-isothiocyanostilbene-2,2-disulfonate (SITS), 10–3
m amiloride. The effects of furosemide and SITS were tested at different concentrations of the inhibitor and with different exposure times: they were maximal at the concentrations reported above and nonadditive. In turn, the effects of amiloride and SITS were not additive. Acetazolamide reached its maximal action after an exposure of about 2 min. When exogenous HCO
3
–
was absent, the residual cellular influx was insensitive to acetazolamide, furosemide and SITS. When exogenous HCO
3
–
was present in the salines, Na+ removal from the mucosal side caused a slow decline of cellular Cl– influx; conversely, it immediately abolished cellular Cl– influx in the absence of HCO
3
–
. In conclusion, about 50% of cellular influx is sensitive to HCO
3
–
, inhibitable by SCN–, acetazolamide, furosemide, SITS and amiloride and furthermore slowly dependent on Na+. The residual cellular influx is insensitive to bicarbonate, inhibitable by SCN–, resistant to acetazolamide, furosemide, SITS and amiloride, and immediately dependent on Na+. Thus, about 50% of apical membrane NaCl influx appears to result from a Na+/H+ and Cl–/HCO
3
–
exchange, whereas the residual influx seems to be due to Na+–Cl– contranport on a single carrier. Whether both components are simultaneously present or the latter represents a cellular homeostatic counterreaction to the inhibition of the former is not clear. 相似文献
19.
Marta Munzarová Daniela Zemanová Jan Kovařík Zdeněk Pačovský Aleš Rejthar Jiří Bártek 《Cancer immunology, immunotherapy : CII》1987,24(3):272-274
Summary Skin tests with autologous cholesteryl hemisuccinate (CHS)-treated and untreated cells were performed in ten metastatic melanoma patients. In the majority of cases evident reaction was noted with CHS-treated cells (9/10) while the reaction with untreated cells was mostly negative (7/10). Tumour cell suspensions used for skin tests were characterized for reactivity with monoclonal antibody TAL 1B5 detecting the HLA-DR alpha chain. There were no differences between CHS-treated and untreated cells with respect to HLA-DR expression and no correlation was found between grade of skin reaction to CHS-treated cells and the proportion of HLA-DR positive cells in the injected cell sample. 相似文献
20.
B. Koukalová J. Reich R. Matyášek V. Kuhrová M. Bezděk 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》1989,78(1):77-80
Summary HRS60.1, a monomer unit (184 bp) of a highly repeated nuclear DNA sequence of Nicotiana tabacum, has been cloned and sequenced. Following BamHI digestion of tobacco DNA, Southern hybridization with HRS60.1 revealed a ladder of hybridization bands corresponding to multiples of the basic monomer unit. If the tobacco DNA was digested with restriction endonucleases which have no target site in HRS60.1, the larger part of DNA homologous to HRS60.1 remained as uncleaved relic DNA. These results suggest a tandem arrangement of this DNA repeat unit. Four other clones of tobacco nuclear DNA cross-hybridized with HRS60.1, thus forming a HRS60-family. Sequencing their inserts has shown their strong mutual homology. HRS60-family comprised about 2% of the nuclear genome of N. tabacum. Computer comparisons with other tandem plant-repeated DNA sequences could not detect any other homologous sequence. 相似文献