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1
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ATP-binding domain of NTPase/helicase as a target for hepatitis C antiviral therapy.

100%
Borowski P., Mueller O., Niebuhr A., Kalitzky M., Hwang L.-H., Schmitz H., Siwecka M. A., Kulikowski T.
Acta Biochimica Polonica
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2000
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vol. 47
|
issue 1
173-180
EN
To enhance the inhibitory potential of 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (ribavirin) vs hepatitis C virus (HCV) NTPase/helicase, ribavirin-5'-triphosphate (ribavirin-TP) was synthesized and investigated. Ribavirin-TP was prepared with the use of modified Yoshikawa-Ludwig-Mishra-Broom procedure (cf. Mishra & Broom, 1991, J. Chem. Soc., Chem. Commun, 1276-1277) involving phosphorylation of unprotected nucleoside. Kinetic analysis revealed enhanced inhibitory potential of ribavirin-TP (IC50=40 μM) as compared to ribavirin (IC50 > 500 μM). Analysis of the inhibition type by means of graphical methods showed a competitive type of inhibition with respect to ATP. In view of the relatively low specificity towards nucleoside-5'-triphosphates (NTP) of the viral NTPase/helicases, it could not be ruled out that the investigated enzyme hydrolyzed the ribavirin-TP to less potent products. Investigations on non- hydrolysable analogs of ribavirin-TP or ribavirin-5'-diphosphate (ribavirin-DP) are currently under way.
2
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Inhibition of the helicase activity of HCV NTPase/helicase by 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide-5'-triphosphate (ribavirin-TP).

100%
Borowski P., Lang M., Niebuhr A., Haag A., Schmitz H., Wiesch J. S. z., Choe J., Siwecka M. A., Kulikowski T.
Acta Biochimica Polonica
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2001
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vol. 48
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issue 3
739-744
EN
In the presented study the ribavirin-TP - an established inhibitor of the NTPase activity of the superfamily NTPase/helicases II - was investigated as an inhibitor of the unwinding activity of the hepatitis C virus (HCV) NTPase/helicase. The kinetics of the reaction revealed that ribavirin-TP reduces the turnover number of the helicase reaction by a mechanism that does not correspond to that of the inhibition of the NTPase activity. Our results suggest that derivatives of ribavirin-TP with enhanced stability towards hydrolytic attack may be effective inhibitors of the enzyme.
3
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An easy procedure to transform the ratio of two polynomials of first degree into Michaelis-Menten-type equations. Application to the ordered Uni Bi enzyme mechanism.

88%
Fontes R., Ribeiro J. M., Sillero A.
Acta Biochimica Polonica
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2000
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vol. 47
|
issue 1
259-268
EN
It is not always clear that some equations affected by complicated factors can, actually, be interpreted as a ratio of two polynomials of first degree and so that they can be, in general, represented by rectangular hyperbolas. In this paper we present an easy procedure to rearrange those equations into Michaelis-Menten-type equations and so to make the aspects of these rectangular hyperbolas more clear, particularly for researchers familiar with general biochemistry. As an example, the method is applied to transform the classical rate equation of the Cleland×s Ordered Uni Bi enzyme mechanism.
4
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Inhibition and activation of enzymes. The effect of a modifier on the reaction rate and on kinetic parameters.

75%
Fontes R., Ribeiro J. M., Sillero A.
Acta Biochimica Polonica
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2000
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vol. 47
|
issue 1
233-257
EN
A combined analysis of enzyme inhibition and activation is presented, based on a rapid equilibrium model assumption in which one molecule of enzyme binds one molecule of substrate (S) and/or one molecule of a modifier X. The modifier acts as activator (essential or non-essential), as inhibitor (total or partial), or has no effect on the reaction rate (v), depending on the values of the equilibrium constants, the rate constants of the limiting velocity steps, and the concentration of substrate ([S]). Different possibilities have been analyzed from an equation written to emphasize that v = Ł([X]) is, in general and at a fixed [S], a hyperbolic function. Formulas for Su (the value of [S], different from zero, at which v is unaffected by the modifier) and vsu (v at that particular [S]) were deduced. In Lineweaver-Burk plots, the straight lines related to different [X] generally cross in a point (P) with coordinates (Su, vsu). In certain cases, point P is located in the first quadrant which implies that X acts as activator, as inhibitor, or has no effect, depending on [S]. Furthermore, we discuss: (1) the apparent Vmax and Km displayed by the enzyme in different situations; (2) the degree of effect (inhibition or activation) observed at different concentrations of substrate and modifier; (3) the concept of Ke, a parameter that depends on the concentration of substrate and helps to evaluate the effect of the modifier: it equals the value of [X] at which the increase or decrease in the reaction rate is half of that achieved at saturating [X]. Equations were deduced for the general case and for particular situations, and used to obtain computer-drawn graphs that are presented and discussed. Formulas for apparent Vmax, Km and Ke have been written in a way making it evident that these parameters can be expressed as pondered means.
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