Inhibition of class C β-lactamases by (1′R,6R)-6-(1′-hydroxy)benzylpenicillanic acid SS-dioxide

Knight, Graham; Waley, S. G.

doi:10.1042/bj2250435

Cited by 38 publications

(21 citation statements)

References 25 publications

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“…The number of turnovers (r), which inactivate the enzyme may be determined from the dependence of the fractional activity remaining against the ratio of the initial concentration of inhibitor to that of the enzyme. The intercept on the abscissa is 1 + r [2]. This dependence is shown in the inset of Fig.…”

Section: Kinetics Of Mechanism-based Inhibitormentioning

confidence: 75%

1,4–Diamino‐2‐butyne as the mechanism‐based pea diamine oxidase inhibitor

Peč

Frésort

1992

European Journal of Biochemistry

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1,4-Diamino-2-butyne is a mechanism-based inhibitor of diamine oxidase (EC 1.4.3.6) from pea cotyledons. It shows saturation kinetics K,,, = 1 mM like a substrate, but its interaction leads to time-dependent loss of enzyme activity which is not restored by gel filtration. The substrate 1,4-diaminobutane and the competitive inhibitor 1,4-diamin0-2-butanone protect the enzyme against inactivation. Changes in the enzyme electronic spectra with 1,4-diamino-2-butyne were found. The mechanism of the interaction involves an intermediate aminoallenic compound, which is formed with covalent bound pyrrole in the reaction of the nucleophile with the enzyme. The presence of a pyrrole in the inactivated enzyme was confirmed by reaction with Ehrlich's reagent. The kinetic data obtained in this study indicate that 1,4-diamino-2-butyne is a mechanism-based inactivator with number of turnovers, r = 17 and characteristic constants K' = 0.32 mM and k,, = 4.89 min-'.Mechanism-based inhibitors interact with enzymes by a mechanism involving a branched pathway, the branches representing turnover of substrate and inactivation of enzyme:Mechanism-based inactivator + enzyme e Complex I e Complex I1 + enzyme + product The action and kinetic behavior of these inactivators were described by Abeles [l] and Waley [2, 31. The mechanismbased inhibitors of beef plasma amine oxidase (Cu-containing) have been described. The oxidative mechanism of inactivation indicates that 2-bromoethylamine [l] is oxidized to bromoacetaldehyde bound at the active site. Many substituted allylamines [l, 41 act as mechanism-based inactivators of FADcontaining amine oxidases. These allylamines form reactive allenic compounds in the active site of the enzyme which react with the nucleophile in the active site and inactivate the enzyme. A similar mechanism has been suggested for beef plasma amine oxidase, which is inhibited by propargylamine, 1,4-diamin0-2-butyne and 2-chloroallylamine [5], but the exact mechanism has not ben confirmed. Also, (a-2-phenyl-3-chloroallylamine, which is a potent mechanism-based inactivator of FAD-containing monoamine oxidase, is a much wcaker inhibitor of hog kidney diamine oxidase (Cu-containing) [4]. Another type ofmechanism-based inactivators of beef plasma aniine oxidases are some esters with relatively acidic Enzymes. Diamine oxidase, diamine : O2 oxidoreductwe (deaminating, copper-containing) (EC 1.4.3.6); amino oxidase (flavincontaining) (EC 1.4.3.4); horseradish pcroxidase (EC 1.11.1.7); catalasc (EC 1.11.1.6).x-protons. These esters are converted to ketenes, which could acylate the active site and inactivate the enzyme [6]. Mechanism-based inactivators of plant Cu-containing amine oxidases have not been described previously.Pea diamine oxidase catalyzes the oxidation of many amines and diamines to aldehydes, H 2 0 2 and NH3; most readily oxidized are the diamines putrescine and cadaverine [7]. The ping-pong mechanism of this oxidation was described [8] and the presence of a cofactor with an o-quinone group in the catalytic cycle ...

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Section: Kinetics Of Mechanism-based Inhibitormentioning

confidence: 75%

1,4–Diamino‐2‐butyne as the mechanism‐based pea diamine oxidase inhibitor

Peč

Frésort

1992

European Journal of Biochemistry

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“…(10). In this case the value of r can be obtained from separate measurements of residual activities at the final time (VA), with different values of [S0], by using the equation (Knight & Waley, 1985;Tudela et al, 1987a):…”

Section: Mechanism Of Schemementioning

confidence: 99%

“…There is a wide range of enzymes that undergo an inactivation process when acting on a substrate (suicide inactivation), following a branched mechanism consisting of a catalytic route and an enzyme inactivation route that gives rise to a transient phase, until total loss of activity is reached (Ingraham, 1955;Tokuyama & Dawson, 1962;Fernandez-Belda et al, 1982;Frere et al, 1982;Walsh, 1984;Knight & Waley, 1985;Faraci & Pratt, 1985). Kinetic studies of these reaction mechanisms have been carried out under approaches of significant (Waley, 1980(Waley, , 1985Tatsunami et al, 1981) and negligible (Galvez et al, 1981;Tudela et al, 1987a) substrate consumption during the assay time.…”

Section: Introductionmentioning

confidence: 99%

A kinetic study of the suicide inactivation of an enzyme measured through coupling reactions. Application to the suicide inactivation of tyrosinase

Escribano

Tudela

García‐Carmona

et al. 1989

Biochemical Journal

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A systematic procedure for the kinetic study of reaction mechanisms with enzyme inactivation induced by a suicide substrate in the presence or in the absence of an auxiliary substrate, when the enzyme activity is measured through coupling reactions, enzymically catalysed or not, was developed and analysed by using the transient-phase approach. The methodology is established to determine the parameters and kinetic constants corresponding to the enzyme suicide inactivation and the coupling reactions. This approach is illustrated by a study of the suicide inactivation of tyrosinase by catechol in the presence of L-proline. Treatment of the experimental data was carried out by non-linear regression.

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“…The intercept on the abscissa is 1 + r (see, e.g., Fig. 1 of Knight & Waley, 1985). The constancy of the partition ratio when the concentrations of inhibitor (substrate) and enzyme are varied is a useful test for this mechanism.…”

Section: (Inactivation) Dead Enzymementioning

confidence: 99%

Kinetics of suicide substrates. Practical procedures for determining parameters

Waley¹

1985

Biochemical Journal

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157

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Many clinically important or mechanistically interesting inhibitors react with enzymes by a branched pathway in which inactivation of the enzyme and formation of product are competing reactions. The steady-state kinetics for this pathway [Waley (1980) Biochem. J. 185, 771-773] gave equations for progress curves that were cumbersome. A convenient linear plot is now described. The time (t1/2) for 50% inactivation of the enzyme (this is also the time for 50% formation of product), or for 50% loss of substrate, is measured in a series of experiments in which the concentration of inhibitor, [I]0, is varied; in these experiments the ratio of the concentration of enzyme to the concentration of inhibitor is kept fixed. Then a plot of [I]0 X t1/2 against [I]0 is linear, and the kinetic parameters can be found from the slope and intercept. Furthermore, simplifications of the equations for progress curves are described that are valid when the concentration of inhibitors is high, or is low, or when the extent of reaction is low. The use of simulated data has shown that the recommended methods are not unduly sensitive to experimental error.

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Inhibition of class C β-lactamases by (1′R,6R)-6-(1′-hydroxy)benzylpenicillanic acid SS-dioxide

Cited by 38 publications

References 25 publications

1,4–Diamino‐2‐butyne as the mechanism‐based pea diamine oxidase inhibitor

1,4–Diamino‐2‐butyne as the mechanism‐based pea diamine oxidase inhibitor

A kinetic study of the suicide inactivation of an enzyme measured through coupling reactions. Application to the suicide inactivation of tyrosinase

Kinetics of suicide substrates. Practical procedures for determining parameters

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