The second-order rate constants for the oxidation of a series of phenol derivatives by horseradish peroxidase compound II
were compared to computer-calculated chemical parameters characteristic for this reaction step. The phenol derivatives studied
were phenol, 4-chlorophenol, 3-hydroxyphenol, 3-methylphenol, 4-methylphenol, 4-hydroxybenzoate, 4-methoxyphenol and 4-hydroxybenzaldehyde.
Assuming a reaction of the phenolic substrates in their non-dissociated, uncharged forms, clear correlations (
r = 0.977 and
r = 0.905) were obtained between the natural logarithm of the second-order rate constants (ln
k
app and ln
k
2 respectively) for their oxidation by compound II and their calculated ionisation potential, i.e. minus the energy of their
highest occupied molecular orbital [E(HOMO)]. In addition to this first approach in which the quantitative structure-activity
relationship (QSAR) was based on a calculated frontier orbital parameter of the substrate, in a second and third approach
the relative heat of formation (ΔΔHF) calculated for the process of one-electron abstraction and H
• abstraction from the phenol derivatives was used as a parameter. Plots of the natural logarithms of the second-order rate
constants (
k
app and
k
2) for the reaction and the calculated ΔΔHF values for the process of one-electron abstraction also provide clear QSARs with
correlation coefficients of –0.968 and –0.926 respectively. Plots of the natural logarithms of the second-order rate constants
(
k
app and
k
2) for the reaction and the calculated ΔΔHF values for the process of H
• abstraction provide QSARs with correlation coefficients of –0.989 and –0.922 respectively. Since both mechanisms considered,
i.e. initial electron abstraction versus initial H
• abstraction, provided clear QSARs, the results could not be used to discriminate between these two possible mechanisms for
phenol oxidation by horseradish peroxidase compound II. The computer calculation-based QSARs thus obtained for the oxidation
of the various phenol derivatives by compound II from horseradish peroxidase indicate the validity of the approaches investigated,
i.e. both the frontier orbital approach and the approach in which the process is described by calculated relative heats of
formation. The results also indicate that outcomes from computer calculations on relatively unrelated phenol derivatives can
be reliably compared to one another. Furthermore, as the actual oxidation of peroxidase substrates by compound II is known
to be the rate-limiting step in the overall catalysis by horseradish peroxidase, the QSARs of the present study may have implications
for the differences in the overall rate of substrate oxidation of the phenol derivatives by horseradish peroxidase.
Received: 29 March 1996 / Accepted: 17 July 1996
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