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A. A. Zakhariants, A. A. Poloznikov, D. M. Hushpulian, T. A. Osipova, V. I. Tishkov, I. G. Gazaryan
Benzimidazoles
as competitive inhibitors of FAD-dependent monooxygenase
Abstract
Benzimidazoles represent the drugs targeting tubulin and widely used to
treat intestinal parasites. Four benzimidazoles were tested with the
well-characterized and commercially available bacterial para-hydroxybenzoate
hydroxylase (PHBH), which belongs to the group of FAD-dependent monooxygenases
class A including such enzymes as FAD-containing monooxygenase domain of MICAL.
PHBH was shown to be competitively inhibited by all four benzimidazoles
(mebendazole, albendazole, fenbendazole, oxibendazole) in the micromolar range
in the hydroxylase reaction, but not in the non-physiological
NADPH-dehydrogenase reaction of ferricyanide reduction. Inhibition pattern is
consistent with benzimidazoles competing with para-hydroxybenzoate for the
resting state of the enzyme, indirectly indicating the ordered mechanism of
substrate binding. Modeling studies support the conclusions derived from
steady-state kinetics.
Key words: para-hydroxybenzoate
hydroxylase, ferricyanide reduction, inhibition analysis, computer modeling,
docking.
Copyright (C) Chemistry Dept., Moscow State University, 2002
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