Regular Article
Potent and Selective Inhibition of Squalene Epoxidase by Synthetic Galloyl Esters

https://doi.org/10.1006/bbrc.2000.2399Get rights and content

Abstract

n-Alkyl esters (ethyl, octyl, dodecyl, and cetyl) of gallic acid were evaluated as enzyme inhibitors of recombinant rat squalene epoxidase (SE), a rate-limiting enzyme of cholesterol biogenesis. Dodecyl (6) (IC50 = 0.061 μM) showed the most potent inhibition, which was far more potent than those of previously reported naturally occurring gallocatechins. Octyl gallate (5) (IC50 = 0.83 μM) and cetyl gallate (7) (IC50 = 0.59 μM) also showed good inhibition, while gallic acid (IC50 = 73 μM) itself was not so active. In addition, chemically synthesized galloyl ester of cholesterol (9) (IC50 = 3.9 μM), farnesol derivative (10) (IC50 = 0.57 μM), and dodecyl galloyl amide (8) (IC50 = 3.0 μM) were also potent inhibitors of SE. Inhibition kinetics revealed that dodecyl gallate inhibited SE in competitive (KI = 0.033 μM) and no-time-dependent manner. The potent inhibition of the flavin monooxygenase would be caused by specific binding to the enzyme, and by scavenging reactive oxygen species required for the epoxidation reaction.

References (18)

  • I. Abe et al.
  • J. Sakakibara et al.

    J. Biol. Chem.

    (1995)
  • A. Nagumo et al.

    J. Lipid Res.

    (1995)
  • I. Abe et al.

    Drug Discovery Today

    (1998)
  • I. Abe et al.

    Biochem. Biophys. Res. Commun.

    (2000)
  • A. Serrano et al.

    Arch. Biochem. Biophys.

    (1998)
  • I. Lázaro et al.

    Anal. Biochem.

    (1995)
  • M. Horie et al.

    J. Biol. Chem.

    (1990)
There are more references available in the full text version of this article.

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