Potent and selective inhibition of squalene epoxidase by synthetic galloyl esters.
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) (IC(50) = 0.061 microM) showed the most potent inhibition, which was far more potent than those of previously reported naturally occurring gallocatechins. Octyl gallate (5) (IC(50) = 0.83 microM) and cetyl gallate (7) (IC(50) = 0.59 microM) also showed good inhibition, while gallic acid (IC(50) = 73 microM) itself was not so active. In addition, chemically synthesized galloyl ester of cholesterol (9) (IC(50) = 3.9 microM), farnesol derivative (10) (IC(50) = 0.57 microM), and dodecyl galloyl amide (8) (IC(50) = 3.0 microM) were also potent inhibitors of SE. Inhibition kinetics revealed that dodecyl gallate inhibited SE in competitive (K(I) = 0.033 microM) 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.
Abe
I
I
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka, 422-8526, Japan. abei@ys7.u-shizuoka-ken.ac.jp
Seki
T
T
Noguchi
H
H
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004952:Esters / Q000494:pharmacology; D005420:Flavoproteins / Q000037:antagonists & inhibitors*; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D010105:Oxygenases / Q000037:antagonists & inhibitors* / Q000235:genetics; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013185:Squalene / Q000378:metabolism*; D050603:Squalene Monooxygenase
D004952:Esters; D005420:Flavoproteins; D011994:Recombinant Proteins; C016627:octyl gallate; C048734:ethyl gallate; C008259:lauryl gallate; D005707:Gallic Acid; D013185:Squalene; D010105:Oxygenases; D050603:Squalene Monooxygenase