生合成酵素反応機構の解析を基盤とする新規生物活性物質の探索

概要

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Squalene epoxidase (SE) is a non-P450 flavoprotein monooxygenase that catalyzes the conversion of squalene to (3.S)2,3-oxidosqualene, one of the rate-limiting steps of cholesterol biogenesis. Naturally occurring galloyl esters such as (-)-epigallocatechin-3-O-gallate (IC_<50> = 0.69 μM, K_I = 0.74 μM), the major components of green tea polyphenols, were found to be potent and selective inhibitors of vertebrate SE. A synthetic n-dodecyl gallate (IC_<50> = 0.061 μM, K_I = 0.033 μM) with a hydrophobic side chain showed even more potent inhibition. The presence of galloyl moiety was thus shown to be essential for the enzyme inhibition. The flavin monooxygenase reaction proceeds through formation of the active oxygen species. It was postulated that the enzyme inhibition would be caused by specific binding of gallates to the active site of the enzyme, possibly in close proximity to the FAD binding domain, and by scavenging the reactive oxygen species required for the enzyme reaction This was supported by molecular modeling studies based on the crystal structure of bacterial p-hydroxybenzoic acid hydroxylase, one of the best characterized flavin monooxygenase that shares 20% amino acid sequence identity with SE.
日本生薬学会の論文
2003-04-20