Metabolism of myristicin by Depressaria pastinacella CYP6AB3v2 and inhibition by its metabolite.
Metabolism of myristicin by Depressaria pastinacella CYP6AB3v2 and inhibition by its metabolite.
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DOI：
10.1016/j.ibmb.2008.03.013
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发表时间：
2008-06
影响因子：
3.8
通讯作者：
W. Mao;A. Zangerl;M. Berenbaum;M. Schuler
中科院分区：
文献类型：
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作者：
W. Mao;A. Zangerl;M. Berenbaum;M. Schuler
尽管亚甲二氧基苯基（MDP）化合物，如肉豆蔻醚，可用于管理抗除草剂昆虫，但它们在哺乳动物和昆虫中作用的分子机制尚未阐明。在这项研究中，GC-MS分析的甲醇提取物的叶子的野生欧洲防风（Pastinaca sativa）已确定肉豆蔻酸作为底物的CYP 6AB 3v 2，欧前胡素代谢细胞色素P450单加氧酶Depressaria pastinacella（欧洲防风线虫）。与其对许多哺乳动物P450的强烈抑制作用相反，肉豆蔻酸被CYP 6AB 3v 2有效代谢（Vmax和Km分别为97.9 pmol/min/pmol P450和17.9μM），其代谢速率超过了先前记录的欧前胡素，欧前胡素是这种高度特异性酶的唯一其他已知底物。CYP 6AB 3v 2的代谢产物为1-（3′，4 ′-亚甲二氧基-5 ′-甲氧基苯基）-2，3-环氧丙烷。分子对接表明，与呋喃香豆素的其他环氧化物代谢物不同，这种环氧化物代谢物可能保留在CYP 6AB 3v 2催化位点，因为其结合能较低（− 31.0 kcal/mol）。抑制试验表明，肉豆蔻酸作为一种混合抑制剂，这种昆虫P450，并建议，环氧化物代谢物可能是一个中间体参与P450-亚甲二氧基苯基复合物的形成。
Although methylenedioxyphenyl (MDP) compounds, such as myristicin, are useful in the management of insecticide-resistant insects, the molecular mechanisms for their action in mammals and insects have not been elucidated. In this study, GC–MS analyses of methanol extracts of foliage of wild parsnip (Pastinaca sativa) have identified myristicin as a substrate for CYP6AB3v2, an imperatorin-metabolizing cytochrome P450 monooxygenase from Depressaria pastinacella (parsnip webworm). In contrast with its strong inhibitory effects on many mammalian P450s, myristicin is effectively metabolized by CYP6AB3v2 (Vmaxand Kmof 97.9pmol/min/pmol P450 and 17.9μM, respectively) at a rate exceeding that recorded previously for imperatorin, the only other known substrate for this highly specialized enzyme. The myristicin metabolite of CYP6AB3v2 is 1-(3′,4′-methylenedioxy-5′-methoxyphenyl)-2,3-epoxypropane. Molecular dockings have indicated that, unlike other epoxide metabolites of furanocoumarins, this epoxide metabolite is likely to remain in the CYP6AB3v2 catalytic site due to its low binding energy (−31.0kcal/mol). Inhibition assays indicate that myristicin acts as a mixed inhibitor of this insect P450 and suggest that the epoxide metabolite may be an intermediate involved in the formation of P450–methylenedioxyphenyl complexes.