Metabolism of myristicin by Depressaria pastinacella CYP6AB3v2 and inhibition by its metabolite

Wenfu Mao, Arthur R. Zangerl, May R. Berenbaum, Mary A. Schuler

Research output: Contribution to journalArticle

Abstract

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 (Vmax and Km of 97.9 pmol/min/pmol P450 and 17.9 μM, 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-epoxypro pane. 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 (-31.0 kcal/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.

Original languageEnglish (US)
Pages (from-to)645-651
Number of pages7
JournalInsect Biochemistry and Molecular Biology
Volume38
Issue number6
DOIs
StatePublished - Jun 1 2008

Keywords

  • Cytochrome P450 monooxygenases (P450s)
  • Enzyme inhibition
  • Insecticide synergists
  • Methylenedioxphenyl (MDP) compounds
  • Myristicin
  • Plant allelochemical

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Insect Science

Fingerprint Dive into the research topics of 'Metabolism of myristicin by Depressaria pastinacella CYP6AB3v2 and inhibition by its metabolite'. Together they form a unique fingerprint.

  • Cite this