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Stereoselectivity in the N'-oxidation of nicotine isomers by flavin-containing monooxygenase.

Authors
  • Damani, L A
  • Pool, W F
  • Crooks, P A
  • Kaderlik, R K
  • Ziegler, D M
Type
Published Article
Journal
Molecular pharmacology
Publication Date
Jun 01, 1988
Volume
33
Issue
6
Pages
702–705
Identifiers
PMID: 3380084
Source
Medline
License
Unknown

Abstract

N'-Oxidation of nicotine isomers by porcine liver flavin-containing monooxygenase shows a clear stereoselectivity in the formation of the diastereomeric N'-oxides. (S)-(-)-Nicotine exhibited no stereoselectivity in the formation of cis-1'R,2'S- and trans-1'S,2'S-products, whereas with (R)-(+)-nicotine, only the trans-1'R,2'R-N'-oxide was formed. The concentration of each isomer required for half maximal activity differs significantly, and access of (S)-(-)-nicotine to the active site appears to be more restricted than for (R)-(+)-nicotine as judged from the observed Km values (Km = 181 and 70 microM, respectively, for the (S)-(-)- and (R)-(+)-isomers). These results indicate that a region adjacent to the active site may sterically prohibit binding of (R)-(+)-nicotine when the N'-methyl and pyridyl groups are in a cis-orientation. N-Methylnicotinium ion (both R- and S-isomers) is not a substrate for either porcine flavin monooxygenase, guinea pig liver microsomes, or ram seminal vesicular microsomes.

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