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Asymmetric metabolic N ‐oxidation of N ‐ethyl‐ N ‐methylaniline by purified flavin‐containing monooxygenase
Author(s) -
Hadley Mark R.,
Oldham Harriet G.,
Damani Lyaquatali A.,
Hutt Andrew J.
Publication year - 1994
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.530060210
Subject(s) - chemistry , monooxygenase , flavin containing monooxygenase , metabolite , enantiomer , microsome , substrate (aquarium) , stereoselectivity , stereochemistry , biotransformation , enzyme , flavin group , biochemistry , cytochrome p450 , catalysis , oceanography , geology
The prochiral tertiary amine N ‐ethyl‐ N ‐methylaniline (EMA) is known to be metabolically N ‐oxygenated in vitro with microsomal preparations. This biotransformation is thought to be mediated predominantly by the flavin‐containing monooxygenase (FMO) enzyme system. Microsomal N ‐oxygenation of EMA is known to be stereoselective and varies between species. In order to further characterise this metabolic transformation, we have examined the in vitro metabolism of EMA using purified porcine hepatic FMO. Following incubation of EMA with purified FMO, EMA N ‐oxide, the only metabolite detected, was found to be produced stereoselectively [ratio (−)‐(S):(+)‐(R), ca. 4:1]. The enantiomeric ratio of the N ‐oxide product did not change markedly with respect to time, enzyme or substrate concentration. Determination of the kinetics of formation of the N ‐oxide indicated a single affinity for the prochiral substrate with differential rates of formation of the enantiomers. The extent of EMA N ‐oxide formation was shown to be affected by activators and inhibitors of FMO and pH, but its stereoselectively was unaltered. © 1994 Wiley‐Liss, Inc.