NDLI: Evidence for a 1-Electron Oxidation Mechanism in N-Dealkylation of N,N-Dialkylanilines by Cytochrome P450 2B1 KINETIC HYDROGEN ISOTOPE EFFECTS, LINEAR FREE ENERGY RELATIONSHIPS, COMPARISONS WITH HORSERADISH PEROXIDASE, AND STUDIES WITH OXYGEN SURROGATES

Content Provider	Journal of Biological Chemistry (JBC)
Author	Guengerich, F. Peter Yun, Chul-Ho Macdonald, Timothy L.
Abstract	Many enzymes catalyze N-dealkylations of alkylamines, including cytochrome P450 (P450) and peroxidase enzymes. Peroxidases, exemplified by horseradish peroxidase (HRP), are generally accepted to catalyze N-dealkylations via 1-electron transfer processes. Several lines of evidence also support a 1-electron mechanism for many P450 reactions, although this view has been questioned in light of reported trends for kinetic hydrogen isotope effects for N-demethylation with a series of 4-substituted N,N-dimethylanilines. No continuous trend for an increase of isotope effects with the electronic parameters of para-substitution was seen for the P450 2B1-catalyzed reactions in this study. The larger value seen with the 4-nitro derivative is consistent with a shift in mechanism due to either a reversible electron transfer step preceding deprotonation or to a hydrogen atom abstraction mechanism. With HRP, the trend is to lower isotope effects with para electron-withdrawing substituents, due to an apparent shift in rate-limiting steps. Biomimetic model high-valent porphyrins showed reduction rates with variously 4-substituted N,N-dialkylanilines that were consistent with a positively charged intermediate; such relationships were not seen for anisole O-demethylation with P450 2B1. In contrast to the case with the NADPH-supported P450 reactions, high deuterium isotope effects (∼7) were seen in the N-dealkylations supported by the oxygen surrogate iodosylbenzene. With iodosylbenzene, colored aminium radicals were observed in the oxidations of aminopyrine, N,N-dimethyl-4-aminothioanisole, and 4-methoxy-N,N-dimethylaniline. With the latter compound, a substantial intermolecular deuterium isotope effect was observed for N-demethylation. In the N-dealkylation of N-ethyl,N-methylaniline by P450 2B1 (NADPH-supported), the ratio of N-demethylation to N-deethylation was 16. Although it is probably possible for P450s to catalyze amine N-dealkylations via hydrogen atom abstraction when such a course is electronically or sterically favored, we interpret the evidence to favor a 1-electron pathway with N,N-dialkylamines with P450 2B1 as well as HRP and several biomimetic models.
Related Links	http://www.jbc.org/content/271/44/27321.abstract
Ending Page	27329
Starting Page	27321
Page Count	9
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	44
Volume Number	271
DOI	10.1074/jbc.271.44.27321
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	1996-11-01
Access Restriction	Open
Subject Keyword	Enzymology
Alternative Title	Evidence for a 1-Electron Oxidation Mechanism in N-Dealkylation of N,N-Dialkylanilines by Cytochrome P450 2B1
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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