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A Mechanistic Comparison between Cytochrome P 450 ‐ and Chloroperoxidase‐Catalyzed N ‐Dealkylation of N , N ‐Dialkyl Anilines
Author(s) -
Bhakta Mehul N.,
Wimalasena Kandatege
Publication year - 2005
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.200500333
Subject(s) - chemistry , catalysis , alkylation , horseradish peroxidase , peroxidase , cytochrome , ligand (biochemistry) , reaction mechanism , stereochemistry , hydrogen atom abstraction , medicinal chemistry , heme , enzyme , organic chemistry , radical , biochemistry , receptor
Most peroxidases use histidine as an axial ligand for heme, while chloroperoxidase (CPO) uses a thiolate, which is similar to the ligand employed by cytochrome P 450 (P 450 ). Several studies have also shown that, unlike other peroxidases, CPO is capable of carrying out monooxygenation reactions in a similar manner to P 450 in addition to typical peroxidase‐like reactions. These observations have been attributed to the similarities of the active‐site architecture of the two enzymes. Both enzymes have been shown to efficiently catalyze the oxidative N ‐dealkylation of amines. The similar magnitudes of the kinetic isotope effects determined for P 450 ‐ and CPO‐catalyzed N ‐dealkylation of N , N ‐dimethylaniline have been used to propose that these reactions proceed through similar mechanisms. In this study, we have examined the mechanism of CPO‐catalyzed N ‐dealkylation using a series of radical probes, 4‐chloro‐ N ‐cyclopropyl‐ N ‐alkylanilines 1 – 3 , which we have recently used in the mechanistic studies of P 450 , and compared the results with those of P 450 ‐catalyzed reactions. The results show that P 450 ‐ and CPO‐catalyzed reactions proceed through distinctly different mechanisms. As previously reported, while P 450 ‐catalyzed reactions appear to proceed through a C α ‐hydrogen abstraction mechanism, CPO‐catalyzed reactions proceed through a single electron/proton transfer (SET/H + ) mechanism, similar to reactions catalyzed by Horseradish peroxidase (HRP). Thus, CPO may not be a good mechanistic model for P 450 ‐catalyzed N ‐dealkylations.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)