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Metabolism of Halogenated Alkanes by Cytochrome P450 enzymes. Aerobic Oxidation versus Anaerobic Reduction
Author(s) -
Ji Li,
Zhang Jing,
Liu Weiping,
de Visser Sam P.
Publication year - 2014
Publication title -
chemistry – an asian journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.18
H-Index - 106
eISSN - 1861-471X
pISSN - 1861-4728
DOI - 10.1002/asia.201301608
Subject(s) - chemistry , cytochrome p450 , enzyme , substrate (aquarium) , density functional theory , oxidative phosphorylation , mechanism (biology) , hydrogen atom abstraction , catalysis , metabolism , reactivity (psychology) , reaction mechanism , drug metabolism , stereochemistry , heme , combinatorial chemistry , computational chemistry , biochemistry , hydrogen , organic chemistry , biology , medicine , ecology , philosophy , alternative medicine , epistemology , pathology
Abstract The cytochromes P450 are a large class of heme‐containing enzymes that catalyze a broad range of chemical reactions in biosystems, mainly through oxygen‐atom transfer to substrates. A relatively unknown reaction catalyzed by the P450s, but very important for human health, is the activation of halogenated substrates, which may lead to toxicity problems. However, its catalytic mechanism is currently unknown and, therefore, we performed a detailed computational study. To gain insight into the metabolism of halogenated compounds by P450 enzymes, we have investigated the oxidative and reductive P450‐mediated activation of tetra‐ and trichloromethane as halogenated models with density functional theory (DFT) methods. We propose an oxidative halosylation mechanism for CCl 4 under aerobic conditions by Compound I of P450, which follows the typical Groves‐type rebound mechanism. By contrast, the metabolism of CHCl 3 occurs preferentially via an initial hydrogen‐atom abstraction rather than halosylation. Kinetic isotope effect studies should, therefore, be able to distinguish the mechanistic pathways of CCl 4 versus CHCl 3 . We find a novel mechanism that is different from the well accepted P450 substrate activation mechanisms reported previously. Moreover, the studies highlight the substrate specific activation pathways by P450 enzymes leading to different products. These reactivity differences are rationalized using Marcus theory equations, which reproduce experimental product distributions.