Theoretical study on monooxygenation mechanism by cytochrome P450: an ultimate species in the substrate oxidation process

Hata, Masayuki; Hirano, Yoshinori; Hoshino, Tyuji; Nishida, Rie; Tsuda, Minoru

doi:10.1016/j.theochem.2004.11.054

Cited by 2 publications

(3 citation statements)

References 36 publications

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“…Accordingly, the present calculation combining MD simulation and docking simulation would not correctly predict the change in V max value as seen in the cases of diclofenac and tolbutamide. Instead, quantum chemical calculations to estimate the activation energy for the oxidizing reaction of the enzyme14–17 will present the index directly corresponding to V max and well explain the change of the value upon amino mutations.…”

Section: Discussionmentioning

confidence: 99%

“…X‐ray crystal analysis of CYP2C9 has been carried out and information on its structure has been accumulated in recent years 12, 13. Elucidation of its three‐dimensional structure has enabled us to perform computational analysis of the interaction between the enzyme and its substrate or inhibitor 14–20. In earlier studies before the human CYP crystal structures were available, homology modeling from bacterial P450 was used to investigate the metabolic reaction mechanism using a computer.…”

Section: Introductionmentioning

confidence: 99%

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Mechanism of the decrease in catalytic activity of human cytochrome P450 2C9 polymorphic variants investigated by computational analysis

Sano

Yuki

et al. 2010

J Comput Chem

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Cytochrome P450 (CYP) is deeply involved in the metabolism of chemicals including pharmaceuticals. Therefore, polymorphisms of this enzyme have been widely studied to avoid unfavorable side effects of drugs in chemotherapy. In this work, we performed computational analysis of the mechanism of the decrease in enzymatic activity for three typical polymorphisms in CYP 2C9 species: *2, *3, and *5. Based on the equilibrated structure obtained by molecular dynamics simulation, the volume of the binding pocket and the fluctuation of amino residues responsible for substrate holding were compared between the wild type and the three variants. Further docking simulation was carried out to evaluate the appropriateness of the binding pocket to accommodate substrate chemicals. Every polymorphic variant was suggested to be inferior to the wild type in enzymatic ability from the structural viewpoint. F-G helices were obviously displaced outward in CYP2C9*2. Expansion of the binding pocket, especially the space near F' helix, was remarkable in CYP2C9*3. Disappearance of the hydrogen bond between K helix and β4 loop was observed in CYP2C9*5. The reduction of catalytic activity of those variants can be explained from the deformation of the binding pocket and the consequent change in binding mode of substrate chemicals. The computational approach is effective for predicting the enzymatic activity of polymorphic variants of CYP. This prediction will be helpful for advanced drug design because calculations forecast unexpected change in drug efficacy for individuals.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mechanism of the decrease in catalytic activity of human cytochrome P450 2C9 polymorphic variants investigated by computational analysis

Sano

Yuki

et al. 2010

J Comput Chem

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“…The P450 enzymes take part in the detoxication, biodegradation, and bioactivation reactions of chemicals. An iron(III) porphyrin complex forms an active site of the cytochrome P450 33–35. The problems of the cytochrome P450 structure‐function relationships were treated in many books and papers on enzymology, xenobiochemistry, and toxicology 32–41.…”

Section: Introductionmentioning

confidence: 99%

Quantum chemical simulation of cytochrome P450 catalyzed aromatic oxidation: Metabolism, toxicity, and biodegradation of benzene derivatives

D’yachkov¹,

Харчевникова²,

Дмитриев³

et al. 2007

Int J of Quantum Chemistry

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ABSTRACT:The dependences of biological oxidation and toxicity of the mono-and multisubstituted benzene derivatives on the nature of substituents are studied using an oxenoid model and the quantum chemical calculations. According to this model, the P450 enzyme breaks the dioxygen molecules and generates the active atomic oxygen species (oxens); these species readily react with substrates. Using MO LCAO MNDO approach, we calculated the differences ⌬E of the total energies of aromatic compounds and corresponding arene oxides containing tetrahedrally coordinated carbon atoms. We obtained that the ⌬E values determine the positions of the enzyme mediated oxidation, rate of substrate biotransformation, and toxicity of the benzene derivatives. In addition to the "dynamic" reactivity index ⌬E related to the enzyme-mediated substrate biotransformation, we calculated many standard "static" reactivity indices, corresponding to the substrate molecules in the starting equilibrium geometry (the energies of the occupied and unoccupied MOs, the effective atomic charges, the free valence indices, and the superdelocalizabilities). The arene oxide stability ⌬E parameter is shown to be the most adequate characteristic of both the biological oxidation process and toxicity of benzenes. The ⌬E parameters were also used successfully to describe the features of di-and trichlorinated biphenyls bacterial metabolism.

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Theoretical study on monooxygenation mechanism by cytochrome P450: an ultimate species in the substrate oxidation process

Cited by 2 publications

References 36 publications

Mechanism of the decrease in catalytic activity of human cytochrome P450 2C9 polymorphic variants investigated by computational analysis

Mechanism of the decrease in catalytic activity of human cytochrome P450 2C9 polymorphic variants investigated by computational analysis

Quantum chemical simulation of cytochrome P450 catalyzed aromatic oxidation: Metabolism, toxicity, and biodegradation of benzene derivatives

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