Theoretical Study on Compound I Formation in Monooxygenation Mechanism by Cytochrome P450

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

doi:10.1021/jp0496248

Cited by 15 publications

(16 citation statements)

References 47 publications

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“…On the other hand, the formation of the hydroperoxo species (Fe–OOH) by the transfer of a proton from His195 to the distal oxygen was also considered, because it has been found to be more stable than Fe–O(H)O in both heme − and nonheme ,, iron enzymes. Our calculations show that the formation of the Fe–OOH ( 11 ) species has a higher barrier (4.9 kcal/mol in Figure c), as compared to that for Fe–O(H)O formation (2.3 kcal/mol for 3 → 4 in Figure b).…”

Section: Results and Discussionmentioning

confidence: 99%

Insights into the Mechanism of Aromatic Ring Cleavage of Noncatecholic Compound 2-Aminophenol by Aminophenol Dioxygenase: A Quantum Mechanics/Molecular Mechanics Study

Dong

Lai

2016

ACS Catal.

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2-Aminophenol 1,6-dioxygenase (APD) is an extradiol dioxygenase responsible for the ring cleavage of 2aminophenol (2AP) at the position ortho to the hydroxyl substituent. To elucidate the reaction mechanism, we conducted quantum mechanical/molecular mechanical (QM/ MM) calculations. The mode of binding of the substrate (monodentate or bidentate) to the iron center was found to have a crucial role in dioxygen activation. The Fe−O 2 adducts with 2AP bound bidentately has a quintet ground state having a Fe III −superoxo character, while the Fe−O 2 adducts with a monodentately bound substrate has been characterized as a substrate radical−Fe II −superoxide. Unlike other extradiol dioxygenases that cleave catechol analogues using the superoxo moiety of the Fe−O 2 adducts to attack the substrate, we found here an Fe II −O(H)O intermediate formed through two sequential proton-coupled electron transfer steps from the initial Fe III −superoxo species is responsible for the attack. Importantly, the second-sphere His195 residue acts as an acid−base catalyst to mediate proton transfer (associated with electron transfer). The study presented here expands our understanding of the extradiol dioxygenases, especially those catalyzing the ring cleavage of noncatecholic substrates.

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Section: Results and Discussionmentioning

confidence: 99%

Insights into the Mechanism of Aromatic Ring Cleavage of Noncatecholic Compound 2-Aminophenol by Aminophenol Dioxygenase: A Quantum Mechanics/Molecular Mechanics Study

Dong

Lai

2016

ACS Catal.

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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%

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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“…The changes of bond length and bond order of key bonds, e. 8,23,28 Other studies that show O(d)−O(p) cleavage followed by proton transfer or proton transfer followed by O(d)−O(p) cleavage 23,24,30 may be due to the different proton sources and the different pathways.…”

Section: ■ Results/discussionmentioning

confidence: 99%

“…Cpd 0 was ever proposed as the “second oxidant” of P450 based on the findings that site-specific mutant of P450, which supposedly blocked the second proton transfer still shows significant activity in substrate oxygenation. , However, a series of experimental and computational studies ,− show that Cpd I is an oxidant superior over Cpd 0. Thus the second proton transfer, which relates to the generation of Cpd I from Cpd 0, is of more interest. ,,− …”

Section: Introductionmentioning

confidence: 99%

Car–Parrinello Molecular Dynamics/Molecular Mechanics (CPMD/MM) Simulation Study of Coupling and Uncoupling Mechanisms of Cytochrome P450cam

Lian

Wang

et al. 2013

J. Phys. Chem. B

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The relevance of the pathway through which the second proton is delivered to the active site of P450cam and the subsequent coupling/uncoupling reactions has been investigated using Car-Parrinello molecular dynamics/molecular mechanics (CPMD/MM) dynamics simulations. Five models have been prepared, representing delivery pathways in the wild-type enzyme and its mutants in which Thr252 mutated into other residues with different side-chain length and hydrophobicity. In the simulations, coupling reaction is observed in the wild-type enzyme (Model A) and its T252S mutant (Model B), while the uncoupling products are obtained in the other three models (C, D, and E). Different from previous studies, a dynamic process of the last stage of coupling/uncoupling was observed. We found that the peroxide bond cleavage in coupling, the Fe-O bond stretching in uncoupling, proton transfer, and electron delivery take place spontaneously. Moreover, besides the intrinsic chemical differences between the two peroxide oxygen atoms, water molecules in the active site and the proton transfer pathway may play an important role in the determination of coupling/uncoupling. We conclude that by maintaining a specific proton transfer channel, Asp251-Thr252 channel, the wild-type enzyme could efficiently deliver the second proton to the ideal position for coupling reaction.

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Theoretical Study on Compound I Formation in Monooxygenation Mechanism by Cytochrome P450

Cited by 15 publications

References 47 publications

Insights into the Mechanism of Aromatic Ring Cleavage of Noncatecholic Compound 2-Aminophenol by Aminophenol Dioxygenase: A Quantum Mechanics/Molecular Mechanics Study

Insights into the Mechanism of Aromatic Ring Cleavage of Noncatecholic Compound 2-Aminophenol by Aminophenol Dioxygenase: A Quantum Mechanics/Molecular Mechanics Study

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

Car–Parrinello Molecular Dynamics/Molecular Mechanics (CPMD/MM) Simulation Study of Coupling and Uncoupling Mechanisms of Cytochrome P450cam

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