Computational modelling of the binding of arachidonic acid to the human monooxygenase CYP2J2

Proietti, G; Abelak, Kavin; Bishop‐Bailey, David; Macchiarulo, Antonio; Nobeli, Irene

doi:10.1007/s00894-016-3134-6

Cited by 10 publications

(8 citation statements)

References 48 publications

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“…Taken together, it appeared that Cβ achieved a desirable compromisation between the distance and bond strength, which could contribute to its regioselectivity of the hydroxylation by CYP2J2. The last substrate discussed is the ARA (M14) whose primary epoxidation site seemed difficult to predict with the homology modeled structure of CYP2J2 21 . The present docking study demonstrated that the distance between the preferred metabolic site (14, 15-) and the heme iron was shorter than other metabolic sites, which Figure 9.…”

Section: M1-m3mentioning

confidence: 99%

“…The metabolic site of M1-M3 was adopted from reference 25 ; The metabolic site of M4 was adopted from reference 14 ; The metabolic site of M5 was adopted from reference 10 ; The metabolic site of M6 was adopted from reference 13 ; The metabolic site of M7 was adopted from reference 11 ; The metabolic site of M8 was adopted from CYP3A4 in complex with two M8 (PDB ID: 2J0C, see reference 23 ) and reference 26 ; The metabolic site of M9-M13 was adopted from reference 12 ; and The metabolic site of M14 was adopted from reference 6 . that yielded the metabolic product of 13,14-EET was not predicted 21 . In addition, the binding modes of the above-mentioned antihistamine drugs in the active site of those developed CYP2J2 models were not carefully examined.…”

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confidence: 94%

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Molecular determinant of substrate binding and specificity of cytochrome P450 2J2

Chen

2020

Sci Rep

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Cytochrome P450 2J2 (CYP2J2) is responsible for the epoxidation of endogenous arachidonic acid, and is involved in the metabolism of exogenous drugs. To date, no crystal structure of CYP2J2 is available, and the proposed structural basis for the substrate recognition and specificity in CYP2J2 varies with the structural models developed using different computational protocols. In this study, we developed a new structural model of CYP2J2, and explored its sensitivity to substrate binding by molecular dynamics simulations of the interactions with chemically similar fluorescent probes. Our results showed that the induced-fit binding of these probes led to the preferred active poses ready for the catalysis by CYP2J2. Divergent conformational dynamics of CYP2J2 due to the binding of each probe were observed. However, a stable hydrophobic clamp composed of residues I127, F310, A311, V380, and I487 was identified to restrict any substrate access to the active site of CYP2J2. Molecular docking of a series of compounds including amiodarone, astemizole, danazol, ebastine, ketoconazole, terfenadine, terfenadone, and arachidonic acid to CYP2J2 confirmed the role of those residues in determining substrate binding and specificity of CYP2J2. In addition to the flexibility of CYP2J2, the present work also identified other factors such as electrostatic potential in the vicinity of the active site, and substrate strain energy and property that have implications for the interpretation of CYP2J2 metabolism.

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Section: M1-m3mentioning

confidence: 99%

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confidence: 94%

Molecular determinant of substrate binding and specificity of cytochrome P450 2J2

Chen

2020

Sci Rep

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“…In this project, we aimed to understand binding of PUFAs in the active site of CYP2J2 using computational methods and leverage this information to investigate the residues essential for ligand positioning and metabolism. In previous work, our groups investigated the interaction of AA with human CYP2J2 and revealed Arg117 as a key player in the recognition of this substrate [3], although these simulations were relatively short (50 ns). Simulations from other studies have come to diverse conclusions about the role of individual residues in the active site [4–6].…”

Section: Objectivementioning

confidence: 99%

Molecular dynamics simulations of the interaction of wild type and mutant human CYP2J2 with polyunsaturated fatty acids

2019

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ObjectivesThe data presented here is part of a study that was aimed at characterizing the molecular mechanisms of polyunsaturated fatty acid metabolism by CYP2J2, the main cytochrome P450 enzyme active in the human cardiovasculature. This part comprises the molecular dynamics simulations of the binding of three eicosanoid substrates to wild type and mutant forms of the enzyme. These simulations were carried out with the aim of dissecting the importance of individual residues in the active site and the roles they might play in dictating the binding and catalytic specificity exhibited by CYP2J2.Data descriptionThe data comprise: (a) a new homology model of CYP2J2, (b) a number of predicted low-energy complexes of CYP2J2 with arachidonic acid, docosahexaenoic acid and eicosapentaenoic acid, produced with molecular docking and (c) a series of molecular dynamics simulations of the wild type and four mutants interacting with arachidonic acid as well as simulations of the wild type interacting with the two other eicosanoid ligands. The simulations may be helpful in identifying the determinants of substrate specificity of this enzyme and in unraveling the role of individual mutations on its function. They may also help guide the generation of mutants with altered substrate preferences.

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“…To date, no crystal structure of CYP2J2 has been published. However, several homology models have been reported for CYP2J2 and some of its mutants [ 30 , 36 , 50 , 51 , 52 , 53 , 54 , 55 ]. In that context, we have found that a series of terfenadone ( Figure 1 ) analogs exhibited a very high affinity for CYP2J2 [ 44 , 45 , 50 ] with K M values up to 140 nM [ 50 ].…”

Section: Introductionmentioning

confidence: 99%

“…This hydrogen bond seems to be important for substrate recognition as replacement of the substrate CO group with a CH 2 group led to a 10-fold decrease of affinity for CYP2J2 [ 45 ] and to a marked change of the hydroxylation regioselectivity [ 50 ]. Moreover, recent data about the binding of AA to CYP2J2 using homology modeling, induced fit docking, and molecular dynamics simulations were in favor of the binding of the AA carboxylate group to Arg117 [ 54 ].…”

Section: Introductionmentioning

confidence: 99%

Role of Arginine 117 in Substrate Recognition by Human Cytochrome P450 2J2

Lafite

André

Graves

et al. 2018

IJMS

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The influence of Arginine 117 of human cytochrome P450 2J2 in the recognition of ebastine and a series of terfenadone derivatives was studied by site-directed mutagenesis. R117K, R117E, and R117L mutants were produced, and the behavior of these mutants in the hydroxylation of ebastine and terfenadone derivatives was compared to that of wild-type CYP2J2. The data clearly showed the importance of the formation of a hydrogen bond between R117 and the keto group of these substrates. The data were interpreted on the basis of 3D homology models of the mutants and of dynamic docking of the substrates in their active site. These modeling studies also suggested the existence of a R117-E222 salt bridge between helices B’ and F that would be important for maintaining the overall folding of CYP2J2.

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Computational modelling of the binding of arachidonic acid to the human monooxygenase CYP2J2

Cited by 10 publications

References 48 publications

Molecular determinant of substrate binding and specificity of cytochrome P450 2J2

Molecular determinant of substrate binding and specificity of cytochrome P450 2J2

Molecular dynamics simulations of the interaction of wild type and mutant human CYP2J2 with polyunsaturated fatty acids

Role of Arginine 117 in Substrate Recognition by Human Cytochrome P450 2J2

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