How Does Ethene Inactivate Cytochrome P450 En Route to Its Epoxidation? A Density Functional Study

Visser, Sam P. de; Ogliaro, François; Shaik, Sason

doi:10.1002/1521-3757(20010803)113:15<2955::aid-ange2955>3.0.co;2-5

Cited by 16 publications

(1 citation statement)

References 19 publications

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“…Overall, epoxidation is a thermoneutral process and at our level of theory, it is slightly endothermic in the quartet spin state (by 4.3 kcal·mol −1 ), while it is slightly exothermic in the doublet spin state (by 3.9 kcal·mol −1 ). Structures along the epoxidation pathway are similar to those calculated before on alternative substrates [29][30][31][32][72][73][74][75].…”

Section: Phthalate Epoxidation and Aromatic Hydroxylationmentioning

confidence: 99%

Biodegradation of Cosmetics Products: A Computational Study of Cytochrome P450 Metabolism of Phthalates

Reinhard

Visser

2017

Inorganics

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Cytochrome P450s are a broad class of enzymes in the human body with important functions for human health, which include the metabolism and detoxification of compounds in the liver. Thus, in their catalytic cycle, the P450s form a high-valent iron(IV)-oxo heme cation radical as the active species (called Compound I) that reacts with substrates through oxygen atom transfer. This work discusses the possible degradation mechanisms of phthalates by cytochrome P450s in the liver, through computational modelling, using 2-ethylhexyl-phthalate as a model substrate. Phthalates are a type of compound commonly found in the environment from cosmetics usage, but their biodegradation in the liver may lead to toxic metabolites. Experimental studies revealed a multitude of products and varying product distributions among P450 isozymes. To understand the regio-and chemoselectivity of phthalate activation by P450 isozymes, we focus here on the mechanisms of phthalate activation by Compound I leading to O-dealkylation, aliphatic hydroxylation and aromatic hydroxylation processes. We set up model complexes of Compound I with the substrate and investigated the reaction mechanisms for products using the density functional theory on models and did a molecular mechanics study on enzymatic structures. The work shows that several reaction barriers in the gas-phase are close in energy, leading to a mixture of products. However, when we tried to dock the substrate into a P450 isozyme, some of the channels were inaccessible due to unfavorable substrate positions. Product distributions are discussed under various reaction conditions and rationalized with valence bond and thermodynamic models.

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Section: Phthalate Epoxidation and Aromatic Hydroxylationmentioning

confidence: 99%

Biodegradation of Cosmetics Products: A Computational Study of Cytochrome P450 Metabolism of Phthalates

Reinhard

Visser

2017

Inorganics

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Differences in and Comparison of the Catalytic Properties of Heme and Non‐Heme Enzymes with a Central Oxo–Iron Group

Visser

2006

Angewandte Chemie

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Warum so aggressiv? Dichtefunktionalrechnungen an den aktiven Oxo‐Eisen‐Spezies von Dioxygenase‐ und Monooxygenase‐Enzymmodellen zufolge sind erstere die aggressiveren Katalysatoren und haben niedrigere Reaktionsbarrieren. Die Unterschiede werden auf elektronische Faktoren zurückgeführt, z. B. auf den Elektronentransfer in ein antibindendes σ*‐Fe‐O‐Orbital und die Reduktion des Metalls zu einem FeIII‐Zentrum im geschwindigkeitsbestimmenden Schritt.

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Modell und Mechanismus: N‐Hydroxylierung primärer aromatischer Amine durch Cytochrom P450

Ji¹,

Schüürmann²

2012

Angewandte Chemie

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Nur ein Weg führt ans Ziel: Bislang sind fünf verschiedene Mechanismen für die P450‐katalysierte N‐Hydroxylierung primärer aromatischer Amine vorgeschlagen worden. Nach einer rechnerischen Analyse mit der Dichtefunktionaltheorie kann nur der H‐Atom‐Transfer‐Weg – über eine H‐Abstraktion vom Amin‐N‐Atom mit anschließender radikalischer Rekombination – im Tiefspin‐Zustand zur Bildung des aromatischen Hydroxylamins beitragen.

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How Does Ethene Inactivate Cytochrome P450 En Route to Its Epoxidation? A Density Functional Study

Cited by 16 publications

References 19 publications

Biodegradation of Cosmetics Products: A Computational Study of Cytochrome P450 Metabolism of Phthalates

Biodegradation of Cosmetics Products: A Computational Study of Cytochrome P450 Metabolism of Phthalates

Differences in and Comparison of the Catalytic Properties of Heme and Non‐Heme Enzymes with a Central Oxo–Iron Group

Modell und Mechanismus: N‐Hydroxylierung primärer aromatischer Amine durch Cytochrom P450

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