Theoretical Perspective on the Structure and Mechanism of Cytochrome P450 Enzymes

Shaik, Sason; Kumar, Devesh; Visser, Sam P. de; Altun, Ahmet; Thiel, Walter

doi:10.1002/chin.200537287

Cited by 117 publications

(248 citation statements)

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“…QM calculations on models of P450 reactions have given results that often correlate reasonably well with experimental observation (14,19,20). However, because the size of models that can feasibly be treated is limited, they may not account for important steric factors and binding preferences.…”

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confidence: 75%

“…The first of these matters is determined largely by the relative abundance of the different isoforms (e.g., many drugs are oxidized by the 3A4 isoform, partly because it is very abundant), by the binding affinity of the substrate in the active site, and by distribution and P450 induction effects. Many techniques have been put forward to predict chemo-and regioselectivity, including traditional quantitative structure-activity relationship (QSAR) (9, 10) as well as three-dimensional QSAR models (10,11), construction of pharmacophore models for individual isoforms (12), substrate docking approaches using either crystal structures or homology models of the relevant enzyme (13), ab initio or density functional theory (DFT) calculations of reaction barriers and/or electronic properties (14), and rule-based methods (15). It is likely that a combination of methods will be required in general; hybrid quantum mechanical-molecular mechanics (QM/MM) methods, which allow modeling of specific effects of the protein on reactivity, have advanced to the stage where they can potentially make an important contribution (16).…”

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confidence: 99%

“…According to experimental and computational evidence, the major part of the large variety of reactions catalyzed by P450 enzymes all involve the same active species, a high-valent iron-oxo derivative of the active site heme group, known as Compound I (14,32). Its ground state has three unpaired electrons, two in Fe-O π Ã orbitals, and one in a π-orbital of the porphyrin.…”

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confidence: 99%

“…Its ground state has three unpaired electrons, two in Fe-O π Ã orbitals, and one in a π-orbital of the porphyrin. Due to the weak coupling between the Fe-O based and porphyrin orbitals, the energy difference between the resulting quartet ( 4 A 2u ) and open-shell doublet ( 4 A 2u ) states of Compound I is very small, giving rise to two-state reactivity of P450 enzymes (14).…”

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confidence: 99%

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Understanding the determinants of selectivity in drug metabolism through modeling of dextromethorphan oxidation by cytochrome P450

Oláh

Mulholland

Harvey

2011

Proc. Natl. Acad. Sci. U.S.A.

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Cytochrome P450 enzymes play key roles in the metabolism of the majority of drugs. Improved models for prediction of likely metabolites will contribute to drug development. In this work, two possible metabolic routes (aromatic carbon oxidation and O-demethylation) of dextromethorphan are compared using molecular dynamics (MD) simulations and density functional theory (DFT). The DFT results on a small active site model suggest that both reactions might occur competitively. Docking and MD studies of dextromethorphan in the active site of P450 2D6 show that the dextromethorphan is located close to heme oxygen in a geometry apparently consistent with competitive metabolism. In contrast, calculations of the reaction path in a large protein model [using a hybrid quantum mechanical-molecular mechanics (QM/MM) method] show a very strong preference for O-demethylation, in accordance with experimental results. The aromatic carbon oxidation reaction is predicted to have a high activation energy, due to the active site preventing formation of a favorable transition-state structure. Hence, the QM/MM calculations demonstrate a crucial role of many active site residues in determining reactivity of dextromethorphan in P450 2D6. Beyond substrate binding orientation and reactivity of Compound I, successful metabolite predictions must take into account the detailed mechanism of oxidation in the protein. These results demonstrate the potential of QM/MM methods to investigate specificity in drug metabolism.C ytochrome P450 enzymes (P450s) form one of the most powerful defense mechanisms of living organisms: They protect against xenobiotics via an oxidative pathway, which in most instances leads to a less harmful and more soluble product with faster excretion. The same mechanism is involved in the metabolism of most drugs and alters the pharmacological activity of many drugs. As a consequence, P450-mediated transformations of drug candidates are of crucial importance in the pharmaceutical industry. The roles of P450s are manifold. Oxidation by P450s can lead to toxic products, but, on the other hand, local activation of, e.g., anticancer prodrugs by P450s to lethal intracellular toxins at the site of the tumor is an important strategy (1). Drug compounds can induce P450 expression but can also inhibit them in various ways (2-4). The metabolic clearance of most drugs depends on P450s, and they have been implicated in a large number of drug-drug interactions (5, 6), which can result in fatalities (7,8). Interactions of drug candidates with P450s must be taken into account during the drug discovery process if the expensive and time-consuming development of active compounds with hidden toxic effects is to be avoided.It is increasingly recognized that methods capable of predicting P450 oxidative activity for a given substrate, and also the predominant site(s) of metabolism, could contribute significantly to drug development. There are many aspects to this problem, including isoform selectivity (i.e., which P450 isoform will contribute mos...

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confidence: 75%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Understanding the determinants of selectivity in drug metabolism through modeling of dextromethorphan oxidation by cytochrome P450

Oláh

Mulholland

Harvey

2011

Proc. Natl. Acad. Sci. U.S.A.

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“…The chemistry of CYP-enzyme-catalyzed reactions has been studied in detail, 32,33 including the properties of heme species involved in the catalytic cycle of CYPs, mechanism of alkane hydroxylation, mechanism of hydride transfer in P450nor enzyme, 34 the biosynthesis of estrogens, 35,36 and the electronic structure of the oxidizing species (Compound I) of CYPs. In a recent combined quantum chemical molecular mechanics study (QM/MM) we showed that Compound I seems to exhibit very similar properties in different CYP enzymes, implying that most likely differences in Compound I do not significantly contribute to the regioselectivity differences observed for CYPs.…”

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confidence: 99%

Combined Docking and Quantum Chemical Study on CYP-Mediated Metabolism of Estrogens in Man

Lábas

Krámos

Oláh

2016

Chem. Res. Toxicol.

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Long-term exposure to estrogens seriously increases the incidence of various diseases including breast cancer. Experimental studies indicate that cytochrome P450 (CYP) enzymes catalyze the bioactivation of estrogens to catechols, which can exert their harmful effects via varies routes. It has been shown that the 4-hydroxylation pathway of estrogens is the most malign, while 2-hydroxylation is considered a benign pathway. It is also known experimentally that with increasing unsaturation of ring B of estrogens the prevalence of the 4-hydroxylation pathway significantly increases. In this study we used a combination of structural analysis, docking and quantum chemical calculations at the B3LYP/6-311+G* level to investigate the factors that influence the regioselectivity of estrogen metabolism in man. We studied the structure of human -estrogen metabolizing enzymes (CYP1A1, CYP1A2, CYP1B1, CYP3A4) in complex with estrone using docking, and investigated the susceptibility of estrone, equilin and equilenin (which only differ in the unsaturation of ring B) to undergo 2-and 4-hydroxylation using several models of CYP enzymes (Compound I, methoxy and phenoxy radical). We found that even the simplest models could account for the experimental difference between the 2-and 4-hydroxylation pathways, thus might be used for fast screening purposes. We also show that reactivity indices, specifically in this case the radical and nucleophilic condensed Fukui functions also correctly predict the likeliness of estrogen derivatives to undergo 2-or 4-hydroxylation.4

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Mechanisms of cytochrome P450 substrate oxidation: MiniReview

Guengerich¹

2007

J Biochem & Molecular Tox

210

177

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Cytochrome P450 (P450) enzymes catalyze a variety of oxidation and some reduction reactions, collectively involving thousands of substrates. A general chemical mechanism can be used to rationalize most of the oxidations and involves a perfenyl intermediate (FeO 3+ ) and odd-electron chemistry, i.e. abstraction of a hydrogen atom or electron followed by oxygen rebound and sometimes rearrangement. This general mechanism can explain carbon hydroxylation, heteroatom oxygenation and dealkylation, epoxidation, desaturation, heme destruction, and other reactions. Another approach to understanding catalysis involves analysis of the more general catalytic cycle, including substrate specificity, because complex patterns of cooperativity are observed with several P450s. Some of the complexity is due to slow conformational changes in the proteins that occur on the same timescale as other steps. C 2007 Wiley Periodicals, Inc.

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Theoretical Perspective on the Structure and Mechanism of Cytochrome P450 Enzymes

Abstract: For Abstract see ChemInform Abstract in Full Text.

Cited by 117 publications

References 1 publication

Understanding the determinants of selectivity in drug metabolism through modeling of dextromethorphan oxidation by cytochrome P450

Understanding the determinants of selectivity in drug metabolism through modeling of dextromethorphan oxidation by cytochrome P450

Combined Docking and Quantum Chemical Study on CYP-Mediated Metabolism of Estrogens in Man

Mechanisms of cytochrome P450 substrate oxidation: MiniReview

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