Molecular orbital study of porphyrin–substrate interactions in cytochrome P450 catalysed aromatic hydroxylation of substituted anilines

Zakharieva, O.; Grodzicki, Michael; Trautwein, Alfred X.; Veeger, C.; Rietjens, Ivonne M. C. M.

doi:10.1016/s0301-4622(98)00111-2

Cited by 14 publications

(13 citation statements)

References 36 publications

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“…Therefore, the reaction coordinate for symmetric oxygen-atom insertion does not lie on the minimum energy path. This conclusion is strongly corroborated by the results of previous theoretical studies dedicated to the arene and olefin oxidation by high-valent iron-oxo species ( − ).…”

Section: Resultssupporting

confidence: 83%

4-Hydroxyphenylpyruvate Dioxygenase: A Hybrid Density Functional Study of the Catalytic Reaction Mechanism

2004

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Density functional calculations using the B3LYP functional has been used to study the reaction mechanism of 4-hydroxyphenylpyruvate dioxygenase. The first part of the catalytic reaction, dioxygen activation, is found to have the same mechanism as in alpha-ketoglutarate-dependent enzymes; the ternary enzyme-substrate-dioxygen complex is first decarboxylated to the iron(II)-peracid intermediate, followed by heterolytic cleavage of the O-O bond yielding an iron(IV)-oxo species. This highly reactive intermediate attacks the aromatic ring at the C1 position and forms a radical sigma complex, which can either form an arene oxide or undergo a C1-C2 side-chain migration. The arene oxide is found to have no catalytic relevance. The side-chain migration is a two-step process; the carbon-carbon bond cleavage first affords a biradical intermediate, followed by a decay of this species forming the new C-C bond. The ketone intermediate formed by a 1,2 shift of an acetic acid group rearomatizes either at the active site of the enzyme or in solution. The hypothetical oxidation of the aromatic ring at the C2 position was also studied to shed light on the 4-HPPD product specificity. In addition, the benzylic hydroxylation reaction, catalyzed by 4-hydroxymandelate synthase, was also studied. The results are in good agreement with the experimental findings.

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Section: Resultssupporting

confidence: 83%

4-Hydroxyphenylpyruvate Dioxygenase: A Hybrid Density Functional Study of the Catalytic Reaction Mechanism

2004

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“…All further products, phenol, ketone and epoxide, are generated by rearrangement of these r-complexes. This is supported by theoretical investigations [54][55][56] ruling out a concerted epoxidation as an initial step in aromatic hydroxylation. Recent DFT computations 56 showed that in contrast to aliphatic hydroxylation, benzene hydroxylation only occurs on the low-spin surface and proceeds predominantly through an electrophilic pathway via a cation-like r-complex intermediate.…”

Section: Benzene Hydroxylationmentioning

confidence: 59%

“…Face-on approach of benzene. In previous work, 54,55,67 Compound I addition to aromatics has been considered to proceed with a face-on approach of the ring towards the oxo group, and we too initially considered this mode of reaction. The lowest energy pathway was found to be an electrophilic addition leading from the 2 A 2u ground state of Compound I to a purely cationic intermediate.…”

Section: Benzene Hydroxylationmentioning

confidence: 99%

Mechanism and structure–reactivity relationships for aromatic hydroxylation by cytochrome P450

Ridder²,

et al. 2004

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Cytochrome P450 enzymes play a central role in drug metabolism, and models of their mechanism could contribute significantly to pharmaceutical research and development of new drugs. The mechanism of cytochrome P450 mediated hydroxylation of aromatics and the effects of substituents on reactivity have been investigated using B3LYP density functional theory computations in a realistic porphyrin model system. Two different orientations of substrate approach for addition of Compound I to benzene, and also possible subsequent rearrangement pathways have been explored. The rate-limiting Compound I addition to an aromatic carbon atom proceeds on the doublet potential energy surface via a transition state with mixed radical and cationic character. Subsequent formation of epoxide, ketone and phenol products is shown to occur with low barriers, especially starting from a cation-like rather than a radical-like tetrahedral adduct of Compound I with benzene. Effects of ring substituents were explored by calculating the activation barriers for Compound I addition in the meta and para-position for a range of monosubstituted benzenes and for more complex polysubstituted benzenes. Two structure-reactivity relationships including 8 and 10 different substituted benzenes have been determined using (i) experimentally derived Hammett sigma-constants and (ii) a theoretical scale based on bond dissociation energies of hydroxyl adducts of the substrates, respectively. In both cases a dual-parameter approach that employs a combination of radical and cationic electronic descriptors gave good relationships with correlation coefficients R2 of 0.96 and 0.82, respectively. These relationships can be extended to predict the reactivity of other substituted aromatics, and thus can potentially be used in predictive drug metabolism models.

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“…In a subsequent nonenzymatic step , the epoxide ring opens to the zwitterionic species, which can further react in two different manners: a hydrogen/deuterium exchange will produce phenol ( P , P ‘), whereas a 1,2-hydride (deuteride) shift to the carbocationic center (NIH shift) will give rise to cyclohexenone ( K ) that can, in turn, enolize to the phenol. ,, Mounting experimental evidence, of various kinds, has revealed, however, that phenol and ketone are unlikely to proceed through arene oxide. , Hence, in the alternative mechanistic hypothesis (b), all products are generated from the tetrahedral intermediate σ-complexes; the phenol and ketone are generated directly from the intermediate cationic σ-complex (σ- C + ), Scheme , ,, while arene oxide formation is suggested 7 to transpire from the radical σ-complex intermediate (σ- C • ). Details and pieces of mechanism (b) have gained indirect support from kinetic isotope effect measurements, regiochemical studies, frontier orbital theoretic arguments, and local density X α type calculations that ruled out concerted epoxidation as the initial activation step of substituted benzene by Cpd I ,,, The role of charge transfer from the arene to the iron porphyrin has nevertheless been inferred from the kinetic isotope effect, for example, for the meta hydroxylation of chlorobenzene …”

Section: Introductionmentioning

confidence: 99%

A Proton-Shuttle Mechanism Mediated by the Porphyrin in Benzene Hydroxylation by Cytochrome P450 Enzymes

2003

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Benzene hydroxylation is a fundamental process in chemical catalysis. In nature, this reaction is catalyzed by the enzyme cytochrome P450 via oxygen transfer in a still debated mechanism of considerable complexity. The paper uses hybrid density functional calculations to elucidate the mechanisms by which benzene is converted to phenol, benzene oxide, and ketone, by the active species of the enzyme, the high-valent iron-oxo porphyrin species. The effects of the protein polarity and hydrogen-bonding donation to the active species are mimicked, as before (Ogliaro, F.; Cohen, S.; de Visser, S. P.; Shaik, S. J. Am. Chem. Soc. 2000, 122, 12892-12893). It is verified that the reaction does not proceed either by hydrogen abstraction or by initial electron transfer (Ortiz de Montellano, P. R. In Cytochrome P450: Structure, Mechanism and Biochemistry, 2nd ed.; Ortiz de Montellano, P. R., Ed.; Plenum Press: New York, 1995; Chapter 8, pp 245-303). In accord with the latest experimental conclusions, the theoretical calculations show that the reactivity is an interplay of electrophilic and radicalar pathways, which involve an initial attack on the pi-system of the benzene to produce sigma-complexes (Korzekwa, K. R.; Swinney, D. C.; Trager, W. T. Biochemistry 1989, 28, 9019-9027). The dominant reaction channel is electrophilic and proceeds via the cationic sigma-complex,( 2)3, that involves an internal ion pair made from a cationic benzene moiety and an anionic iron porphyrin. The minor channel proceeds by intermediacy of the radical sigma-complex, (2)2, in which the benzene moiety is radicalar and the iron-porphyrin moiety is neutral. Ring closure in these intermediates produces the benzene oxide product ((2)4), which does not rearrange to phenol ((2)7) or cyclohexenone ((2)6). While such a rearrangement can occur post-enzymatically under physiological conditions by acid catalysis, the computations reveal a novel mechanism whereby the active species of the enzyme catalyzes directly the production of phenol and cyclohexenone. This enzymatic mechanism involves proton shuttles mediated by the porphyrin ring through the N-protonated intermediate, (2)5, which relays the proton either to the oxygen atom to form phenol ((2)7) or to the ortho-carbon atom to produce cyclohexenone product ((2)6). The formation of the phenol via this proton-shuttle mechanism will be competitive with the nonenzymatic conversion of benzene oxide to phenol by external acid catalysis. With the assumption that (2)5 is not fully thermalized, this novel mechanism would account also for the observation that there is a partial skeletal retention of the original hydrogen of the activated C-H bond, due to migration of the hydrogen from the site of hydroxylation to the adjacent carbon (so-called "NIH shift" (Jerina, D. M.; Daly, J. W. Science 1974, 185, 573-582)). Thus, in general, the computationally discovered mechanism of a porphyrin proton shuttle suggests thatthere is an enzymatic pathway that converts benzene directly to a phenol and ketone, in addition to non...

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Molecular orbital study of porphyrin–substrate interactions in cytochrome P450 catalysed aromatic hydroxylation of substituted anilines

Cited by 14 publications

References 36 publications

4-Hydroxyphenylpyruvate Dioxygenase: A Hybrid Density Functional Study of the Catalytic Reaction Mechanism

4-Hydroxyphenylpyruvate Dioxygenase: A Hybrid Density Functional Study of the Catalytic Reaction Mechanism

Mechanism and structure–reactivity relationships for aromatic hydroxylation by cytochrome P450

A Proton-Shuttle Mechanism Mediated by the Porphyrin in Benzene Hydroxylation by Cytochrome P450 Enzymes

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