The “Rebound Controversy”: An Overview and Theoretical Modeling of the Rebound Step in C−H Hydroxylation by Cytochrome P450

Shaik

2005

Chemistry A European J

Self Cite

108

102

Density functional theoretical calculations are used to elucidate the epoxidation mechanism of styrene with a cytochrome P450 model Compound I, and the formation of side products. The reaction features multistate reactivity (MSR) with different spin states (doublet and quartet) and different electromeric situations having carbon radicals and cations, as well as iron(III) and iron(IV) oxidation states. The mechanisms involve state-specific product formation, as follows: a) The low-spin pathways lead to epoxide formation in effectively concerted mechanisms. b) The high-spin pathways have finite barriers for ring-closure and may have a sufficiently long lifetime to undergo rearrangement and lead to side products. c) The high-spin radical intermediate, (4)2(rad)-IV, has a ring closure barrier as small as the C--C rotation barrier. This intermediate will therefore lose stereochemistry and lead to a mixture of cis and trans epoxides. The barriers for the production of aldehyde and suicidal complexes are too high for this intermediate. d) The high-spin radical intermediate, (4)2(rad)-III, has a substantial ring closure barrier and may survive long enough time to lead to suicidal, phenacetaldehyde and 2-hydroxostyrene side products. e) The phenacetaldehyde and 2-hydroxostyrene products both originate from crossover from the (4)2(rad)-III radical intermediate to the cationic state, (4)2(cat,z(2) ). The process involves an N-protonated porphyrin intermediate that re-shuttles the proton back to the substrate to form either phenacetaldehyde or 2-hydroxostyrene products. This resembles the internally mediated NIH-shift observed during benzene hydroxylation.

Section: Discussionmentioning

confidence: 99%

Section: -Ivmentioning

confidence: 99%

Multistate Reactivity in Styrene Epoxidation by Compound I of Cytochrome P450: Mechanisms of Products and Side Products Formation

Kumar

Shaik

2005

Chemistry A European J

Self Cite

108

102

“…Indeed, the rebound barriers of substrate hydroxylation by the iron(IV)-oxo species of P450 enzymes gives negligible barriers on the doublet spin state surface. [14,33,41] By contrast, significant rebound barriers of 17.7 kcal mol À1 for hydroxyl rebound to n-C 3 H 7 C (Figure 4) and 23.1 kcal mol À1 for hydroxyl rebound to CH 3 C were calculated.…”

Section: De°¼ Fg H àB ð5þmentioning

confidence: 99%

Origin of the Correlation of the Rate Constant of Substrate Hydroxylation by Nonheme Iron(IV)–oxo Complexes with the Bond‐Dissociation Energy of the CH Bond of the Substrate

Latifi

Bagherzadeh

2009

Chemistry A European J

Mononuclear nonheme iron containing systems are versatile and vital oxidants of substrate hydroxylation reactions in many biosystems, whereby the rate constant of hydroxylation correlates with the strength of the C-H bond that is broken in the process. The thermodynamic reason behind these correlations, however, has never been established. In this work results of a series of density functional theory calculations of substrate hydroxylation by a mononuclear nonheme iron(IV)-oxo oxidant with a 2 His/1 Asp structural motif analogous to alpha-ketoglutarate dependent dioxygenases are presented. The calculations show that these oxidants are very efficient and able to hydroxylate strong C-H bonds, whereby the hydrogen abstraction barriers correlate linearly with the strength of the C-H bond of the substrate that is broken. These trends have been rationalized using a valence bond (VB) curve-crossing diagram, which explains the correlation using electron transfer mechanisms in the hydrogen abstraction processes. We also rationalized the subsequent reaction step for radical rebound and show that the barrier is proportional to the electron affinity of the iron(III)-hydroxo intermediate complex. It is shown that nonheme iron(IV)-hydroxo complexes have a larger electron affinity than heme iron(IV)-hydroxo complexes and therefore also experience larger radical rebound barriers, which may have implications for product distributions and rearrangement reactions. Thus, detailed comparisons between heme and nonheme iron(IV)-oxo oxidants reveal the fundamental differences in monoxygenation capabilities of these important classes of oxidants in biosystems and synthetic analogues for the first time and enable us to make predictions of experimental processes.

“…The most extensively studied reaction pathway is aliphatic hydroxylation [24][25][26][27], which happens via a stepwise mechanism with an initial hydrogen atom abstraction to form an iron(IV)-hydroxo intermediate, followed by OH transfer-also called rebound-to the radical to give the alcohol product complexes. With most substrates, the hydrogen atom abstraction step is rate-determining, while the rebound barrier is much smaller [28]. In particular, the doublet spin state mechanism tends to have negligible rebound barriers, while they are generally higher on the quartet spin state surface.…”

Section: Introductionmentioning

confidence: 99%

“…With most substrates, the hydrogen atom abstraction step is rate-determining, while the rebound barrier is much smaller [28]. In particular, the doublet spin state mechanism tends to have negligible rebound barriers, while they are generally higher on the quartet spin state surface.…”

Section: Introductionmentioning

confidence: 99%

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

Reinhard

2017

Inorganics

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.