Molecular Orbital-Based Quantitative Structure-Activity Relationship for the Cytochrome P450-Catalyzed 4-Hydroxylation of Halogenated Anilines

Cnubben, N.H.P.; Peelen, Sjaak; Borst, J.W.; Vervoort, Jacques; Veeger, C.; Rietjens, I M C M

doi:10.1021/tx00041a002

Cited by 56 publications

(38 citation statements)

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“…The objective of the present study is to investigate a possible influence of substrate characteristics on the overall conversion rates of phenol derivatives by phenol hydroxylase. The rationale for this study was based on the so-called frontier orbital theory [ 111 and recent molecular-orbital-based quantitative structureactivity relationship (MO-QSAR) results obtained for the 4-hydroxybenzoate-hydroxylase-catalysed conversion of fluorinated 4-hydroxybenzoates [ 121, the cytochrome-P450-catalysed conversion of a series of aniline derivatives [13], and the regioselectivity of the cytochrome-P450-catalysed hydroxylation of a series of fluorobenzenes [14]. This MO-QSAR approach is based on the following considerations.…”

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confidence: 99%

Conversion of Phenol Derivatives to Hydroxylated Products by Phenol Hydroxylase from Trichosporon cutaneum

Peelen

Rietjens

Boersma

et al. 1995

European Journal of Biochemistry

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This study describes the regioselective hydroxylation and the rates of conversion of a series of fluorinated phenol derivatives by phenol hydroxylase from the yeast Trichosporon cutuneurn. The natural logarithm of the k,,, value for the conversion of the phenolic substrates correlates with the calculated energy of the reactive electrons in the highest occupied molecular orbital of the substrate ( r = 0.85). This observation supports the hypothesis that at physiological pH (7.6) and 25"C, in the absence of monovalent anions, the nucleophilic attack of the electrons in the highest occupied molecular orbital of the substrate on the C(4a)-hydroperoxyflavin enzyme intermediate is of major importance in determining the overall rate of catalysis. Results from 19F-NMR analysis of the incubation mixtures demonstrate for phenols with two identical ortho substituents, that the ortho position which becomes preferentially hydroxylated is the one with the highest density of the reactive electrons in the highest occupied molecular orbital. A halogen substituent at a metu position decreases the chances for hydroxylation at the adjacent ortho position further than expected on the basis of the calculated reactivity. This result indicates a contribution of a proteinkubstrate dipolar interaction, influencing the time-averaged orientation of the substrate with respect to the reactive C(4a)-hydroperoxyflavin intermediate. Keywords.Flavin ; 29F-NMR ; molecular orbital ; monooxygenase ; phenol hydroxylase.Phenol hydroxylase is a flavin-dependent monooxygenase that can be isolated from a variety of sources, e.g. bacteria, actinomycetes and yeasts. The present study focuses on the phenol hydroxylase from the strictly aerobic yeast Trichosporon cumneurn [l]. The catalytic mechanism of the enzyme is reported to proceed by formation of a C(4a)-hydroperoxyflavin intermediate, formed upon two-electron reduction of the flavin prosthetic group by NADPH, incorporation of an oxygen molecule, and protonation of the lperoxy moiety [l -31. The mechanism by which the C(4a)-hydroperoxyflavin intermediate converts the substrate to its hydroxylated form is supposed to proceed analogously to the mechanism for other aromatic hydroxylases, i.e. by an electrophilic attack of the hydroperoxide function on the substrate [4-61. The enzyme has been reported to catalyse the hydroxylation of a variety of substituted phenols, such as fluoro-, chloro-, amino-and methyl-phenols and also dihydroxybenzenes, at the ortho position with respect to the hydroxyl moiety [7, 81. The reaction cycle consists of various separate steps and is supposed to proceed by successive substrate binding, NADPH binding, flavin reduction, NADP' release, oxygen Correspondence to S. Peelen, Department of Biochemistry, Agricultural University, Dreijenlaan 3, NL-6703 HA Wageningen, The Netherlands Fax: +31 8370 84801. Abbreviations. MO-QSAR, molecular-orbital-based quantitative structure-activity relationship; HOMO, highest occupied molecular orbital; E(HOMO), energy of the highest occupied mol...

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confidence: 99%

Conversion of Phenol Derivatives to Hydroxylated Products by Phenol Hydroxylase from Trichosporon cutaneum

Peelen

Rietjens

Boersma

et al. 1995

European Journal of Biochemistry

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“…QC properties have been used previously to predict "site of reactivity" for cytochrome P450 substrates with reasonable success. 3 The prediction of glucuronidation regioselectivity, and hence the structure of the metabolite(s), would be of significant value because of the altered toxicological and pharmacological effects of metabolites and the challenge of characterizing metabolite structure in a high-throughput setting. Furthermore, it is likely that in the absence of regioselectivity data for a large number of chemicals it will prove to be very difficult to combine understanding of structural/steric (e.g., from pharmacophore analyses) and electronic (this study) determinants of chemical binding and metabolic turnover by UGT.…”

Section: Discussionmentioning

confidence: 99%

“…These include molecular toxicity, absorption, metabolism, receptor binding, octanol/water partition coefficients, stability, pK a , and chromatographic retention times. [1][2][3][4][5][6][7][8][9][10][11][12][13] Numerous types of descriptors have been developed to capture QC properties. Prominent among these are atomic charges, polarizability, molecular orbital energies, superdelocalizabilities, dipole moments, frontier orbital densities, and molecular quantum similarity measures.…”

Section: Introductionmentioning

confidence: 99%

Rapid Prediction of Chemical Metabolism by Human UDP-glucuronosyltransferase Isoforms Using Quantum Chemical Descriptors Derived with the Electronegativity Equalization Method

et al. 2004

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This study aimed to evaluate in silico models based on quantum chemical (QC) descriptors derived using the electronegativity equalization method (EEM) and to assess the use of QC properties to predict chemical metabolism by human UDP-glucuronosyltransferase (UGT) isoforms. Various EEM-derived QC molecular descriptors were calculated for known UGT substrates and nonsubstrates. Classification models were developed using support vector machine and partial least squares discriminant analysis. In general, the most predictive models were generated with the support vector machine. Combining QC and 2D descriptors (from previous work) using a consensus approach resulted in a statistically significant improvement in predictivity (to 84%) over both the QC and 2D models and the other methods of combining the descriptors. EEM-derived QC descriptors were shown to be both highly predictive and computationally efficient. It is likely that EEM-derived QC properties will be generally useful for predicting ADMET and physicochemical properties during drug discovery.

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“…Of interest to note is that ultimately £uoride anions appear to represent the major £uorine containing fraction pointing at e⁄cient dehalogenation along the bioconversion pathway. The absence of formation of 3-£uo-roaniline and/or 4-£uoroaniline (at 3117.6 ppm and at 3130.0 ppm [29], respectively) in the incubations with 3,4-di£uoro-and 3-chloro-4-£uoroaniline reveals that reductive deamination or amino modi¢cations precede the process of de£uorination. In addition, no resonances representing 3,4-di£uorobenzoic acid or 3-chloro-4-£uoroben-zoic acid are observed (Figs.…”

Section: 4mentioning

confidence: 96%

Reductive deamination as a new step in the anaerobic microbial degradation of halogenated anilines

Travkin

2002

FEMS Microbiology Letters

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In this paper we report the isolation and characterization of an anaerobic enrichment culture as well as of a Rhodococcus sp. strain 2 capable of degrading 3,4-dihaloanilines under nitrate reducing conditions. Using mass spectrometry several of the intermediates formed in the process of 3,4-dichloroaniline conversion were identified. Most interesting is the observation of reductive deamination and the formation of 1,2-dichlorobenzene as one of the intermediates. Using 19 F NMR and fluorinated 3,4-dihaloaniline model substrates it was corroborated that reductive deamination of the anilines to give dihalobenzene intermediates represents a new initial step in the anaerobic microbial degradation of these halogenated anilines. ß

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Molecular Orbital-Based Quantitative Structure-Activity Relationship for the Cytochrome P450-Catalyzed 4-Hydroxylation of Halogenated Anilines

Cited by 56 publications

References 25 publications

Conversion of Phenol Derivatives to Hydroxylated Products by Phenol Hydroxylase from Trichosporon cutaneum

Conversion of Phenol Derivatives to Hydroxylated Products by Phenol Hydroxylase from Trichosporon cutaneum

Rapid Prediction of Chemical Metabolism by Human UDP-glucuronosyltransferase Isoforms Using Quantum Chemical Descriptors Derived with the Electronegativity Equalization Method

Reductive deamination as a new step in the anaerobic microbial degradation of halogenated anilines

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