Computational models for cytochrome P450: a predictive electronic model for aromatic oxidation and hydrogen atom abstraction.

Experimental observations suggest that electronic characteristics play a role in the rates of substrate oxidation for cytochrome P450 enzymes. For example, the tendency for oxidation of a certain functional group generally follows the relative stability of the radicals that are formed (e.g., N-dealkylation > O-dealkylation > 2 degrees carbon oxidation > 1 degree carbon oxidation). In addition, results show that useful correlations between the rates of product formation can be developed using electronic models. In this article, we attempt to determine whether a combined computational model for aromatic and aliphatic hydroxylation can be developed. Toward this goal, we used a combination of experimental data and semiempirical molecular orbital calculations to predicted activation energies for aromatic and aliphatic hydroxylation. The resulting model extends the predictive capacity of our previous aliphatic hydroxylation model to include the second most important group of oxidations, aromatic hydroxylation. The combined model can account for about 83% of the variance in the data for the 20 compounds in the training set and has an error of about 0.7 kcal/mol.

[1]  J. Harris,et al.  Pentahaloethane-based chlorofluorocarbon substitutes and halothane: correlation of in vivo hepatic protein trifluoroacetylation and urinary trifluoroacetic acid excretion with calculated enthalpies of activation. , 1992, Chemical research in toxicology.

[2]  G. Tucker,et al.  Regioselective hydroxylation of debrisoquine by cytochrome P4502D6: implications for active site modelling , 2000, Xenobiotica; the fate of foreign compounds in biological systems.

[3]  W. Trager,et al.  Intramolecular isotope effects for benzylic hydroxylation of isomeric xylenes and 4,4'-dimethylbiphenyl by cytochrome P450: relationship between distance of methyl groups and masking of the intrinsic isotope effect. , 1997, Biochemistry.

[4]  Jeffrey P. Jones,et al.  A refined 3-dimensional QSAR of cytochrome P450 2C9: computational predictions of drug interactions. , 2000, Journal of medicinal chemistry.

[5]  Lesley-Anne Sayers SERGEI DIAGHILEV'S "SOVIET" BALLET: LE PAS D'ACIER AND ITS RELATIONSHIP TO RUSSIAN CONSTRUCTIVISM* , 1996 .

[6]  K. Korzekwa,et al.  An assessment of the reaction energetics for cytochrome P450-mediated reactions. , 2001, Archives of biochemistry and biophysics.

[7]  R. Hanzlik,et al.  Active site dynamics of toluene hydroxylation by cytochrome P-450 , 1990 .

[8]  W. Trager,et al.  Isotope effect studies on the mechanism of the cytochrome P-450IIA1-catalyzed formation of delta 6-testosterone from testosterone. , 1990, Drug metabolism and disposition: the biological fate of chemicals.

[9]  J. Halpert,et al.  Use of homology modeling in conjunction with site-directed mutagenesis for analysis of structure-function relationships of mammalian cytochromes P450. , 1997, Life sciences.

[10]  S. Sligar,et al.  Metabolic switching in cytochrome P-450cam: Deuterium isotope effects on regiospecificity and the monooxygenase/oxidase ratio , 1987 .

[11]  G. Szklarz,et al.  Molecular modeling of mammalian cytochromes P450: application to study enzyme function. , 2000, Vitamins and hormones.

[12]  J. Smith,et al.  Model systems for cytochrome P450 dependent mono-oxygenases. Part 2. Kinetic isotope effects for the oxidative demethylation of anisole and [Me-2H3]anisole by cytochrome P450 dependent mono-oxygenases and model systems , 1983 .

[13]  S. Sligar,et al.  Regioselectivity in the cytochromes P-450: control by protein constraints and by chemical reactivities. , 1984, Archives of biochemistry and biophysics.

[14]  A. Alex,et al.  A novel approach to predicting P450 mediated drug metabolism. CYP2D6 catalyzed N-dealkylation reactions and qualitative metabolite predictions using a combined protein and pharmacophore model for CYP2D6. , 1999, Journal of medicinal chemistry.

[15]  Jeffrey P. Jones,et al.  Designing safer chemicals: predicting the rates of metabolism of halogenated alkanes. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Eamonn F. Healy,et al.  Development and use of quantum mechanical molecular models. 76. AM1: a new general purpose quantum mechanical molecular model , 1985 .

[17]  R. E. White,et al.  Stereochemical dynamics of aliphatic hydroxylation by cytochrome P-450. , 1986, Journal of the American Chemical Society.

[18]  A. Rettie,et al.  Positional specificity of rabbit CYP4B1 for omega-hydroxylation1 of short-medium chain fatty acids and hydrocarbons. , 1998, Biochemical and biophysical research communications.

[19]  D. Swinney,et al.  Isotopically labeled chlorobenzenes as probes for the mechanism of cytochrome P-450 catalyzed aromatic hydroxylation. , 1989, Biochemistry.

[20]  J. H. van Lenthe,et al.  Metabolite predictions for para-substituted anisoles based on ab initio complete active space self-consistent field calculations. , 1995, Chemical research in toxicology.

[21]  Jeffrey P. Jones,et al.  Mechanism of Oxidative Amine Dealkylation of Substituted N,N-Dimethylanilines by Cytochrome P-450: Application of Isotope Effect Profiles , 1995 .

[22]  J. Halpert,et al.  Influence of P450 3A4 SRS-2 residues on cooperativity and/or regioselectivity of aflatoxin B(1) oxidation. , 2001, Chemical research in toxicology.

[23]  J. Jones,et al.  Evaluation of cytochrome P450 mechanism and kinetics using kinetic deuterium isotope effects. , 1998, Biochemistry.

[24]  K R Korzekwa,et al.  Modeling cyanide release from nitriles: prediction of cytochrome P450 mediated acute nitrile toxicity. , 1992, Chemical research in toxicology.

[25]  J. Trudell,et al.  Intramolecular determination of primary kinetic isotope effects in hydroxylations catalyzed by cytochrome P-450. , 1977, Biochemical and biophysical research communications.

[26]  Jeffrey P. Jones,et al.  Isotopically sensitive branching and its effect on the observed intramolecular isotope effects in cytochrome P-450 catalyzed reactions: a new method for the estimation of intrinsic isotope effects , 1986 .

[27]  K. Korzekwa,et al.  Theoretical studies on cytochrome P-450 mediated hydroxylation: a predictive model for hydrogen atom abstractions , 1990 .

[28]  W. Trager,et al.  Intrinsic isotope effects suggest that the reaction coordinate symmetry for the cytochrome P-450 catalyzed hydroxylation of octane is isozyme independent. , 1990, Journal of medicinal chemistry.

[29]  K. Morohashi,et al.  Position specificity in n-hexane hydroxylation by two forms of cytochrome P-450 in rat liver microsomes. , 1983, Journal of Biochemistry (Tokyo).

[30]  R. Hanzlik,et al.  Microsomal hydroxylation of specifically deuterated monosubstituted benzenes. Evidence for direct aromatic hydroxylation. , 1984, Biochemistry.