A Model "Rebound" Mechanism of Hydroxylation by Cytochrome P450: Stepwise and Effectively Concerted Pathways, and Their Reactivity Patterns
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- 作者：Franç ; ois Ogliaro ; Nathan Harris ; Shimrit Cohen ; Michael Filatov ; Samuë ; l P. de Visser ; and Sason Shaik
- 刊名：Journal of the American Chemical Society
- 出版年：2000
- 出版时间：September 20, 2000
- 年：2000
- 卷：122
- 期：37
- 页码：8977 - 8989
- 全文大小：284K
- 年卷期：v.122,no.37(September 20, 2000)
- ISSN：1520-5126
文摘
A two-state rebound mechanism of alkane hydroxylation by a model active species of the enzymecytochrome P450 is studied using density functional theoretic calculations. Theory corroborates Groves's reboundmechanism (Groves, J. T. J. Chem. Educ. 1985, 62, 928), with a key difference, namely that in the two-staterebound the reactivity and product distribution result from the interplay of two reactive states of the activeferryl-oxene (Por+
FeO) species of the enzyme: one state is low-spin (doublet) and the other high-spin (quartet).Transition-state structures, intermediates, and product complexes are identified for the two states. The bondactivation in either one of the two states involves a hydrogen abstraction-like transition structure. However,while in the high-spin state there forms a radical that has a significant barrier for rebound, in the low-spinstate the rebound is virtually barrierless. Even though one cannot ignore incursion of a small amount of radicalsin the low-spin state, it is clear that the radical has a significant lifetime mainly on the high-spin surface. Theresults are used to gain insight into puzzling experimental data which emerge from studies of ultrafast radicalclocks (e.g., Toy, P. H.; Newcomb, M.; Hollenberg, P. F., J. Am. Chem. Soc. 1998, 120, 7719), vis à vis thenature the transition state, deduced from kinetic isotope effect measurements (Manchester, J. I.; Dinnocenzo,J. P.; Higgins, L. A.; Jones, J. P. J. Am. Chem. Soc. 1997, 119, 5069) and stereochemical scrambling patterns(Groves, J. T.; McClusky, G. A.; White, R. E.; Coon, M. J. Biochem. Biophys. Res. Commun. 1978, 81, 154).Understanding the electronic structure of the various species leads to a predictive structure-reactivity picture,based on the two-state reactivity scenario (Shaik, S.; Filatov, M.; Schröder, D.; Schwarz, H. Chem. Eur. J.1998, 4, 193). The model makes it possible to predict the dependence of the relative rates of the two states,and of the corresponding steps as a function of the nature of the alkane, the resulting alkyl radical, and thebinding capability of the thiolate proximal ligand of the active species.
FeO) species of the enzyme: one state is low-spin (doublet) and the other high-spin (quartet).Transition-state structures, intermediates, and product complexes are identified for the two states. The bondactivation in either one of the two states involves a hydrogen abstraction-like transition structure. However,while in the high-spin state there forms a radical that has a significant barrier for rebound, in the low-spinstate the rebound is virtually barrierless. Even though one cannot ignore incursion of a small amount of radicalsin the low-spin state, it is clear that the radical has a significant lifetime mainly on the high-spin surface. Theresults are used to gain insight into puzzling experimental data which emerge from studies of ultrafast radicalclocks (e.g., Toy, P. H.; Newcomb, M.; Hollenberg, P. F., J. Am. Chem. Soc. 1998, 120, 7719), vis à vis thenature the transition state, deduced from kinetic isotope effect measurements (Manchester, J. I.; Dinnocenzo,J. P.; Higgins, L. A.; Jones, J. P. J. Am. Chem. Soc. 1997, 119, 5069) and stereochemical scrambling patterns(Groves, J. T.; McClusky, G. A.; White, R. E.; Coon, M. J. Biochem. Biophys. Res. Commun. 1978, 81, 154).Understanding the electronic structure of the various species leads to a predictive structure-reactivity picture,based on the two-state reactivity scenario (Shaik, S.; Filatov, M.; Schröder, D.; Schwarz, H. Chem. Eur. J.1998, 4, 193). The model makes it possible to predict the dependence of the relative rates of the two states,and of the corresponding steps as a function of the nature of the alkane, the resulting alkyl radical, and thebinding capability of the thiolate proximal ligand of the active species.