oa Editorial [Hot Topic: Cytochromes P450: Flexibility and Plasticity - Properties Determining Substrate Preferences (Guest Editors: Michal Otyepka and Pavel Anzenbacher)]

Cytochromes P450 represent a class of hemoproteins participating in reactions leading to drug metabolism as well as in biotransformations of endogenous substrates. Variability of drugs is reflected in structures of human liver microsomal drug metabolizing cytochromes P450. Effective biotransformation is conditioned by the ability of both partners, of the substrate as well as of the enzyme, to bind in a correct manner; in other words, by the ability of a substrate to reach the active site, to bind there and undergo the chemical reaction and to leave the protein after successful biotransformation. Recent results of experimental as well as theoretical work on structure of cytochromes P450 document that the flexibility and plasticity of the enzyme is one of the most important properties which (together with the amino acid web of the active site and of the lining of the access/egress channels) determine substrate specificity of individual cytochrome P450 enzymes. Seven contributions of this Special issue named “Cytochromes P450: Flexibility and Plasticity - Properties Determining Substrate Preferences” discuss the structural properties of the respective cytochromes P450 as well as of substrates, structural adaptation of structures of cytochromes P450 determining their function [1, 2], the plasticity/malleability of the protein structure [3], flexible regions of individual enzymes, flexibility and solvation of their active sites [4], access/egress of the substrates/metabolites [5], as well as the structural adaptation and recognition of substrates in the respective active sites [6, 7]. Both approaches, theoretical and/or experimental, are jointly applied to contribute to solution of the questions raised. REFERENCES [1] Seifert, A.; Pleiss, J., Identification of Selectivity Determinants in CYP Monooxygenases by Modelling and Systematic Analysis of Sequence and Structure by Seifert and Pleiss. Curr. Drug Metab., 2012, 13(2): 197-202. [2] Otyepka, M.; Berka, K.; Anzenbacher, P., Is There a Relationship Between the Substrate Preferences and Structural Flexibility of Cytochromes P450? Curr. Drug Metab., 2012, 13(2): 130-142. [3] Wilderman, P., R.; Halpert, J., R., Plasticity of CYP2B Enzymes: Structural and Solution Biophysical Methods. Curr. Drug Metab., 2012, 13(2): 167- 176. [4] Hendrychova, T.; Berka, K.; Navratilova, V.; Anzenbacher, P.; Otyepka, M., Dynamics and Hydration of the Active Sites of Mammalian Cytochromes P450 Probed by Molecular Dynamics Simulations. Curr. Drug Metab., 2012, 13(2): 177-189. [5] Cojocaru, V.; Winn, P.J.; Wade, R., C., Multiple, Ligand-dependent Routes from the Active Site of Cytochrome P450 2C9. Curr. Drug Metab., 2012, 13(2): 143-154. [6] Oostenbrink, Ch.; de Ruiter, A.; Hritz, J.; Vermeulen, N., P., E., Malleability and Versatility of Cytochrome P450 Active Sites Studied by Molecular Simulations. Curr. Drug Metab., 2012, 13(2): 190-196. [7] de Beer, S., B., A.; van Bergen, L., A., H.; Keijzer, K.; Rea, V.; Venkataraman, H.; Fonseca Guerra, C.; Bickelhaupt, F., M.; Vermeulen, N., P., E., Commandeur, J., N., M.; Geerke, D., P., The Role of Protein Plasticity in Computational Rationalization Studies on Regioselectivity in Testosterone Hydroxylation by Cytochrome P450 BM3 mutants. Curr. Drug Metab., 2012, 13(2): 155-166.