%0 Journal Article
%T Studies on 16 -Hydroxylation of Steroid Molecules and Regioselective Binding Mode in Homology-Modeled Cytochrome P450-2C11
%A Hamed I. Ali
%A Morio Yamada
%A Yukihisa Fujita
%A Mitsuko Maeda
%A Eiichi Akaho
%J International Journal of Medicinal Chemistry
%D 2011
%I Hindawi Publishing Corporation
%R 10.1155/2011/918168
%X We investigated the 16 -hydroxylation of steroid molecules and regioselective binding mode in homology-modeled cytochrome P450-2C11 to correlate the biological study with the computational molecular modeling. It revealed that there was a positive relationship between the observed inhibitory potencies and the binding free energies. Docking of steroid molecules into this homology-modeled CYP2C11 indicated that 16 -hydroxylation is favored with steroidal molecules possessing the following components, (1) a bent A-B ring configuration (5 -reduced), (2) C-3 -hydroxyl group, (3) C-17 -acetyl group, and (4) methyl group at both the C-18 and C-19. These respective steroid components requirements were defined as the inhibitory contribution factor. Overall studies of the male rat CYP2C11 metabolism revealed that the above-mentioned steroid components requirements were essential to induce an effective inhibition of [3H]progesterone 16 -hydroxylation. As far as docking of homology-modeled CYP2C11 against investigated steroids is concerned, they are docked at the active site superimposed with flurbiprofen. It was also found that the distance between heme iron and C16 -H was between 4 to 6£¿£¿ and that the related angle was in the range of . 1. Introduction Cytochrome P450 (P450) constitutes a large superfamily of heme-containing enzymes capable of oxidizing a variety of substrates, both of endogenous (such as steroids) and exogenous (xenobiotics) origins [1¨C7]. Although a variety of P450s are able to metabolize a broad range of substrates, the enzymes often exhibit strict regio- and stereoselectivity towards pertinent compounds, such as various steroids [1]. One of the most active and versatile P450 is rat CYP2C11, a microsomal P450 isoform catalyzing more than 90% of steroid 16 -hydroxylations [8¨C10]. It is well-known that several 3-keto-4-ene steroids such as progesterone and testosterone are metabolized in a gender-specific and predominant manner by the adult rat liver microsomes. In the male, these steroids are primarily metabolized into two oxidized (16 -hydroxyl and 6 -hydroxyl) products mainly by the respective, male-specific cytochrome P450 subforms, CYP2C11 and CYP3A2, while they are primarily metabolized into the 5 -reduced products by female predominant 5 -reductase [11]. Most of P450 structures reveal that the heme group is buried deep within the protein matrix, indicating that residues outside of the active site may also be required to guide the substrate into the heme pocket by recognizing substrates at the protein surface and/or comprising part of a
%U http://www.hindawi.com/journals/ijmc/2011/918168/