title: Do mammalian cytochrome P450s show multiple ligand access pathways and ligand channelling?
abstract: Understanding substrate binding and product release in cytochrome P450 (CYP) enzymes is important for explaining their key role in drug metabolism, toxicity, xenobiotic degradation and biosynthesis. Here, molecular simulations of substrate and product exit from the buried active site of a mammalian P450, the microsomal CYP2C5, identified a dominant exit channel, termed pathway (pw) 2c. Previous simulations with soluble bacterial P450s showed a different dominant egress channel, pw2a. Combining these, we propose two mechanisms in CYP2C5: (i) a one-way route by which lipophilic substrates access the enzyme from the membrane by pw2a and hydroxylated products egress along pw2c; and (ii) a two-way route for access and egress, along pw2c, for soluble compounds. The proposed differences in substrate access and product egress routes between membrane-bound mammalian P450s and soluble bacterial P450s highlight the adaptability of the P450 fold to the requirements of differing cellular locations and substrate specificity profiles.
authors: EML Research gGmbH, Villa Bosch, Schloss-Wolfsbrunnenweg 33, 69118 Heidelberg, Germany
authors: Karin
authors: K
authors: Schleinkofer
authors: Sudarko
authors: Peter J
authors: PJ
authors: Winn
authors: Susanne K
authors: SK
authors: Lüdemann
authors: Rebecca C
authors: RC
authors: Wade
mesh_terms: D000818:Animals; D003198:Computer Simulation; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D003900:Desoxycorticosterone / Q000378:metabolism; D008024:Ligands; D008322:Mammals / Q000378:metabolism*; D008958:Models, Molecular; D011374:Progesterone / Q000378:metabolism; D011485:Protein Binding; D013255:Steroid 21-Hydroxylase / Q000737:chemistry* / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D008024:Ligands; D003900:Desoxycorticosterone; D011374:Progesterone; D003577:Cytochrome P-450 Enzyme System; C065407:CYP2C5 protein, Oryctolagus cuniculus; D000072467:Cytochrome P450 Family 2; D013255:Steroid 21-Hydroxylase