title: Correlating structure and function of drug-metabolizing enzymes: progress and ongoing challenges.
abstract: This report summarizes a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics at Experimental Biology held April 20-24 in Boston, MA. Presentations discussed the status of cytochrome P450 (P450) knowledge, emphasizing advances and challenges in relating structure with function and in applying this information to drug design. First, at least one structure of most major human drug-metabolizing P450 enzymes is known. However, the flexibility of these active sites can limit the predictive value of one structure for other ligands. A second limitation is our coarse-grain understanding of P450 interactions with membranes, other P450 enzymes, NADPH-cytochrome P450 reductase, and cytochrome b5. Recent work has examined differential P450 interactions with reductase in mixed P450 systems and P450:P450 complexes in reconstituted systems and cells, suggesting another level of functional control. In addition, protein nuclear magnetic resonance is a new approach to probe these protein/protein interactions, identifying interacting b5 and P450 surfaces, showing that b5 and reductase binding are mutually exclusive, and demonstrating ligand modulation of CYP17A1/b5 interactions. One desired outcome is the application of such information to control drug metabolism and/or design selective P450 inhibitors. A final presentation highlighted development of a CYP3A4 inhibitor that slows clearance of human immunodeficiency virus drugs otherwise rapidly metabolized by CYP3A4. Although understanding P450 structure/function relationships is an ongoing challenge, translational advances will benefit from continued integration of existing and new biophysical approaches.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California (E.F.J.); Department of Pharmacology and Experimental Therapeutics and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.P.C., J.R.R., W.L.B.); Department of Medicinal Chemistry, Gilead Sciences, Inc., Foster City, California (M.C.D., L.X.); Department of Pharmaceutical Chemistry (J.S.L.) and Department of Medicinal Chemistry (D.F.E., E.E.S.), University of Kansas, Lawrence, Kansas.
authors.forename: Eric F
authors.initials: EF
authors.lastname: Johnson
authors.forename: J Patrick
authors.initials: JP
authors.lastname: Connick
authors.forename: James R
authors.initials: JR
authors.lastname: Reed
authors.forename: Wayne L
authors.initials: WL
authors.lastname: Backes
authors.forename: Manoj C
authors.initials: MC
authors.lastname: Desai
authors.forename: Lianhong
authors.initials: L
authors.lastname: Xu
authors.forename: D Fernando
authors.initials: DF
authors.lastname: Estrada
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Laurence
authors.forename: Emily E
authors.initials: EE
authors.lastname: Scott
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015786:Cytochromes b5 / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic / Q000502:physiology*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs / Q000502:physiology
chemical_list: D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D009251:NADPH-Ferrihemoprotein Reductase