title: The Role of Protein-Protein and Protein-Membrane Interactions on P450 Function.
abstract: This symposium summary, sponsored by the ASPET, was held at Experimental Biology 2015 on March 29, 2015, in Boston, Massachusetts. The symposium focused on: 1) the interactions of cytochrome P450s (P450s) with their redox partners; and 2) the role of the lipid membrane in their orientation and stabilization. Two presentations discussed the interactions of P450s with NADPH-P450 reductase (CPR) and cytochrome b5. First, solution nuclear magnetic resonance was used to compare the protein interactions that facilitated either the hydroxylase or lyase activities of CYP17A1. The lyase interaction was stimulated by the presence of b5 and 17α-hydroxypregnenolone, whereas the hydroxylase reaction was predominant in the absence of b5. The role of b5 was also shown in vivo by selective hepatic knockout of b5 from mice expressing CYP3A4 and CYP2D6; the lack of b5 caused a decrease in the clearance of several substrates. The role of the membrane on P450 orientation was examined using computational methods, showing that the proximal region of the P450 molecule faced the aqueous phase. The distal region, containing the substrate-access channel, was associated with the membrane. The interaction of NADPH-P450 reductase (CPR) with the membrane was also described, showing the ability of CPR to "helicopter" above the membrane. Finally, the endoplasmic reticulum (ER) was shown to be heterogeneous, having ordered membrane regions containing cholesterol and more disordered regions. Interestingly, two closely related P450s, CYP1A1 and CYP1A2, resided in different regions of the ER. The structural characteristics of their localization were examined. These studies emphasize the importance of P450 protein organization to their function.
authors: Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
authors: Emily E
authors: EE
authors: Scott
authors: Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
authors: C Roland
authors: CR
authors: Wolf
authors: Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
authors: Michal
authors: M
authors: Otyepka
authors: Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
authors: Sara C
authors: SC
authors: Humphreys
authors: Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
authors: James R
authors: JR
authors: Reed
authors: Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
authors: Colin J
authors: CJ
authors: Henderson
authors: Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
authors: Lesley A
authors: LA
authors: McLaughlin
authors: Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
authors: Markéta
authors: M
authors: Paloncýová
authors: Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
authors: Veronika
authors: V
authors: Navrátilová
authors: Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
authors: Karel
authors: K
authors: Berka
authors: Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
authors: Pavel
authors: P
authors: Anzenbacher
authors: Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
authors: Upendra P
authors: UP
authors: Dahal
authors: Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
authors: Carlo
authors: C
authors: Barnaba
authors: Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
authors: James A
authors: JA
authors: Brozik
authors: Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
authors: Jeffrey P
authors: JP
authors: Jones
authors: Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
authors: D Fernando
authors: DF
authors: Estrada
authors: Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
authors: Jennifer S
authors: JS
authors: Laurence
authors: Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
authors: Ji Won
authors: JW
authors: Park
authors: Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.) wbacke@lsuhsc.edu.
authors: Wayne L
authors: WL
authors: Backes
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs / Q000502:physiology*; D017433:Protein Structure, Secondary; D058028:Research Report
chemical_list: D003577:Cytochrome P-450 Enzyme System