The Role of Protein-Protein and Protein-Membrane Interactions on P450 Function

Emily E Scott; C Roland Wolf; Michal Otyepka; Sara C Humphreys; James R Reed; Colin J Henderson; Lesley A McLaughlin; Markéta Paloncýová; Veronika Navrátilová; Karel Berka; Pavel Anzenbacher; Upendra P Dahal; Carlo Barnaba; James A Brozik; Jeffrey P Jones; D Fernando Estrada; Jennifer S Laurence; Ji Won Park; Wayne L Backes

doi:10.1124/dmd.115.068569

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The Role of Protein-Protein and Protein-Membrane Interactions on P450 Function

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The Role of Protein-Protein and Protein-Membrane Interactions on P450 Function

Emily E Scott, C Roland Wolf, Michal Otyepka, Sara C Humphreys, James R Reed, Colin J Henderson, Lesley A McLaughlin, Markéta Paloncýová, Veronika Navrátilová, Karel Berka, …

Drug metabolism and disposition, Vol.44(4), pp.576-590

04/2016

DOI: https://doi.org/10.1124/dmd.115.068569

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https://hdl.handle.net/2376/107648

PMCID: PMC4810767

PMID: 26851242

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Abstract

Cytochrome P-450 Enzyme System - chemistry

Animals

Protein Structure, Secondary

Protein Interaction Domains and Motifs - physiology

Humans

Microsomes, Liver - metabolism

Endoplasmic Reticulum - metabolism

Research Report

Cell Membrane - metabolism

Cytochrome P-450 Enzyme System - physiology

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.

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Title: The Role of Protein-Protein and Protein-Membrane Interactions on P450 Function
Creators: Emily E Scott - 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.)
C Roland Wolf - 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.)
Michal Otyepka - 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.)
Sara C Humphreys - 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.)
James R Reed - 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.)
Colin J Henderson - 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.)
Lesley A McLaughlin - 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.)
Markéta Paloncýová - 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.)
Veronika Navrátilová - 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.)
Karel Berka - 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.)
Pavel Anzenbacher - 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.)
Upendra P Dahal - 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.)
Carlo Barnaba - 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.)
James A Brozik - 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.)
Jeffrey P Jones - 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.)
D Fernando Estrada - 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.)
Jennifer S Laurence - 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.)
Ji Won Park - 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.)
Wayne L Backes - 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
Publication Details: Drug metabolism and disposition, Vol.44(4), pp.576-590
Academic Unit: Chemistry, Department of
Publisher: United States
Grant note: P42 ES013648 / NIEHS NIH HHS R01 GM114369 / NIGMS NIH HHS R01 GM110790 / NIGMS NIH HHS R01 GM102505 / NIGMS NIH HHS GM110790 / NIGMS NIH HHS F32 GM103069 / NIGMS NIH HHS 10822 / Cancer Research UK R01 ES004344 / NIEHS NIH HHS GM102505 / NIGMS NIH HHS C4639/A10822 / Cancer Research UK R37 GM076343 / NIGMS NIH HHS R01 GM076343 / NIGMS NIH HHS
Identifiers: 99900547233301842
Language: English
Resource Type: Journal article