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Open AccessArticle

Differing Membrane Interactions of Two Highly Similar Drug-Metabolizing Cytochrome P450 Isoforms: CYP 2C9 and CYP 2C19

1
Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), 69118 Heidelberg, Germany
2
Zentrum für Molekulare Biologie der Universität Heidelberg, DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany
3
Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, 69120 Heidelberg, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(18), 4328; https://doi.org/10.3390/ijms20184328
Received: 6 August 2019 / Revised: 31 August 2019 / Accepted: 1 September 2019 / Published: 4 September 2019
(This article belongs to the Special Issue Cytochromes P450: Drug Metabolism, Bioactivation and Biodiversity 2.0)
The human cytochrome P450 (CYP) 2C9 and 2C19 enzymes are two highly similar isoforms with key roles in drug metabolism. They are anchored to the endoplasmic reticulum membrane by their N-terminal transmembrane helix and interactions of their cytoplasmic globular domain with the membrane. However, their crystal structures were determined after N-terminal truncation and mutating residues in the globular domain that contact the membrane. Therefore, the CYP-membrane interactions are not structurally well-characterized and their dynamics and the influence of membrane interactions on CYP function are not well understood. We describe herein the modeling and simulation of CYP 2C9 and CYP 2C19 in a phospholipid bilayer. The simulations revealed that, despite high sequence conservation, the small sequence and structural differences between the two isoforms altered the interactions and orientations of the CYPs in the membrane bilayer. We identified residues (including K72, P73, and I99 in CYP 2C9 and E72, R73, and H99 in CYP 2C19) at the protein-membrane interface that contribute not only to the differing orientations adopted by the two isoforms in the membrane, but also to their differing substrate specificities by affecting the substrate access tunnels. Our findings provide a mechanistic interpretation of experimentally observed effects of mutagenesis on substrate selectivity. View Full-Text
Keywords: cytochrome P450; isoform; membrane protein; protein-membrane interactions; enzyme substrate specificity; mutagenesis; molecular dynamics simulation cytochrome P450; isoform; membrane protein; protein-membrane interactions; enzyme substrate specificity; mutagenesis; molecular dynamics simulation
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MDPI and ACS Style

Mustafa, G.; Nandekar, P.P.; Bruce, N.J.; Wade, R.C. Differing Membrane Interactions of Two Highly Similar Drug-Metabolizing Cytochrome P450 Isoforms: CYP 2C9 and CYP 2C19. Int. J. Mol. Sci. 2019, 20, 4328. https://doi.org/10.3390/ijms20184328

AMA Style

Mustafa G, Nandekar PP, Bruce NJ, Wade RC. Differing Membrane Interactions of Two Highly Similar Drug-Metabolizing Cytochrome P450 Isoforms: CYP 2C9 and CYP 2C19. International Journal of Molecular Sciences. 2019; 20(18):4328. https://doi.org/10.3390/ijms20184328

Chicago/Turabian Style

Mustafa, Ghulam; Nandekar, Prajwal P.; Bruce, Neil J.; Wade, Rebecca C. 2019. "Differing Membrane Interactions of Two Highly Similar Drug-Metabolizing Cytochrome P450 Isoforms: CYP 2C9 and CYP 2C19" Int. J. Mol. Sci. 20, no. 18: 4328. https://doi.org/10.3390/ijms20184328

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