The Localization of Cytochrome P450s CYP1A1 and CYP1A2 into Different Lipid Microdomains Is Governed by Their N-terminal and Internal Protein Regions

Park, Ji Won; Reed, James R.; Backes, Wayne L.

doi:10.1074/jbc.m115.687103

Cited by 23 publications

(19 citation statements)

References 44 publications

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“…This research was originally published in the Journal of Biological Chemistry Role of the Membrane in the P450 System domains do form in reconstituted systems and that lipid phase separation was seen at lipid compositions similar to those found in liver ER. Furthermore, CYP1A2 was found to reside in the l o regions of these reconstituted systems in a manner analogous to that observed with the ER (Brignac-Huber et al, 2011, 2013Park et al, 2014Park et al, , 2015.…”

Section: Lipid Microdomainssupporting

confidence: 64%

“…Until our recent publications (Brignac-Huber et al, 2011, 2013Park et al, 2014Park et al, , 2015, there were no studies illustrating the effects of such lipid domains in microsomal tissue and their potential to affect P450 function. However, the existence of ER lipid domains has become more widely recognized and can significantly influence the localization of P450 system proteins.…”

Section: Anionic Phospholipidsmentioning

confidence: 99%

“…P, pellet; S, supernatant. This research was originally published in the Journal of Biological Chemistry (Park et al, 2015). Fig.…”

Section: Lipid Microdomainsmentioning

confidence: 99%

See 2 more Smart Citations

Cytochrome P450 Organization and Function Are Modulated by Endoplasmic Reticulum Phospholipid Heterogeneity

Brignac‐Huber¹,

Park²,

Reed³

et al. 2016

Drug Metab Dispos

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Cytochrome P450s (P450s) comprise a superfamily of proteins that catalyze numerous monooxygenase reactions in animals, plants, and bacteria. In eukaryotic organisms, these proteins not only carry out reactions necessary for the metabolism of endogenous compounds, but they are also important in the oxidation of exogenous drugs and other foreign compounds. Eukaryotic P450 system proteins generally reside in membranes, primarily the endoplasmic reticulum or the mitochondrial membrane. These membranes provide a scaffold for the P450 system proteins that facilitate interactions with their redox partners as well as other P450s. This review focuses on the ability of specific lipid components to influence P450 activities, as well as the role of the membrane in P450 function. These studies have shown that P450s and NADPH-cytochrome P450 reductase appear to selectively associate with specific phospholipids and that these lipid-protein interactions influence P450 activities. Finally, because of the heterogeneous nature of the endoplasmic reticulum as well as other biologic membranes, the phospholipids are not arranged randomly but associate to generate lipid microdomains. Together, these characteristics can affect P450 function by 1) altering the conformation of the proteins, 2) influencing the P450 interactions with their redox partners, and 3) affecting the localization of the proteins into specific membrane microdomains.

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Section: Lipid Microdomainssupporting

confidence: 64%

Section: Anionic Phospholipidsmentioning

confidence: 99%

See 1 more Smart Citation

Cytochrome P450 Organization and Function Are Modulated by Endoplasmic Reticulum Phospholipid Heterogeneity

Brignac‐Huber¹,

Park²,

Reed³

et al. 2016

Drug Metab Dispos

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“…Moreover, these thirty residues would also be mediating the interaction with NADPH-CYP reductase [121–124]. …”

Section: Structural Characteristics Of Human Cyp1a1 and Its Ligandsmentioning

confidence: 99%

Regulation of Human Cytochrome P4501A1 (hCYP1A1): A Plausible Target for Chemoprevention?

Santes-Palacios¹,

Ornelas-Ayala²,

Cabañas³

et al. 2016

BioMed Research International

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Human cytochrome P450 1A1 (hCYP1A1) has been an object of study due to its role in precarcinogen metabolism; for this reason it is relevant to know more in depth the mechanisms that rule out its expression and activity, which make this enzyme a target for the development of novel chemiopreventive agents. The aim of this work is to review the origin, regulation, and structural and functional characteristics of CYP1A1 letting us understand its role in the bioactivation of precarcinogen and the consequences of its modulation in other physiological processes, as well as guide us in the study of this important protein.

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“…In this crystal structure, CYP1A2 was modified to remove the N-terminal transmembrane region to improve solubility and to reduce aggregation. However, the N-terminal transmembrane region is essential for recognizing and binding to the cell membranes of the endoplasmic reticulum (Jang et al, 2010; Park et al, 2015). In the current study, we remodeled the N-terminal transmembrane region and constructed a membrane-binding model for the full-length human CYP1A2.…”

Section: Introductionmentioning

confidence: 99%

Impact of peripheral mutations on the access channels of human cytochrome P450 1A2

Ying

Zhong

Wang

2019

Preprint

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As an important member of cytochrome P450 (CYP) enzymes, human CYP1A2 is associated with the metabolism of caffeine and melatonin and the activation of precarcinogens. Besides, this CYP protein also involves in metabolizing 5-10% of clinical medicines. Some peripheral mutations in CYP1A2 (P42R, I386F, R431W, and R456H) significantly decrease the enzyme activities, resulting in a vital reduction in substrate metabolisms. To explore the effects of these peripheral mutations, we constructed a membrane-binding model for the full-length human CYP1A2 and studied their dynamic behaviors on lipid membranes. Free energy calculations indicate that the peripheral mutations donot influence substrate binding. P42R is located in the N-terminal anchor, and its positive charged sidechain is adverse to membrane binding. I386F enhances the van der Waals contacts of the water channel bottleneck and R456H breaks the hydrogen bonding interactions that function to position the BC loop, both of which result in a significant inhibition on the water channel. R431W causes a sidechain conformational rearrangement for aromatic residues around the substrate channel, making it in a closed state in most cases. Our computational simulations demonstrate that pi-pi stacking interactions are essential for substrate binding and channel opening. We hope that these findings may be of general relevance to the mutation-induced activity changes for CYP proteins, providing useful information for understanding the CYP-mediated drug metabolism.

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The Localization of Cytochrome P450s CYP1A1 and CYP1A2 into Different Lipid Microdomains Is Governed by Their N-terminal and Internal Protein Regions

Cited by 23 publications

References 44 publications

Cytochrome P450 Organization and Function Are Modulated by Endoplasmic Reticulum Phospholipid Heterogeneity

Cytochrome P450 Organization and Function Are Modulated by Endoplasmic Reticulum Phospholipid Heterogeneity

Regulation of Human Cytochrome P4501A1 (hCYP1A1): A Plausible Target for Chemoprevention?

Impact of peripheral mutations on the access channels of human cytochrome P450 1A2

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