Jensen, Simon Bo; Thodberg, Sara; Parween, Shaheena; Moses, Matias E.; Hansen, Cecilie C.; Thomsen, Johannes; Sletfjerding, Magnus B.; Knudsen, Camilla; Del Giudice, Rita; Lund, Philip M.; Castaño, Patricia R.; Bustamante, Yanet G.; Rojas Velazquez, Maria Natalia; Jørgensen, Flemming Steen; Pandey, Amit Vikram; Laursen, Tomas; Møller, Birger Lindberg; Hatzakis, Nikos S. (2021). Biased cytochrome P450-mediated metabolism via small-molecule ligands binding P450 oxidoreductase. Nature Communications, 12(1), p. 2260. Springer Nature 10.1038/s41467-021-22562-w
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Metabolic control is mediated by the dynamic assemblies and function of multiple redox enzymes. A key element in these assemblies, the P450 oxidoreductase (POR), donates electrons and selectively activates numerous (>50 in humans and >300 in plants) cytochromes P450 (CYPs) controlling metabolism of drugs, steroids and xenobiotics in humans and natural product biosynthesis in plants. The mechanisms underlying POR-mediated CYP metabolism remain poorly understood and to date no ligand binding has been described to regulate the specificity of POR. Here, using a combination of computational modeling and functional assays, we identify ligands that dock on POR and bias its specificity towards CYP redox partners, across mammal and plant kingdom. Single molecule FRET studies reveal ligand binding to alter POR conformational sampling, which results in biased activation of metabolic cascades in whole cell assays. We propose the model of biased metabolism, a mechanism akin to biased signaling of GPCRs, where ligand binding on POR stabilizes different conformational states that are linked to distinct metabolic outcomes. Biased metabolism may allow designing pathway-specific therapeutics or personalized food suppressing undesired, disease-related, metabolic pathways.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine > Endocrinology/Metabolic Disorders |
Graduate School: |
Graduate School for Cellular and Biomedical Sciences (GCB) |
UniBE Contributor: |
Parween, Shaheena, Rodríguez Castaño, Patricia, Rojas Velazquez, Maria Natalia, Pandey, Amit Vikram |
Subjects: |
600 Technology > 610 Medicine & health 500 Science > 570 Life sciences; biology |
ISSN: |
2041-1723 |
Publisher: |
Springer Nature |
Funders: |
[4] Swiss National Science Foundation ; [UNSPECIFIED] Novartis Foundation for Medical Biological Research |
Language: |
English |
Submitter: |
Amit Vikram Pandey |
Date Deposited: |
20 May 2021 11:09 |
Last Modified: |
06 Jan 2023 18:28 |
Publisher DOI: |
10.1038/s41467-021-22562-w |
PubMed ID: |
33859207 |
BORIS DOI: |
10.48350/155910 |
URI: |
https://boris.unibe.ch/id/eprint/155910 |
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