Biased cytochrome P450-mediated metabolism via small-molecule ligands binding P450 oxidoreductase

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)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Endokrinologie / Diabetologie / Metabolik (Pädiatrie)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine
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 and 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:

23 May 2021 02:59

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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