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

Simon Bo Jensen, Sara Thodberg, Shaheena Parween, Matias E. Moses, Cecilie C. Hansen, Johannes Thomsen, Magnus B. Sletfjerding, Camilla Knudsen, Rita Giudice, Philip M. Lund, Patricia R. Castaño, Yanet G. Bustamante, Maria Natalia Rojas Velazquez, Flemming Steen Jørgensen, Amit V. Pandey, Tomas Laursen, Birger Lindberg Møller and Nikos S. Hatzakis ()
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Simon Bo Jensen: University of Copenhagen
Sara Thodberg: University of Copenhagen
Shaheena Parween: Pediatric Endocrinology, Diabetology, and Metabolism, University Children’s Hospital
Matias E. Moses: University of Copenhagen
Cecilie C. Hansen: University of Copenhagen
Johannes Thomsen: University of Copenhagen
Magnus B. Sletfjerding: University of Copenhagen
Camilla Knudsen: University of Copenhagen
Rita Giudice: University of Copenhagen
Philip M. Lund: University of Copenhagen
Patricia R. Castaño: Pediatric Endocrinology, Diabetology, and Metabolism, University Children’s Hospital
Yanet G. Bustamante: University of Copenhagen
Maria Natalia Rojas Velazquez: Pediatric Endocrinology, Diabetology, and Metabolism, University Children’s Hospital
Flemming Steen Jørgensen: University of Copenhagen
Amit V. Pandey: Pediatric Endocrinology, Diabetology, and Metabolism, University Children’s Hospital
Tomas Laursen: University of Copenhagen
Birger Lindberg Møller: University of Copenhagen
Nikos S. Hatzakis: University of Copenhagen

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22562-w

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DOI: 10.1038/s41467-021-22562-w

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