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

Author

Listed:
  • Simon Bo Jensen

    (University of Copenhagen)

  • Sara Thodberg

    (University of Copenhagen
    Center for Synthetic Biology
    VILLUM Research Center “Plant Plasticity”)

  • Shaheena Parween

    (Pediatric Endocrinology, Diabetology, and Metabolism, University Children’s Hospital
    University of Bern)

  • Matias E. Moses

    (University of Copenhagen)

  • Cecilie C. Hansen

    (University of Copenhagen
    Center for Synthetic Biology
    VILLUM Research Center “Plant Plasticity”)

  • Johannes Thomsen

    (University of Copenhagen)

  • Magnus B. Sletfjerding

    (University of Copenhagen)

  • Camilla Knudsen

    (University of Copenhagen
    Center for Synthetic Biology
    VILLUM Research Center “Plant Plasticity”)

  • Rita Giudice

    (University of Copenhagen
    Center for Synthetic Biology
    VILLUM Research Center “Plant Plasticity”)

  • Philip M. Lund

    (University of Copenhagen)

  • Patricia R. Castaño

    (Pediatric Endocrinology, Diabetology, and Metabolism, University Children’s Hospital
    University of Bern)

  • Yanet G. Bustamante

    (University of Copenhagen)

  • Maria Natalia Rojas Velazquez

    (Pediatric Endocrinology, Diabetology, and Metabolism, University Children’s Hospital
    University of Bern)

  • Flemming Steen Jørgensen

    (University of Copenhagen)

  • Amit V. Pandey

    (Pediatric Endocrinology, Diabetology, and Metabolism, University Children’s Hospital
    University of Bern)

  • Tomas Laursen

    (University of Copenhagen
    Center for Synthetic Biology
    VILLUM Research Center “Plant Plasticity”)

  • Birger Lindberg Møller

    (University of Copenhagen
    Center for Synthetic Biology
    VILLUM Research Center “Plant Plasticity”
    Carlsberg Research Laboratory)

  • Nikos S. Hatzakis

    (University of Copenhagen
    Novo Nordisk Foundation Centre for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen)

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.

Suggested Citation

  • 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. Cas, 2021. "Biased cytochrome P450-mediated metabolism via small-molecule ligands binding P450 oxidoreductase," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22562-w
    DOI: 10.1038/s41467-021-22562-w
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