Article

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

Simon Bo JensenDepartment of Chemistry & Nanoscience Centre, University of Copenhagen, Copenhagen Ø, DenmarkSara ThodbergCenter for Synthetic Biology, Copenhagen, DenmarkShaheena ParweenDepartment of Biomedical Research, University of Bern, Bern, SwitzerlandMatias E. MosesDepartment of Chemistry & Nanoscience Centre, University of Copenhagen, Copenhagen Ø, DenmarkCecilie Cetti HansenCenter for Synthetic Biology, Copenhagen, DenmarkJohannes ThomsenDepartment of Chemistry & Nanoscience Centre, University of Copenhagen, Copenhagen Ø, DenmarkMagnus Berg SletfjerdingDepartment of Chemistry & Nanoscience Centre, University of Copenhagen, Copenhagen Ø, DenmarkCamilla KnudsenCenter for Synthetic Biology, Copenhagen, DenmarkRita Del GiudiceCenter for Synthetic Biology, Copenhagen, DenmarkPhilip M. LundDepartment of Chemistry & Nanoscience Centre, University of Copenhagen, Copenhagen Ø, DenmarkPatricia Rodríguez CastañoDepartment of Biomedical Research, University of Bern, Bern, SwitzerlandYanet G. BustamanteDepartment of Chemistry & Nanoscience Centre, University of Copenhagen, Copenhagen Ø, DenmarkMaria Natalia Rojas VelazquezDepartment of Biomedical Research, University of Bern, Bern, SwitzerlandFlemming Steen JørgensenDepartment of Drug Design and Pharmacology, University of Copenhagen, Copenhagen Ø, DenmarkAmit V. PandeyDepartment of Biomedical Research, University of Bern, Bern, SwitzerlandTomas LaursenCenter for Synthetic Biology, Copenhagen, DenmarkBirger Lindberg MøllerCarlsberg Research Laboratory, Copenhagen V, DenmarkNikos S. HatzakisDepartment of Chemistry & Nanoscience Centre, University of Copenhagen, Copenhagen Ø, Denmark. [email protected]

2021en

ABI

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.

Identifiers

DOI: 10.1038/s41467-021-22562-w

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