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.
Highlights
Metabolic control is mediated by the dynamic assemblies and function of multiple redox enzymes
G protein-coupled receptors (GPCRs) are the prime example of this phenomenon, acting as key signaling hubs with several conformational states linked to distinct downstream cellular processes[15,16,17]
While our data do not distinguish between the swinging and rotating motion models of POR8 they provide a correlation between the existence of P450 oxidoreductase (POR) equilibrium conformational states with distinct phenotypic metabolic outcomes
Summary
Metabolic control is mediated by the dynamic assemblies and function of multiple redox enzymes. 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. Mutations in human POR alter POR specificity towards activation of CYPs leading to severe disorders with multiple clinical manifestations varying from skeletal malformations with craniosynostosis (similar to Antley-Bixler Syndrome) to ambiguous genitalia and disorder of sexual development, amongst others[3,4,12,13,14] Exploiting this regulatory layer is central for the treatment of metabolic disorder and tailored biosynthesis of natural products, the mechanisms regulating, or biasing, POR specificity towards CYPs are not well understood. Ligand-mediated control of POR conformational sampling appears to inhibit the activation of a subset of CYPs and/or enhance activation of others offering a new paradigm of metabolic control
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
