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

Autor: Sara Thodberg, Rita Del Giudice, Matias E. Moses, Tomas Laursen, Nikos S. Hatzakis, Amit V. Pandey, Yanet G. Bustamante, Flemming Jørgensen, Maria Natalia Rojas Velazquez, Cecilie Cetti Hansen, Shaheena Parween, Birger Lindberg Møller, Simon Bo Jensen, Camilla Knudsen, Magnus Berg Sletfjerding, Philip M. Lund, Johannes Thomsen, Patricia Rodríguez Castaño
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Science
General Physics and Astronomy
610 Medicine & health
Plasma protein binding
Ligands
010402 general chemistry
01 natural sciences
Article
General Biochemistry
Genetics and Molecular Biology
Cell Line
Substrate Specificity
03 medical and health sciences
Aromatase
Protein structure
Cytochrome P-450 Enzyme System
Single-molecule biophysics
Fluorescence Resonance Energy Transfer
Humans
Synthetic biology
Enzyme Assays
G protein-coupled receptor
Multidisciplinary
biology
Chemistry
Steroid 17-alpha-Hydroxylase
Cytochrome P450
General Chemistry
Single-molecule FRET
Small molecule
Recombinant Proteins
Single Molecule Imaging
Protein Structure
Tertiary
0104 chemical sciences
Cell biology
Molecular Docking Simulation
Metabolic pathway
030104 developmental biology
Liposomes
Enzyme mechanisms
Biocatalysis
biology.protein
570 Life sciences
Steroid 21-Hydroxylase
Metabolic Networks and Pathways
Function (biology)
Protein Binding
Zdroj: 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
Nature Communications, Vol 12, Iss 1, Pp 1-14 (2021)
Nature Communications
Jensen, S B, Thodberg, S, Parween, S, Moses, M E, Hansen, C C, Thomsen, J, Sletfjerding, M B, Knudsen, C, Del Giudice, R, Lund, P M, Castaño, P R, Bustamante, Y G, Velazquez, M N R, Jørgensen, F S, Pandey, A V, Laursen, T, Møller, B L & Hatzakis, N S 2021, ' Biased cytochrome P450-mediated metabolism via small-molecule ligands binding P450 oxidoreductase ', Nature Communications, vol. 12, no. 1, 2260 . https://doi.org/10.1038/s41467-021-22562-w
DOI: 10.1038/s41467-021-22562-w
Popis: 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.
P450 oxidoreductase (POR) selectively activates numerous cytochromes P450 (CYP), crucial for metabolism of drugs, steroids and xenobiotics and natural product biosynthesis. Here, the authors identify ligands that bind POR and bias its specificity towards CYP redox partners, activating distinct metabolic cascades in cells.
Databáze: OpenAIRE
Externí odkaz: