TY - JOUR
T1 - Biased cytochrome P450-mediated metabolism via small-molecule ligands binding P450 oxidoreductase
AU - Jensen, Simon Bo
AU - Thodberg, Sara
AU - Parween, Shaheena
AU - Moses, Matias E.
AU - Hansen, Cecilie C.
AU - Thomsen, Johannes
AU - Sletfjerding, Magnus B.
AU - Knudsen, Camilla
AU - Del Giudice, Rita
AU - Lund, Philip M.
AU - Castaño, Patricia R.
AU - Bustamante, Yanet G.
AU - Velazquez, Maria Natalia Rojas
AU - Jørgensen, Flemming Steen
AU - Pandey, Amit V.
AU - Laursen, Tomas
AU - Møller, Birger Lindberg
AU - Hatzakis, Nikos S.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-021-22562-w
DO - 10.1038/s41467-021-22562-w
M3 - Journal article
C2 - 33859207
AN - SCOPUS:85104384221
VL - 12
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 2260
ER -