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

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Standard

Biased cytochrome P450-mediated metabolism via small-molecule ligands binding P450 oxidoreductase. / 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.; Velazquez, Maria Natalia Rojas; Jørgensen, Flemming Steen; Pandey, Amit V.; Laursen, Tomas; Møller, Birger Lindberg; Hatzakis, Nikos S.

I: Nature Communications, Bind 12, Nr. 1, 2260, 2021.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Jensen, SB, Thodberg, S, Parween, S, Moses, ME, Hansen, CC, Thomsen, J, Sletfjerding, MB, Knudsen, C, Del Giudice, R, Lund, PM, Castaño, PR, Bustamante, YG, Velazquez, MNR, Jørgensen, FS, Pandey, AV, Laursen, T, Møller, BL & Hatzakis, NS 2021, 'Biased cytochrome P450-mediated metabolism via small-molecule ligands binding P450 oxidoreductase', Nature Communications, bind 12, nr. 1, 2260. https://doi.org/10.1038/s41467-021-22562-w

APA

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, 12(1), [2260]. https://doi.org/10.1038/s41467-021-22562-w

Vancouver

Jensen SB, Thodberg S, Parween S, Moses ME, Hansen CC, Thomsen J o.a. Biased cytochrome P450-mediated metabolism via small-molecule ligands binding P450 oxidoreductase. Nature Communications. 2021;12(1). 2260. https://doi.org/10.1038/s41467-021-22562-w

Author

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. ; Velazquez, Maria Natalia Rojas ; Jørgensen, Flemming Steen ; Pandey, Amit V. ; Laursen, Tomas ; Møller, Birger Lindberg ; Hatzakis, Nikos S. / Biased cytochrome P450-mediated metabolism via small-molecule ligands binding P450 oxidoreductase. I: Nature Communications. 2021 ; Bind 12, Nr. 1.

Bibtex

@article{1c346700e3c542d9942d72f4bd0ebc8e,
title = "Biased cytochrome P450-mediated metabolism via small-molecule ligands binding P450 oxidoreductase",
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.",
author = "Jensen, {Simon Bo} and Sara Thodberg and Shaheena Parween and Moses, {Matias E.} and Hansen, {Cecilie C.} and Johannes Thomsen and Sletfjerding, {Magnus B.} and Camilla Knudsen and {Del Giudice}, Rita and Lund, {Philip M.} and Casta{\~n}o, {Patricia R.} and Bustamante, {Yanet G.} and Velazquez, {Maria Natalia Rojas} and J{\o}rgensen, {Flemming Steen} and Pandey, {Amit V.} and Tomas Laursen and M{\o}ller, {Birger Lindberg} and Hatzakis, {Nikos S.}",
year = "2021",
doi = "10.1038/s41467-021-22562-w",
language = "English",
volume = "12",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "nature publishing group",
number = "1",

}

RIS

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 -

ID: 261515065