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The novel antibacterial compound walrycin A induces human PXR transcriptional activity.

Abstract : The human pregnane X receptor (PXR) is a ligand-regulated transcription factor belonging to the nuclear receptor superfamily. PXR is activated by a large, structurally diverse, set of endogenous and xenobiotic compounds and coordinates the expression of genes central to metabolism and excretion of potentially harmful chemicals and therapeutic drugs in humans. Walrycin A is a novel antibacterial compound targeting the WalK/WalR two-component signal transduction system of Gram (+) bacteria. Here, we report that, in hepatoma cells, walrycin A potently activates a gene set known to be regulated by the xenobiotic sensor PXR. Walrycin A was as efficient as the reference PXR agonist rifampicin to activate PXR in a transactivation assay at noncytotoxic concentrations. Using a limited proteolysis assay, we show that walrycin A induces conformational changes at a concentration which correlates with walrycin A ability to enhance the expression of prototypic target genes, suggesting that walrycin A interacts with PXR. The activation of the canonical human PXR target gene CYP3A4 by walrycin A is dose and PXR dependent. Finally, in silico docking experiments suggest that the walrycin A oxidation product Russig's blue is the actual ligand for PXR. Taken together, these results identify walrycin A as a novel human PXR activator.
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https://www.hal.inserm.fr/inserm-00672104
Contributor : Marie-Hélène Derudas <>
Submitted on : Monday, February 20, 2012 - 3:09:04 PM
Last modification on : Friday, July 17, 2020 - 10:54:05 AM

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Alexandre Berthier, Frédérik Oger, Céline Gheeraert, Abdel Boulahtouf, Rémy Le Guével, et al.. The novel antibacterial compound walrycin A induces human PXR transcriptional activity.. Toxicological Sciences, Oxford University Press (OUP), 2012, 127 (1), pp.225-35. ⟨10.1093/toxsci/kfs073⟩. ⟨inserm-00672104⟩

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