Taste-Guided Isolation of Bitter Compounds from the Mushroom <i>Amaropostia stiptica</i> Activates a Subset of Human Bitter Taste Receptors

Bitter taste perception cautions humans against the ingestion of potentially toxic compounds. However, current knowledge about natural bitter substances and their activation of human bitter taste receptors (TAS2Rs) is biased toward substances from flowering plants, whereas other sources are underrepresented. Although numerous mushrooms taste bitter, the corresponding substances and receptors are unexplored. Three previously undescribed triterpene glucosides, named oligoporins D-F, together with the known oligoporins A and B, were isolated from <i>Amaropostia stiptica</i>. The structures of oligoporins D-F were determined using spectroscopic analyses. The isolated oligoporins and the bitter indolalkaloid infractopicrin from <i>Cortinarius infractus</i> were functionally screened with all TAS2Rs. For all compounds, at least one responding receptor was identified. Oligoporin D activated TAS2R46 already at a submicromolar concentration and thus belongs to the family of most potent bitter agonists. The addition of mushroom compounds to the list of cognate TAS2R activators lowers the existing bias of knowledge about bitter agonists.