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The bitter taste sensation is elicited by molecules of widely varying chemical structure (http://bitterdb.agri.huji.ac.il/1) and prevents consumption of poisons, many of which are thought to be bitter. The bitter tastants are recognized by bitter taste receptors (TAS2Rs), a subfamily of GPCRs2. Some of the receptors are orphan, or have few known ligands, while others can be activated by numerous, structurally dissimilar compounds3. Furthermore, some compounds are selective towards a single TAS2R, while others activate multiple TAS2Rs. We show that TAS2R-promiscuous and TAS2R-selective bitter molecules differ in size, globularity, and other properties, and develop a selectivity predictor. Selective TAS2Rs are activated by promiscuous compounds, which are anyway recognized by additional TAS2Rs. Thus, unique ligands, that may have been the evolutionary driving force for the development of selective TAS2Rs, still need to be unraveled4.
BitterPredict is a new machine-learning based bitterness prediction tool (Dagan-Wiener et al, in revision). It predicts 70% of FDA-approved drugs, but less than 40% of toxic compounds, to be bitter. Additionally, bitter compounds have higher LD50 values (indicating less toxicity) than toxic compounds, challenging the paradigm "bitterness signals toxicity".
Interestingly, bitter mouth-rinse leads to lower PANAS mood scores and the effect depends on perceiving the solution as bitter, raising further questions about bitterness in the context of food consumption5.
In summary, we explore the selectivity of bitter compounds towards their receptors, and show that the bitterness-toxicity overlap is partial. This supports the idea that activation of bitter taste receptors, which are expressed both orally and extra-orally, has physiological roles beyond alerting against poisons.
[1] Wiener, A., Shudler, M., Levit, A., and Niv, M. Y. (2012) BitterDB: a database of bitter compounds, Nucleic acids research 40, D413-419.
[2] Di Pizio, A., and Niv, M. Y. (2014) Computational Studies of Smell and Taste Receptors, Israel Journal of Chemistry 54, 1205-1218.
[3] Levit, A., Nowak, S., Peters, M., Wiener, A., Meyerhof, W., Behrens, M., and Niv, M. Y. (2014) The bitter pill: clinical drugs that activate the human bitter taste receptor TAS2R14, Faseb J 28, 1181-1197.
[4] Di Pizio, A., and Niv, M. Y. (2015) Promiscuity and selectivity of bitter molecules and their receptors, Bioorg Med Chem 23, 4082-4091.
[5] Dubovski, N., Ert, E., and Niv, M. Y. (2017) Bitter mouth-rinse affects emotions, Food Quality and Preference 60, 154-164.