Bitter taste is an innately aversive taste modality that is considered to protect animals from consuming toxic compounds. Yet, bitterness is not always noxious and some bitter compounds have ...beneficial effects on health. Hundreds of bitter compounds were reported (and are accessible via the BitterDB http://bitterdb.agri.huji.ac.il/dbbitter.php ), but numerous additional bitter molecules are still unknown. The dramatic chemical diversity of bitterants makes bitterness prediction a difficult task. Here we present a machine learning classifier, BitterPredict, which predicts whether a compound is bitter or not, based on its chemical structure. BitterDB was used as the positive set, and non-bitter molecules were gathered from literature to create the negative set. Adaptive Boosting (AdaBoost), based on decision trees machine-learning algorithm was applied to molecules that were represented using physicochemical and ADME/Tox descriptors. BitterPredict correctly classifies over 80% of the compounds in the hold-out test set, and 70-90% of the compounds in three independent external sets and in sensory test validation, providing a quick and reliable tool for classifying large sets of compounds into bitter and non-bitter groups. BitterPredict suggests that about 40% of random molecules, and a large portion (66%) of clinical and experimental drugs, and of natural products (77%) are bitter.
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•l-glucose activates the sweet taste receptor TAS1R2/TAS1R3 in cells.•Modeling suggests two sub-pockets in the orthosteric binding site of TAS1R2, each capable of accommodating each ...one of glucose enantiomers.•Lack of stereospecificity stems from multiple hydroxyls in glucose molecules and in each of the sub-pockets.•d- and l-glucose have similar sensory detection thresholds and are perceived as similarly sweet at suprathreshold concentrations.
Naturally occurring sugars usually have d-chirality. While a change in chirality typically affects ligand–receptor interaction, non-caloric l-glucose was reported as sweet for humans. Here we show that l- and d-glucose have similar sensory detection thresholds (0.041 ± 0.006 M for d-glucose, and 0.032 ± 0.007 M for l-glucose) and similar sweetness intensities at suprathreshold concentrations. We demonstrate that l-glucose acts via the sweet taste receptor TAS1R2/TAS1R3, eliciting a dose-dependent activation in cell-based functional assays. Computational docking of glucose to the VFT domain of TAS1R2 suggests two sub-pockets, each compatible with each of the enantiomers. While some polar residues (Y103, D142, N143, S144, Y215) are unique for sub-pocket A and others (D307, T326, E382, R383) for sub-pocket B, no interaction is unique for only one enantiomer. The many options for creating hydrogen bonds with the hydroxyl moieties of glucose explain how both enantiomers can fit each one of the sub-pockets.
An important question in taste research is how 25 receptors of the human TAS2R family detect thousands of structurally diverse compounds. An answer to this question may arise from the observation ...that TAS2Rs in general are broadly tuned to interact with numerous substances. Ultimately, interaction with chemically diverse agonists requires architectures of binding pockets tailored to combine flexibility with selectivity. The present study determines the structure of hTAS2R binding pockets. We focused on a subfamily of closely related hTAS2Rs exhibiting pronounced amino acid sequence identities but unique agonist activation spectra. The generation of chimeric and mutant receptors followed by calcium imaging analyses identified receptor regions and amino acid residues critical for activation of hTAS2R46, -R43, and -R31. We found that the carboxyl-terminal regions of the investigated receptors are crucial for agonist selectivity. Intriguingly, exchanging two residues located in transmembrane domain seven between hTAS2R46, activated by strychnine, and hTAS2R31, activated by aristolochic acid, was sufficient to invert agonist selectivity. Further mutagenesis revealed additional positions involved in agonist interaction. The transfer of functionally relevant amino acids identified in hTAS2R46 to the corresponding positions of hTAS2R43 and -R31 resulted in pharmacological properties indistinguishable from the parental hTAS2R46. In silico modeling of hTAS2R46 allowed us to visualize the putative mode of interaction between agonists and hTAS2Rs. Detailed structure-function analyses of hTAS2Rs may ultimately pave the way for the development of specific antagonists urgently needed for more sophisticated analyses of human bitter tasté perception.
Bitter taste is a basic taste modality, required to safeguard animals against consuming toxic substances. Bitter compounds are recognized by G-protein-coupled bitter taste receptors (TAS2Rs). The ...human TAS2R10 responds to the toxic strychnine and numerous other compounds. The mechanism underlying the development of the broad tuning of some TAS2Rs is not understood. Using comparative modeling, site-directed mutagenesis, and functional assays, we identified residues involved in agonist-induced activation of TAS2R10, and investigated the effects of different substitutions on the receptor's response profile. Most interestingly, mutations in S85(3.29) and Q175(5.40) have differential impact on stimulation with different agonists. The fact that single point mutations lead to improved responses for some agonists and to decreased activation by others indicates that the binding site has evolved to optimally accommodate multiple agonists at the expense of reduced potency. TAS2R10 shares the agonist strychnine with TAS2R46, another broadly tuned receptor. Engineering the key determinants for TAS2R46 activation by strychnine in TAS2R10 caused a loss of response to strychnine, indicating that these paralog receptors display different strychnine-binding modes, which suggests independent acquisition of agonist specificities. This implies that the gene duplication event preceding primate speciation was accompanied by independent evolution of the strychnine-binding sites.
Abstract
Deuterium oxide (D2O) is water in which the heavier and rare isotope deuterium replaces both hydrogens. We have previously shown that D2O has a distinctly sweet taste, mediated by the ...T1R2/T1R3 sweet taste receptor. Here, we explore the effect of heavy water on T1R2 and T1R3 subunits. We show that D2O activates T1R3-transfected HEK293T cells similarly to T1R2/T1R3-transfected cells. The response to glucose dissolved in D2O is higher than in water. Mutations of phenylalanine at position 7305.40 in the transmembrane domain of T1R3 to alanine, leucine, or tyrosine impair or diminish activation by D2O, suggesting a critical role for T1R3 TMD domain in relaying the heavy water signal.
In humans, bitterness perception is mediated by ~25 bitter taste receptors present in the oral cavity. Among these receptors three, TAS2R10, TAS2R14 and TAS2R46, exhibit extraordinary wide agonist ...profiles and hence contribute disproportionally high to the perception of bitterness. Perhaps the most broadly tuned receptor is the TAS2R14, which may represent, because of its prominent expression in extraoral tissues, a receptor of particular importance for the physiological actions of bitter compounds beyond taste.
To investigate how the architecture and composition of the TAS2R14 binding pocket enables specific interactions with a complex array of chemically diverse bitter agonists, we carried out homology modeling and ligand docking experiments, subjected the receptor to point-mutagenesis of binding site residues and performed functional calcium mobilization assays.
In total, 40 point-mutated receptor constructs were generated to investigate the contribution of 19 positions presumably located in the receptor's binding pocket to activation by 7 different TAS2R14 agonists. All investigated positions exhibited moderate to pronounced agonist selectivity.
Since numerous modifications of the TAS2R14 binding pocket resulted in improved responses to individual agonists, we conclude that this bitter taste receptor might represent a suitable template for the engineering of the agonist profile of a chemoreceptive receptor.
The detailed structure-function analysis of the highly promiscuous and widely expressed TAS2R14 suggests that this receptor must be considered as potentially frequent target for known and novel drugs including undesired off-effects.
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•Determination of bitter agonist-receptor contacts involved in TAS2R14 activation.•All 40 receptor mutants retained responsiveness for at least one of the 7 test agonists.•Almost all receptor positions exhibit highly selective agonist interactions.•Numerous mutations improved potency and/or efficacy of individual agonists.•Extraordinary promiscuity of TAS2R14 explained by flexibility of binding site.
Subjectively perceived impairment of taste is a common and distinct symptom of coronavirus disease 2019 (COVID‐19). Large meta‐analyses identified this symptom in approximately 50% of cases. However, ...this high prevalence is not supported by blinded and validated psychophysical gustatory testing, which showed a much lower prevalence in up to 26% of patients. This discrepancy may be due to misinterpretation of impaired retronasal olfaction as gustatory dysfunction. In addition, we hypothesized that COVID‐19–associated hyposmia is involved in the decrease of gustatory function, as found for hyposmia of different origin. This indirect mechanism would be based on the central‐nervous mutual amplification between the chemical senses, which fails in COVID‐19–associated olfactory loss. However, further research is necessary on how severe acute respiratory syndrome‐coronavirus‐2 (SARS‐CoV‐2) may directly impair the gustatory pathway as well as its subjective perception.
•Isolation and synthesis of 28 saponins by a sensomics approach from Glycyrrhiza glabra.•Structural characterization of two unknown saponins in Glycyrrhiza glabra.•Structural features, e.g., ...triterpenoid E-ring, important for different taste sensations.•Triterpenoid E-ring important for sweet receptor hTAS1R2/R3 stimulation.•Licorice sensation not mediated by hTAS1R2/R3 sweet or hTAS2R bitter receptors.
Licorice saponins, the main constituents of Glycyrrhiza glabra L. roots, are highly appreciated by the consumer for their pleasant sweet and long lasting licorice taste. The objective of the present study was to understand the molecular features that contribute to bitter, sweet and licorice sensation of licorice roots, and whether individual compounds elicit more than one of these sensations. Therefore, a sensomics approach was conducted, followed by purification of the compounds with highest sensory impact, and by synthesis as well as full characterization via HRESIMS, ESIMS/MS and 1D/2D-NMR experiments. This led to the discovery and structure determination of 28 sweet, bitter and licorice tasting key phytochemicals, including two unknown compounds. A combination of sensorial, cell-based and computational analysis revealed distinct structural features, such as spatial arrangement of functional groups in the triterpenoid E-ring, driving to different taste sensations and sweet receptor hTAS1R2/R3 stimulation.
Bitter taste receptors (T2Rs) are G protein‑coupled receptors originally detected in the gustatory system. More recently, T2Rs have been shown to be expressed in extra‑oral cells eliciting ...non‑gustatory functions. Emerging evidence has suggested a potential role for T2R signaling in diverse pathophysiological conditions, including cancer. -The aim of the present study was to evaluate the expression of T2R14 in pancreatic ductal adenocarcinoma (PDAC) and to assess its involvement in the anticancer effects induced by apigenin, a natural ligand of T2R14. For this purpose, T2R14 expression was explored in PDAC tumor tissue and tumor‑derived cell lines. Using the cell lines expressing the highest levels of T2R14, its effects on chemoresponsiveness and migration upon activation with apigenin were investigated
. To the best of our knowledge, the present study was the first to confirm the expression of the T2R family member T2R14 in PDAC. Patients with relatively high levels of T2R14 expression exhibited significantly prolonged overall survival compared with that of patients with low T2R14 expression. Furthermore, novel functions for apigenin were revealed; notably, apigenin was shown to elicit cytotoxic, anti‑migratory and chemosensitizing effects to 5‑fluoruracil (5‑FU) and to 5‑FU, leucovorin, irinotecan and oxaliplatin in pancreatic cancer cells. In conclusion, the present study extended the evidence for the anticancer effects of apigenin and strongly indicated the functional relevance of T2R14 in PDAC, even though their respective underlying pathways appear to be independent of each other.
Bitter taste elicits an aversive reaction, and is believed to protect against consuming poisons. Bitter molecules are detected by the Tas2r family of G-protein-coupled receptors, with a ...species-dependent number of subtypes. Chickens demonstrate bitter taste sensitivity despite having only three bitter taste receptors-ggTas2r1, ggTas2r2 and ggTas2r7. This minimalistic bitter taste system in chickens was used to determine relationships between in-vitro (measured in heterologous systems) and in-vivo (behavioral) detection thresholds. ggTas2r-selective ligands, nicotine (ggTas2r1), caffeine (ggTas2r2), erythromycin and (+)-catechin (ggTas2r7), and the Tas2r-promiscuous ligand quinine (all three ggTas2rs) were studied. Ligands of the same receptor had different in-vivo:in-vitro ratios, and the ggTas2r-promiscuous ligand did not exhibit lower in-vivo:in-vitro ratios than ggTas2r-selective ligands. In-vivo thresholds were similar or up to two orders of magnitude higher than the in-vitro ones.
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