In Silico Molecular Study of Tryptophan Bitterness

Pizio, Antonella Di; Nicoli, Alessandro

doi:10.3390/molecules25204623

Cited by 13 publications

(6 citation statements)

References 52 publications

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“…To optimize the binding site, we need to sample the conformational space allowing for residue flexibility. For this purpose, we used induced-fit docking (IFD), an approach that was already applied to GPCR models, including ORs. − Using this technique, we can select specific residues to be sampled by excluding regions of uncertain modeling. On the contrary, MD simulations can optimize the binding site while considering the entire structure’s flexibility, and this is highly affected by the quality of the model. , We performed IFD simulations with the most active compounds (compound 1 ) for both AF2 and HM, allowing the binding site side chains to be flexible.…”

Section: Resultsmentioning

confidence: 99%

Modeling the Orthosteric Binding Site of the G Protein-Coupled Odorant Receptor OR5K1

Nicoli

Haag

Marcinek

et al. 2023

J. Chem. Inf. Model.

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With approximately 400 encoding genes in humans, odorant receptors (ORs) are the largest subfamily of class A G protein-coupled receptors (GPCRs). Despite its high relevance and representation, the odorant-GPCRome is structurally poorly characterized: no experimental structures are available, and the low sequence identity of ORs to experimentally solved GPCRs is a significant challenge for their modeling. Moreover, the receptive range of most ORs is unknown. The odorant receptor OR5K1 was recently and comprehensively characterized in terms of cognate agonists. Here, we report two additional agonists and functional data of the most potent compound on two mutants, L104 3.32 and L255 6.51 . Experimental data was used to guide the investigation of the binding modes of OR5K1 ligands into the orthosteric binding site using structural information from AI-driven modeling, as recently released in the AlphaFold Protein Structure Database, and from homology modeling. Induced-fit docking simulations were used to sample the binding site conformational space for ensemble docking. Mutagenesis data guided side chain residue sampling and model selection. We obtained models that could better rationalize the different activity of active (agonist) versus inactive molecules with respect to starting models and also capture differences in activity related to minor structural differences. Therefore, we provide a model refinement protocol that can be applied to model the orthosteric binding site of ORs as well as that of GPCRs with low sequence identity to available templates.

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Section: Resultsmentioning

confidence: 99%

Modeling the Orthosteric Binding Site of the G Protein-Coupled Odorant Receptor OR5K1

Nicoli

Haag

Marcinek

et al. 2023

J. Chem. Inf. Model.

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“…We recently modeled and analyzed the orthosteric binding site of TAS2R4; 51 this structure was used here for the docking analysis of GA. Specifically, we used TAS2R4 in complex with tryptophan.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

Astringent Gallic Acid in Red Wine Regulates Mechanisms of Gastric Acid Secretion via Activation of Bitter Taste Sensing Receptor TAS2R4

Sterneder

Stoeger

Dugulin

et al. 2021

J. Agric. Food Chem.

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Red wine is rich in phenolic compounds, which chiefly determine its characteristic taste. One of its major phenolic acid constituents for which an astringency, yet no clear contribution to bitter taste has been reported, is gallic acid (GA). In previous studies, we have demonstrated bitter-tasting constituents to regulate cellular proton secretion (PS) as a key mechanism of gastric acid secretion via activation of bitter taste sensing receptors (TAS2Rs). Here, we hypothesized a contributing role of GA to the red wine-stimulated effect on PS in human gastric tumor cells (HGT-1 cells). Sensory analyses revealed that 10 μM GA as the lowest concentration tested more bitter than tap water, with increasing bitter ratings up to 1000 μM. In HGT-1 cells, the concentration of 10 μM GA evoked the most pronounced effect on PS secretion, either when added to cells as in-water solution or when spiked to a red wine matrix. GA-spiking of Zweigelt and Blaufrankisch red wine samples up to a concentration of 10 μM resulted in an equally stimulated PS, whereas the non-GA-spiked wine samples demonstrated contrary effects on PS, indicating a functional role of GA on PS. Involvement of TAS2R4 in the GA-induced PS was verified by means of an HGT-1 homozygote CRISPR-Cas9 TAS2R4 knockout approach. Moreover, gene expression analyses revealed GA to increase TAS2R4. These results demonstrate a functional role of TAS2R4 in GA-evoked PS as a key mechanism of gastric acid secretion aiding digestion. Moreover, our data provide mechanistic insights, which will help to produce stomach-friendly red wines.

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“…Tryptophan and phenylalanine, derived from the chorismate pathway, are essential amino acids known for their strong bitterness in previous studies [ 56 , 57 ]. In P. juliae , we observed a significant accumulation of tryptophan and phenylalanine during leaf maturation.…”

Section: Discussionmentioning

confidence: 99%

Combined full-length transcriptomic and metabolomic analysis reveals the molecular mechanisms underlying nutrients and taste components development in Primulina juliae

Zhang,

Yang,

Liu

et al. 2024

BMC Genom Data

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Background Primulina juliae has recently emerged as a novel functional vegetable, boasting a significant biomass and high calcium content. Various breeding strategies have been employed to the domestication of P. juliae. However, the absence of genome and transcriptome information has hindered the research of mechanisms governing the taste and nutrients in this plant. In this study, we conducted a comprehensive analysis, combining the full-length transcriptomics and metabolomics, to unveil the molecular mechanisms responsible for the development of nutrients and taste components in P. juliae. Results We obtain a high-quality reference transcriptome of P. juliae by combing the PacBio Iso-seq and Illumina sequencing technologies. A total of 58,536 cluster consensus sequences were obtained, including 28,168 complete protein coding transcripts and 8,021 Long Non-coding RNAs. Significant differences were observed in the composition and content of compounds related to nutrients and taste, particularly flavonoids, during the leaf development. Our results showed a decrease in the content of most flavonoids as leaves develop. Malate and succinate accumulated with leaf development, while some sugar metabolites were decreased. Furthermore, we identified the different accumulation of amino acids and fatty acids, which are associated with taste traits. Moreover, our transcriptomic analysis provided a molecular basis for understanding the metabolic variations during leaf development. We identified 4,689 differentially expressed genes in the two developmental stages, and through a comprehensive transcriptome and metabolome analysis, we discovered the key structure genes and transcription factors involved in the pathways. Conclusions This study provides a high-quality reference transcriptome and reveals molecular mechanisms associated with the development of nutrients and taste components in P. juliae. These findings will enhance our understanding of the breeding and utilization of P. juliae as a vegetable.

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In Silico Molecular Study of Tryptophan Bitterness

Cited by 13 publications

References 52 publications

Modeling the Orthosteric Binding Site of the G Protein-Coupled Odorant Receptor OR5K1

Modeling the Orthosteric Binding Site of the G Protein-Coupled Odorant Receptor OR5K1

Astringent Gallic Acid in Red Wine Regulates Mechanisms of Gastric Acid Secretion via Activation of Bitter Taste Sensing Receptor TAS2R4

Combined full-length transcriptomic and metabolomic analysis reveals the molecular mechanisms underlying nutrients and taste components development in Primulina juliae

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