The binding site for neohesperidin dihydrochalcone at the human sweet taste receptor

Winnig, Marcel; Bufe, Bernd; Kratochwil, Nicole A.; Slack, Jay P.; Meyerhof, Wolfgang

doi:10.1186/1472-6807-7-66

Cited by 128 publications

(129 citation statements)

References 45 publications

(74 reference statements)

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“…Also, sweetness inhibition was overcome at higher concentrations of sucrose and cyclamate. This observation is consistent with competitive inhibition, similar to previously studied sweet taste inhibitors (Schiffman et al 1999;Winnig et al 2007). The highest molar concentrations of sucrose and cyclamate used in this study were greater than those of acesulfame K and sucralose.…”

Section: Discussionsupporting

confidence: 77%

Lipid-Lowering Pharmaceutical Clofibrate Inhibits Human Sweet Taste

Kochem

Breslin

2016

CHEMSE

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T1R2-T1R3 is a heteromeric receptor that binds sugars, high potency sweeteners, and sweet taste blockers. In rodents, T1R2-T1R3 is largely responsible for transducing sweet taste perception. T1R2-T1R3 is also expressed in non-taste tissues, and a growing body of evidence suggests that it helps regulate glucose and lipid metabolism. It was previously shown that clofibric acid, a blood lipid-lowering drug, binds T1R2-T1R3 and inhibits its activity in vitro. The purpose of this study was to determine whether clofibric acid inhibits sweetness perception in humans and is, therefore, a T1R2-T1R3 antagonist in vivo. Fourteen participants rated the sweetness intensity of 4 sweeteners (sucrose, sucralose, Na cyclamate, acesulfame K) across a broad range of concentrations. Each sweetener was prepared in solution neat and in mixture with either clofibric acid or lactisole. Clofibric acid inhibited sweetness of every sweetener. Consistent with competitive binding, inhibition by clofibric acid was diminished with increasing sweetener concentration. This study provides in vivo evidence that the lipid-lowering drug clofibric acid inhibits sweetness perception and is, therefore, a T1R carbohydrate receptor inhibitor. Our results are consistent with previous in vitro findings. Given that T1R2-T1R3 may in part regulate glucose and lipid metabolism, future studies should investigate the metabolic effects of T1R inhibition.

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Section: Discussionsupporting

confidence: 77%

Lipid-Lowering Pharmaceutical Clofibrate Inhibits Human Sweet Taste

Kochem

Breslin

2016

CHEMSE

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“…[34,35] In later work, Meyerhof and co-workers demonstrated that the T1R3 TMD is also the site for binding of the sweetener neohesperidin dihydrochalcone. [36] 2006: The Three Binding Site Sweetener Receptor Model. A collaborative team of the Max, Margolskee, and Osman groups developed a model of the T1R2/T1R3 receptor where some small molecule sweeteners (e.g.…”

Section: -2006mentioning

confidence: 99%

Validity of early indirect models of taste active sites and advances in new taste technologies enabled by improved models

DuBois

2011

Flavour & Fragrance J

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The relationship between chemical structure and taste has always been a subject of keen interest to chemists. In an effort to rationalize these relationships, chemists have built models, particularly for sweeteners and the sweetener receptor. Early models were exclusively pharmacophore models but, later, receptor models and even computational models with predictive capability were developed. In this paper, models for all the five primary tastes are reviewed. In recent years, the receptors which mediate sweet, bitter and umami (savoury) taste have been identified. The receptors mediating sour and salty tastes, however, are still not known with certainty. The current states of knowledge on the receptors which mediate all five taste modalities are reviewed. Then a perspective is provided on the validity of the models developed. The sequencing of the human genome has enabled great advances in our understanding of the receptors which initiate taste responses. Yet, there remains much we do not understand. A listing of questions still unanswered is provided. Finally, a discussion is provided of new technologies enabled by an advanced understanding of sweetener and bitterant receptors. Specifically, positive allosteric modulators of the sweetener receptor have been identified which enable dramatic reduction in the concentrations of carbohydrate sweeteners while, at the same time, retaining the high quality taste of carbohydrate sweeteners. In addition, bitterness inhibitors have been identified which may have value in the reduction of the negative taste attributes of some foods and beverages. Lastly, an improved understanding of the bio-rationale for the slow sweetness onset and sweetness linger of high-potency sweeteners has led to an approach to improvement of their tastes.

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“…Sensitivity to brazzein requires the CRD of hT1R3 as well as the ATD of hT1R2 (15,16). The TMD of hT1R3 is required for sensitivity to cyclamate, neohesperidin dihydrochalcone, and the sweet inhibitor lactisole (17)(18)(19).…”

mentioning

confidence: 99%

Molecular Mechanisms for Sweet-suppressing Effect of Gymnemic Acids

Sanematsu

Kusakabe

Shigemura

et al. 2014

Journal of Biological Chemistry

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Background: Gymnemic acids inhibit sweet taste responses in humans. Results: Gymnemic acids and glucuronic acid inhibited human sweet receptor T1R2 ϩ T1R3. Conclusion: Interaction between transmembrane domains of human T1R3 and the glucuronosyl group of gymnemic acids is mainly required for the sweet-suppressing effect. Significance: Our model may provide further insights into drug design to modify sensitivity of sweet receptor.

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The binding site for neohesperidin dihydrochalcone at the human sweet taste receptor

Cited by 128 publications

References 45 publications

Lipid-Lowering Pharmaceutical Clofibrate Inhibits Human Sweet Taste

Lipid-Lowering Pharmaceutical Clofibrate Inhibits Human Sweet Taste

Validity of early indirect models of taste active sites and advances in new taste technologies enabled by improved models

Molecular Mechanisms for Sweet-suppressing Effect of Gymnemic Acids

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