Sweet-taste receptor, model

The experimental data suggest that sweetness and bitterness are recognized at the same receptor. Furthermore, the receptor discriminates between bitter and sweet tastes based upon differences in functional unit combination. A new taste receptor model is proposed and presented. 

The low energy sweetening properties of aspartame have been discussed on the basis of structural relationships [1, 83] within the context of the three point contact model of the sweet taste receptor. This model involves a hydrogen bond donor, a hydrogen bond acceptor, and a hydrophobic region with specific geometric relationships. The model accounts for the fact that only one of the four diastereomers of aspartylphenylalanyl methyl ester is sweet. 

FIGURE 4 Three of the most popular indirect models of the active site of the sweet taste receptor. (A) Main contour ofthe active site proposed by Temussi and coworkers (Kamphuis et al., 1992 Temussi et al., 1978,1984,1991), hosting a molecular model of aspartame in an extended conformation. (B) A topological model, developed by Goodman et al. (1987). The L -shaped model and an L -shaped conformation of aspartame are superimposed. The hydrophobic side chain of Phe is denoted X, since it corresponds to the Kier s dispersion point. (C) 3D model of an idealized sweetener proposed by Tinti and Nofre (1991). Besides the AH-B entity, the model has six additional interaction points connected by a complex network of distances. 

The very likely presence in the sweet taste receptor of cavities similar to those hosting Glu in mGluRl, a metabotropic glutamate receptor of known structure (Kunishima et al., 2000), tells us that the sweet taste of small molecular weight sweeteners can certainly be accounted for, even if the details will remain in part obscure, at least till a receptor structure with better resolution than homology models will be available. Can the taste of sweet proteins be also explained by the knowledge of the receptor There is no obvious answer. Let us first examine possible receptor models in detail. 

B. Computer-generated models ofthe sweet taste receptor... 

Early indirect models of the active site of the sweet taste receptor tried to... 

Holtje, H.-D., Kier, L. B. Sweet taste receptor studies using model interaction energy calculations. J. Pharm. Sci. 1974, 63, 1722-1725. 

The latest model for the sweet-taste receptor, proposed by Piero Temussi of the University of Naples, postulates that there are four binding sites on the receptor that can be occupied independently. Small sweet-tasting molecules might bind to one of the sites, while a large molecule would bind to more than one site simultaneously. 

CSPs [27], In biological systems, the TPI model was first successfully applied by Ogston to explain the enzymatic formation of ketoglutarate from achiral citrate and decarboxylation of L-serine to glycine by enzymes [28], Based on the same principle, Shallenberger et al. [29] established a similar model to explain how a sweet-taste receptor of the tongue distinguished D- and L-amino acids. In medicinal chemistry, the TPI model is a key element in structure-activity relationship studies [30],... 

An alternative view (123) is that no single model can adequately explain why any given compound is sweet. This hypothesis derives from several features. First, there is the observation that all carbohydrates having a critical ratio of OH to C are sweet tasting. In other words, there are no stmctural constraints to the sweetness of carbohydrates. Second, not all sweeteners can be fit to the same SAR model. Rather, some fit one, others fit another. Third, studies on the transduction mechanisms of sweetness suggest more than a single mechanism for sweet taste, implying multiple receptors for sweeteners. 

However, the model is defined such that the terms ir, a, fi, and a may all be measures of different types of receptor-sweetener binding. These all reflect the probability of that event s occurring, while, at the same time, the probability of the sweetener s reaching its receptor, and that of the receptor complex s undergoing the response-eliciting reaction, may both be unity The sole criterion for the sweet-taste response would thus require the formation of the proper sweetener-receptor complex. The validity of such a hypothesis has yet to be proved. " ... 

Fig. 3. The Model of Sweetness and Bitterness Production at the Taste Receptor...

Sweet taste is produced by a wide variety of compounds. SHAL-LENBERGER and ACREE (6) regard an acid/base system (AH/B-System) as the shared structural element. This system must satisfy certain steric conditions and can interact with a complementary system of a receptor via 2 hydrogen bonds (Fig. 1). KIER (7) expanded this model by assuming an additional interaction witfi an apolar group X in a suitable position (Fig. 1). Both models are applicable to compounds with great variations in structure. There are no similar comprehensive concepts for bitter compounds which can also occur in the most varying chemical classes. 

In Ama-L-Phe-OMe (47) (14, 15), it is also not known whether the sweet-tasting isomer has the L-L(or S-S) or the D-L(or R-S) configuration. In the case of aspartyl dipeptide esters, the L-L isomer was sweet. By analogy, other researchers deduced that the L-L(or S-S) isomer ((47b) in Figure 4) would be sweet. However, it seemed to us that the D(or i )-configuration would be preferred for the aminomalonic acid because the D-L(or R-S) isomer ((47a) in Figure 4) was compatible with the sweet formula and could also fit the spatial barrier model (13), whereas the L-L(or S-S) isomer could neither fit the receptor model nor meet the sweet formula. 

The above discussions, in conjunction with previous results, support our previous idea that the receptor site for sweet taste is composed of the AH-B-X system and its most likely shape is a "pocket" as shown in Figure 6 (5). In this model, the spatial... 

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