Sweet dipeptide

Fig. 3. Structure—activity summary of dipeptide sweeteners, where n may be 0 or 1 (62). There are no known replacements for the acid or amide groups denoted by arrows, although thioamide has some sweetness. If the NH2 is replaced by NHC(0)R, the potency is increased when...

Aspartame, a nonnutritive sweetener marketed under the trade name Nutra-Sweet (among others), is the methyl ester of a simple dipeptide, Asp-Phe-OCH.3. 

Lindley proposed an oblique, planar, stereogeometric arrangement between AH,B and y that is strikingly similar to Kier s tripartite glucophore, with distance and direction parameters as shown in Fig. 12. A similar y site for other sweeteners, such as the sweet dipeptides, has also been proposed, and it appears that the location of y in relation to AH,B is directional rather than positional. 

The binding specificity of d-[ C]glucose by the taste-papillae membranes, compared to that of control membranes isolated from epithelial tissue, has been confirmed in two studies. One inherent problem in the approach is that the stimuli, primarily carbohydrate sweeteners, are not ideal model compounds to use, as they are not active at low concentrations and do not show sufficiently high binding-constants. The use of other stimulus compounds that are at least several hundred times sweeter than sucrose, such as saccharin, dihydrochalcone sweeteners, dipeptide sweeteners, stevioside, perillartine and other sweet oximes, the 2-substituted 5-nitroanilines, and... 

Aspartame is the most successful and widely used artificial sweetener. It is roughly 100 times as sweet as cane sugar. It is methyl ester of dipeptide formed from aspartic acid and phenylalanine. Use of aspartame is limited to cold foods and soft drinks because it is unstable at cooking temperature. 

Other Food Industries. Aspartame is a synthetic dipeptide ester, L-asp-L-phe-OMe which is about 200 times as sweet as sucrose. It has recently been released for sale in North America and Europe by G. D. Searle. It was originally synthesized chemically and reported by Mazur et al. 38). Subsequent improved methods of synthesis have been developed which involve the use of metalloproteases such as thermolysin in reverse . Metalloproteases are used because, unlike the more common proteases, they have no esterase activity. 

During work on a series of aspartyl dipeptides containing ACC 71 (vide supra, Eq. (28), Sect. 4) at the carboxyl terminus, it was reported that dispartame Asp-ACC-OMe had a distinct sweet taste [302] and that the corresponding n-propyl ester had 250-300 times the sweetness of sucrose [303]. However, replacement of phenylalanine by 2,3-methanophenylalanine gave tasteless analogues of aspartame [293, 304], and some dimethyl-ACC 214 (methanovaline) and tri-methyl-ACC 215 aspartame analogues [Asp-(Me)n-ACC-OMe] have a bitter taste. These taste properties, which depend on the number and position of the methyl substituents, have been explained on the basis of topochemical models thus, a L-shaped conformation of the dipeptide is necessary for sweet taste, Eq. (86) [3051. 

Aspartame is a high intensity dipeptide sweetener, ca. 200 times as sweet as sncrose. It was originally developed by G.D.Searle Co. prior to their acqnisition by Monsanto. Chemically synthesised aspartame has rapidly acqnired a major share of the world high intensity sweetener market, particnlarly in soft drinks. Until recently it has all been snpplied by a monopoly snpplier, the Nntrasweet Corp (a Monsanto-AJinomoto joint ventnre) protected by prodnct patents. Recently biocatalytic methods... 

Taste of Dipeptides Containing Lys and/or Gly. Since Lys-Gly HCl produces the saltiness, we prepared some dipeptides composed of Lys and/or Gly. The results are listed in Table XI. Gly-Lys, of which the amino acid sequence is opposite to the salty peptide Lys-Gly-HCl, produced a weakly sweet taste instead of the salty taste. Dipeptide composed of only Lys or Gly did not any taste. 

Aspartame, sweetness production, 28-30 Aspartic acid, as food material, 138-147 Aspartic acid dipeptides, taste, 141-142r Astringpncy, sensation based on generalized membrane responses, 16-18 Automated data analysis and pattern recognition tool kit, 102... 

Iwamura(51) has investigated the structure-sweetness relationship in four classes of L-aspartyl dipeptides using linear free energy descriptors and multi-dimensional regression analysis. In essence, the Hansch methodology was employed. The four classes of compounds are - ... 

The analysis, in composite over the four classes of L-aspartyl dipeptides suggests that the electron-withdrawing effect of substituents directed to the peptide bond, and the steric dimensions of the molecules, are important in eliciting the sweet taste. The values of the regression coefficients of the a term in the QSAR equations for L-aspartic acid amides, L-aspartylaminoethylesters, and L-aspartylaminopropionates all... 

Aspartame. Aspartame [22839-47-0] [53906-69-1] (APM, L-aspartyl-L-phenylalanine methyl ester) (1), also known under the trade names of NutraSweet and EQUAL, is the most widely used nonnutritive sweetener worldwide. This dipeptide ester was synthesized as an intermediate for an antiulcer peptide at G. D. Searle in 1965. Although this compound was known in the literature, its sweet taste was serendipitously discovered when a chemist licked his finger which was contaminated with it. Many analogues, especially the more stable esters, were made (6) and their taste qualities and potencies determined. It was the first compound to be chosen for commercial development. Following the purchase of G. D. Searle by Monsanto, the aspartame business was split off to become a separate Monsanto subsidiary called the NutraSweet Company. 

Other peptides, such as L-aspartyl-L-phenylalanine methyl ester (aspartame), have a sweet taste. Several studies have been carried out to relate the structure and taste of analogs of this dipeptide (25). Tsang et al. (26) reported that the analogs at the lower end of the L-aspartyl-a-aminocycloalkanecarboxylic acid methyl ester series were sweet, the dipeptides containing a-... 

Aspartame is a diastereomeric dipeptide ester, with the two asymmetric carbons ( ) being derived from (Z)-amino acids. The other three diastereomers of aspartame (the D.D-, D,L- and L,D- diastereomers) are not sweet. The three dimensional structure of aspartame in the zwitterionic form can be depicted in the following stereoscopic figure ... 

The sweet dipeptide esters of the L-aspartic acid and the L-amino malonic acid (15-21) are interesting exceptions to the bitter taste shared by all other members of the peptide series. Fig. 

After the finding of a sweet taste in L-Asp-L-Phe-OMe (aspartame) by Mazur et at. (6), a number of aspartyl dipeptide esters were synthesized by several groups in order to deduce structure-taste relationships, and to obtain potent sweet peptides. In the case of the peptides, the configuration and the conformation of the molecule are important in connection with the space-filling properties. The preferred conformations of amino acids can be shown by application of the extended Hiickel theory calculation. However, projection of reasonable conformations for di- and tripeptide molecules is not easily accomplished. 

In the course of investigations of aspartyl dipeptide esters, we had to draw their chemical structures in a unified formula. In an attempt to find a convenient method for predicting the sweettasting property of new peptides and, in particular, to elucidate more definite structure-taste relationships for aspartyl dipeptide esters, we previously applied the Fischer projection technique in drawing sweet molecules in a unified formula 04). 

The sweet-tasting property of aspartyl dipeptide esters has been successfully explained on the basis of the general structures shown in Figure 1 (4). A peptide will taste sweet when it takes... 

The structure-taste relationships will be discussed in detail. Dipeptide esters are closely related to amino acids in chemical structure and properties. Hence, we selected amino acids as the standard to which sweet peptides were related. The structural features of sweet-tasting amino acids have been best explained by Kaneko (12) as shown in Figure 2, in which an amino acid will taste sweet when R2 is H, CH3 or C2H5, whereas the size of Ri is not restricted if the amino acid is soluble in water. 

The studies on peptides began with a correlation between sweet amino acids and peptides. Since the projection formula of L-Asp-Gly-OMe (4) is similar in size and shape to that of e-Ac-D-Lys (3) which is sweet, we predicted that L-Asp-Gly-OMe would taste sweet in spite of the bitter taste in the literature. Therefore, we synthesized the peptide and tasted it. As expected, it was sweet and its sweetness potency was almost equal to that of e-Ac-D-Lys. Thus, the dipeptide could be correlated to the amino acid. Lengthening (5) or enlargement (6) of the alkyl group of the ester did not affect its sweetness potency (Table 1). 

Therefore, we have concluded that sweet-tasting aspartyl dipeptide esters can be drawn as the unified formula (A), whereas nonsweet peptides as (B) as shown in Figure 1. 

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. 

Further examinations of the molecular features and of the model of receptor have suggested that several aspartyl tripeptide esters may also taste sweet. In confirmation of the idea, several tripeptide esters have been synthesized. In the first place, L-Asp-Gly-Gly-OMe (38) was synthesized as an arbitrarily-selected standard of tripeptides, because it was considered that this peptide ester had the simplest structure, and correlation of other peptides to (38) was easy. The tripeptide ester was predicted that it would be slightly sweet or tasteless because its projection formula was similar in size and shape to that of L-Asp-Gly-0Bum which is 13 times sweeter than sucrose (16) and because it is more hydrophilic than the dipeptide. The tripeptide (38) was devoid of sweetness and almost tasteless. 

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