Aspartyl sweet-tasting

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. 

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 an intense sweetener first discovered in 1965 by J. Schlatter it is available under the brand names of Nutrasweet , Equal , and Canderel . Chemically, aspartame is N-L-a-aspartyl-L-phenylalanine methyl ester (Fig. 1), withamolecularformulaofC14H 805N2 (MW = 294.30). It is a white, odorless, crystalline powder. It is slightly soluble in water and sparingly soluble in alcohol. The solubility increases as the pH is lowered (2,6,57). It has 100-200 times the sweetness of sucrose and exhibits a sweet, clean taste and a sweetness profile similar to that of sucrose, without bitter or metallic aftertaste (Table 1). However, it displays a slow onset of sweetness coupled with lingering sweet taste. It extends and intensifies tastes and enhances fruit flavors. Aspartame exhibits synergism, a superior taste profile, and improved stability when used with other sweeteners (1,4,14,55,75). 

Alitame [L- -aspartyl-/V-(2,2,4,4-tetramethyl-3-thioethanyl)-D-alaninamide] is an amino acid-based sweetener developed by Pfizer from L-aspartic acid, D-alanine, and an amine 2,2,4,4-tetraethylthioethanyl amine (Fig. 1). Its formula is CI4H2504N3S with a molecular weight of 331.06. It is produced under the brand name Aclame . It is a crystalline, odorless, nonhygro-scopic powder that is soluble in water (130 g/L at pH 5.6) and alcohol and significantly more stable than aspartame (Table 1). Alitame is 2000 times as sweet as sucrose and has a clean, sweet taste, with no unpleasant aftertaste. It blends with other sweeteners, such as acesulfame-K, saccharin, and cyclamate, to maximize the quality of sweetness (3,7-9). 

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. 

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... 

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. 

Finally, L-Asp-D-Val-Gly-OMe (41) was synthesized in order to see whether it remained sweet. The peptide was devoid of sweetness and almost tasteless, though D-valine-containing aspartyl dipeptide esters such as L-Asp-D-Val-0Pr (17) and L-Asp-D-Val-OPrt (8, 17), which are similar to the tripeptide ester in size and shape and have potent sweet taste. 

Alitame [L-a-aspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alaninamide] is a sweetener based on an amino acid. It is a very intense sweetener, possessing a sweetening power of about 2000 times that of sucrose. It also exhibits a clean sweet taste similar to sucrose. Although it is metabolized, so little is needed that its caloric contribution is insignificant. Alitame is prepared from the amino acids, L-aspartic acid, D-alamine, and a novel amine [9]. 

Lelj, F., Tancredi, T., Temussi, P.A., and Toniolo, C. (1976). Interaction of alpha-L-aspartyl-L-phenylalanine methyl ester with the receptor site of the sweet taste bud. J. Amer. Chem. Soc. 98,6669-6675. 

A sweetener must be soluble in water and the molecule must bind readily to a specific kind of receptor molecule at the surface of the tongue. The receptor is coupled to a G-protein, which dissociates when the sweetener binds to the receptor, activating a nearby enzyme, and triggering a sequence of events resulting in signals that are carried to and interpreted by the brain. The sweetness signal depends on this interaction between receptor and sweetener. The importance of molecular shape to sweemess is illustrated by the case of aspartame, as its stereo isomer, L-aspartyl-D-phenylalanine methyl ester, has a bitter, not a sweet, taste. 

In human nutrition, free amino acids play an important role in aromatisa-tion, as flavour enhancers, and as sweeteners. Monosodium glutamate, in concentrations of 0.1-0.4%, is probably the most prominent flavour enhancer for spices, soups, sauces, meat and fish. (L)-Cysteine amplifies the flavour of onions. Glycine is used to mask the aftertaste of saccharin. Whereas (L)-amino acids may taste slightly bitter, the (D)-enantiomers have a sweet taste. This is in general also true for the corresponding di- and oligopeptides - except for the methyl ester of (L)-aspartyl-(L)-phenylalanine (Aspartame). 

The sweet taste of aspartic acid dipeptide esters (I) was discovered by chance in 1969 for a-L-aspartyl-L-phenylalanine methyl ester ( Aspartame , NutraSweet ). The corresponding peptide ester of L-aminomalonic acid (II) is also sweet. 

Aspartame was discovered by accident by Jim Schlatter, a chemist at G.D. Searle in 1965. Jim Schlatter was working on drugs for the treatment of gastric ulcers when he spilled some aspartyl-phenylalanine on his hand. He later licked his finger and noticed the sweet taste of the compound, which later became aspartame. Aspartame is the methyl ester of the dipeptide of the natural amino acids L-aspartic acid and L-phenylalanine. There are four possible diastereoiso-mers for aspartame but aspartame is the only one having sweetening properties. The taste of aspartame would not have been predictable based on its amino acid constituents. 

Some peptides have special tastes. L-Aspartyl phenylalanine methyl ester is very sweet and is used as an artificial sweetener (see Sweeteners). In contrast, some oligopeptides (such as L-ornithinyltaurine HQ. and L-oriuthinyl-jB-alariine HQ), and glycine methyl or ethyl ester HQ have been found to have a very salty taste (27). 

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). 

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. 

Aspartame is a relatively new sweetener which is readily available and known commercially as Canderel. It is the methyl ester of the dipeptide L-aspartyl-L-phenylalanine and has a natural sugar-like taste. It is about 200 times as sweet as sucrose and, in addition, has flavour-enhancing... 

---