Aspartame structure relationship

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. 

Today, it is well-known that peptides or proteins exhibit various kinds of taste. Our group has been researching on the relationship between taste and structure of peptides, BPIa (Bitter peptide la, Arg-Gly-Pro-Pro-Phe-Ile-Val) (7 as a bitter peptide, Om-p-Ala-HCl (OBA), Om-Tau-HCl as salty peptides(2j, and "Inverted-Aspartame-Type Sweetener" (Ac-Phe-Lys-OH) as a sweet peptide(5). The relationship between taste and chemical structure was partly made clear. Since commercial demand for these flavor peptides is increasing, we need to develop new synthetic methods which can prepare these peptides in large scale. We developed the following two methods (1) protein recombination method as a chemical method, (2) enzymatic synthesis using chemically modified enzyme as a biochemical method. 

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. 

Sweeteners are natural or synthetic compounds which imprint a sweet sensation and possess no or negligible nutritional value ( nonnutritive sweeteners ) in relation to the extent of sweetness. There is considerable interest in new sweeteners. The rise in obesity in industrialized countries has established a trend for calorie-reduced nutrition. Also, there is an increased discussion about the safety of saccharin and cyclamate, the two sweeteners which were predominant for a long time. The search for new sweeteners is complicated by the fact that the relationship between chemical structure and sweetness perception is not yet satisfactorily resolved. In addition, the safety of suitable compounds has to be certain. Some other criteria must also be met, for example, the compound must be adequately soluble and stable over a wide pH and temperature range, have a clean sweet taste without side or post-flavor effects, and provide a sweetening effect as cost-effectively as does sucrose. At present, some new sweeteners are on the market (e. g., acesulfame and aspartame). The application of a number of other compounds will be discussed here. 

Since the second amino acid has a D configuration, its side chain must be small, corresponding to the structure activity relationships discussed for dipeptide esters of the aspartame type (cf. 1.3.3). On the other hand, the carbonyl group should carry the largest possible hydrophobic residue. 

Since the accidental discovery of aspartame in 1965, much effort has been focused on development of an understanding of the biochemical mechanism of sweet taste with the expectation that such knowledge would facilitate the rational design of novel sweeteners with increased stability and potency relative to that of aspartame. To date, although a great deal of inferential data suggests that sweetener receptors are members of the G-protein coupled receptor super family, no sweetener receptor has been isolated or characterized. As a consequence, many sweetener receptor and pharmacophore models have been developed based on the structure-activity relationships (SAR) among known sweeteners. 

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