1F: Nutrasweet: Sweeteners - II

One of the most interesting and challenging aspects of biomedical/biochemical research is relating the structure of a chemical substance to its bio or chemical activity (reactivity). Why is aspirin or ibuprofen an effective analgesic? Why does penicillin act as an antibiotic? How does Tagamet work its anti-ulcer wonders? Why does NutraSweet taste as it does? Answering these questions not only leads to a better understanding of human biochemistry but can lead to improved, more effective medicines or sweeteners.

Analyzing structure often means studying both the connected atoms (i.e., the chemical structure) and the molecular shape in the environment in which the molecule’s bio-action occurs. The former analysis is much easier than the latter. Hundreds of compounds similar in structure to known sweeteners have been prepared in the laboratory and tested for sweetness. Promising prospects are explored further, though the cost of development and formidable health testing screen out all but the most exciting possibilities. In the past 20 years, only a handful have made it into commerce and NutraSweet still remains dominant since its introduction in 1981.

Many biomolecules display their properties by interacting with molecular sites within the body. This interaction may be a chemical reaction or it may be more akin to a physical-chemical association, such as a hydrogen bond. For a sweetener to act, it must associate with one or more receptor sites that function as "taste buds." The receptor sites are themselves chemicals and have a particular shape associated with them. The sweetener will need to possess a chemical structure whose components and shape will allow it to be attracted to and associate with the receptor site to be effective. It must structurally complement the receptor, somewhat like the oft-used analogy of lock and key or glove and hand. Once the appropriate interaction occurs, signals can be sent to the brain that register as a sweet sensation.

The most logical approach to studying the structure-activity relationships (SAR) between receptor site and sweetener would be to determine the structure of the receptor site. However, this is not an easy task and has yet to be accomplished, though work continues. A second approach is to investigate the structural characteristics of all those compounds known to be sweet to find those features that are in common. This is also a rather daunting task since exact bond lengths and preferred conformations need to be determined. It is also possible that a little or a lot of structural variations may impart sweet properties, so that there is no "one" SAR requirement. Nonetheless, considerable work has gone into investigating the SAR of sweeteners and several theories have emerged, both simple and complex.

With such diverse types of chemicals showing sweetness, it is immediately clear that a specific type of functional group or groups is not a prerequisite. Instead, it is believed that the important structural features require proper electronic features such as a H-bond donor, a H-bond receptor, a nonpolar region, and a three-dimensional shape that allows those electronic sites to complement similar sites in the receptor. The three-dimensional shape relates to bond lengths, functional group separation distances, and, if present, the configuration of, say, the amino acid.

Shallenberge and Acree (1969) have suggested a sweetener model that requires a hydrogen bond donor (AH) and a hydrogen bond acceptor (B) about 2.5 to 4.0 Å (angstroms) apart in the sweetener. From this simple di-interactive model have evolved other theories that suggest the need for additional interactive requirements. Most additional theories suggest at least a third structural requirement, a nonpolar or hydrophobic domain (G). (See Figure 14.)

Figure 14

NutraSweet clearly has these three requirements for a sweetener. Depending upon whether aspartame is written as the zwitterion or as the unchanged amino acid, the A-H site is either the –COOH or the –NH₃⁺ group or, perhaps, the N-H of the amide; the B site is the –COO^- or –NH₂; the G region is either or both the phenyl and the –COOCH₃ ester group. Some models for the sweetness of aspartame suggest the simultaneous utilization of all three sites for interaction with the receptor in a three-dimensional model.

Note

What is especially instructive for those of us in introductory chemistry is how the fundamental theories regarding molecular interactions—polarity difference and dipoles, Van der Waals forces, hydrogen bonding, attraction of opposite charges, and repulsion of like charges—can be transferred from how salt dissolves in water but not in gasoline to how a more complex dipeptide can interact with a taste receptor or taste receptors to provide the pleasurable sensation of sweetness.