Making Sense of Sweetness

BIOCHEMISTRY

Among the five senses, taste is probably the least understood. A new model of the human sweet-taste receptor now explains why diverse molecules, large and small, taste sweet and why sweet tastes are often additive.

The model was created by chemistry professor Piero A. Temussi of the University of Naples and coworkers (J. Med. Chem. 2005, 48, 5520). If confirmed, it could aid the rational design of new sweeteners and lead to better treatments for diseases linked to sugar consumption (such as diabetes and obesity).

For decades, most researchers believed there had to be multiple receptors for sweet taste, comments professor of biochemistry and molecular biology D. Eric Walters of Rosalind Franklin University of Medicine & Science, North Chicago, a specialist in computer modeling and sweet-taste transduction. "Sugars, amino acids, peptides, proteins, terpenes, heterocycles like saccharin, sulfamic acids, ureas, guanidines, and dozens of other classes of compounds taste sweet, and it was hard to envision any single binding site that could interact with all of them."

The new study "suggests a way in which these results can be rationalized--[through] different binding sites on the receptor," Walters says. "The model is sufficiently detailed that you can now devise experiments to test the proposed sites. You can do specific mutations of residues implicated by the model and see whether receptor binding is affected."

A group based at Senomyx, a flavorings biotech company in La Jolla, Calif., reported earlier that the perception of sweetness depends totally on the heterodimeric G-protein-coupled receptor (GPCR) T1R2-T1R3, suggesting that it was the sole sweet-taste receptor. Temussi and coworkers have now modeled T1R2-T1R3 by comparing it with the glutamate receptor, a better understood GPCR of similar sequence, and have calculated the way sweeteners bind to the receptor.

The model reveals four binding sites that can be occupied independently. Small-molecule sweeteners bind to an extracellular pocket on each of the subunits or a site on the receptor's transmembrane domain, and sweet proteins can bind to a "wedge site" above one of the pockets.

"Our model incorporates all previous hypotheses formulated on the basis of the comparison of sweet compounds and explains why sweet taste can be elicited by substances as diverse as low-molecular-weight sweeteners, such as sugars and saccharin, and large sweet proteins, like monellin or thaumatin," Temussi says. Because sweeteners can bind independently, the model also explains how sweet tastes can be additive, Temussi says.