The Molecular Theory of Sweet Taste: Revisit, Update, and Beyond

Abstract

The molecular origin of the sweet taste is still elusive. Herein, the canonical AH-B-X theory of sweet taste is extended by resurveying various sweeteners, which provides deeper insights into an analogous intramolecular connectivity pattern of both glucophores in sweeteners and their interaction counterparts in sweet taste receptor TAS1R2/TAS1R3: electrostatic complementarity and topochemical compatibility. Furthermore, their complementary interaction is elaborately illustrated, accounting for the common molecular feature of eliciting sweetness. Moreover, it highlights that multiple glucophores in a topological system synergistically mediate the elicitation and performance of sweetness. This perspective presents a meaningful framework for the structure−activity relationship-based molecular design and modification of sweeteners and sheds light on the mechanism of molecular evolution of TAS1R2s/TAS1R3s. The link between palatability of sweeteners and harmony relationships between their structural components via stereochemistry and network has significant implications to illuminate the underlying mechanisms by which nature designs chemical reactions to elicit the most important taste. ■ SIGNIFICANCEResearch on the molecular theory of sweet taste has made substantial advances in recent years. It is shown that an analogous intramolecular connectivity pattern of sweeteners and sweet taste receptor mediates their complementary interaction for elicitation and performance of sweetness. Multiple glucophores in a stereochemical network accounting for the sweetness are also revealed. These perspectives update the canonical AH-B-X theory of sweet taste and are significant for elucidating the structure−activity relationships of various sweeteners.