The Renowned Flavor Compound Cinnamaldehyde Induces Sweet Taste by Targeting the Transmembrane Domain of T1R3 in the Sweet Taste Receptor

Numerous flavor compounds are known to evoke sweet taste sensations, yet their direct interaction with the sweet taste receptor remains poorly understood. Traditionally, flavor-induced sweetness was attributed to aromatic properties rather than the taste qualities of these compounds. This study aims to elucidate whether the sweet taste receptor mediates flavor-induced sweet sensations by investigating the agonistic activities of 94 flavor compounds on cultured cells expressing the sweet taste receptor (T1R2/T1R3). The results demonstrated that cinnamaldehyde (CA) and p-methoxycinnamaldehyde (PMCA) activate the sweet taste receptor. These compounds not only induce the receptor response but also enhance receptor activity when combined with various sweeteners or sweet proteins. Due to PMCAs structural similarity to lactisole, a well-known negative allosteric modulator (NAM) of the sweet taste receptor interacting with the transmembrane domain (TMD) of T1R3, CA and PMCA are hypothesized to interact with the T1R3 TMD as ago-PAMs (agonists and positive allosteric modulators). Mutational analyses confirmed that CA and PMCA interact with the T1R3 TMD, with distinct binding sites compared to lactisole. Additionally, because of structural parallels between PMCA and lactisole, we investigated the structure-activity relationships among 79 compounds to determine whether they function as ago-PAMs or NAMs. Most compounds acted as inhibitors, while those with specific planar structures acted as ago-PAMs. In conclusion, this study identified CA and PMCA as novel ago-PAMs that interact with the T1R3 TMD of the sweet taste receptor. These findings significantly advance our understanding of how flavor compounds influence sweet taste perception at the molecular level. Significance StatementNumerous flavor compounds evoke sweet taste sensations, yet their interaction with the sweet taste receptor is not well understood. This study identifies cinnamaldehyde (CA) and p-methoxycinnamaldehyde (PMCA) as activators of the sweet taste receptor, interacting with the transmembrane domain (TMD) of T1R3. CA and PMCA also act as positive allosteric modulators of other sweeteners (ago-PAMs). We discovered two binding sites in the T1R3 TMD, with CA and PMCA binding to different sites than lactisole, a known negative allosteric modulator. These findings identify CA and PMCA as novel ago-PAMs and significantly advance our understanding of how flavor compounds influence sweet taste perception at the molecular level.