Bitter 2,5‐Diketopiperazines From Cocoa Activate Human Bitter Taste Receptors

The human taste system enables a rapid analysis of nutritional and non-nutritional food constituents. Although a bitter taste is considered a warning signal against ingesting potentially harmful substances, not all bitter substances are toxic, and a moderate bitterness is frequently tolerated or even preferred. Responsible for the detection of bitter substances in food are the ∼25 human bitter taste receptors residing in the oral cavity. An important class of bitter compounds found in thermally treated foods is the 2,5-diketopiperazines, cyclic dipeptides made from two L-amino acids, which are frequently formed as degradation products of polypeptides. Although 2,5-diketopiperazines are established as major contributors to the bitter taste of many food items, it is still unknown which of the human bitter taste receptors mediate their detection. Using functional calcium-mobilization assays, we identified two human bitter taste receptors, TAS2R14 and TAS2R43, being responsive to 2,5-diketopiperazines. Of the two identified 2,5-diketopiperazines activating TAS2R43, cis-cyclo(L-Leu-L-Phe) exhibited the highest potency with a threshold concentration of 100 µM. Further testing of 2,5-diketopiperazine-related linear dipeptides revealed that 2,5-diketopiperazines represent their own class of bitter compounds, as no overlapping activation patterns with the corresponding dipeptides were evident.