Glutathione as a taste modulator: molecular mechanisms of interaction with umami and sweet taste receptors

Reduced L-glutathione (GSH) is a kokumi active tripeptide that enhances umami, salty, and sweet taste perceptions, probably via the calcium-sensing receptor (CaSR). In this study, we report that GSH is a partial agonist of the umami Taste Receptor (hTAS1R1/rTAS1R3). Using cellular assays, we revealed synergistic effects of GSH with L-glutamic acid (L-Glu) but not with 5'-ribonucleotides. Combining molecular modeling and mutagenesis studies, we mapped the GSH binding site located between the two lobes of the Venus Flytrap domain (VFT) of hTAS1R1. Interestingly, GSH is a weak agonist of the sweet Taste Receptor (hTAS1R2/hTAS1R3) and synergizes with sucralose via the rTAS1R3 subunit. Using the chimeric TAS1R3 receptor and site-directed mutagenesis, we showed that GSH binds to TAS1R3-VFT. This research provides increased understanding of the molecular interactions between GSH and TAS1Rs and suggests that the kokumi activity of GSH is more complex than affecting CaSR alone.

G protein-coupled receptor; Guanosine 5′-monophosphate disodium salt (PubChem CID: 135414246); Inosine 5′-monophosphate disodium salt hydrate (PubChem CID: 135565601); Kokumi; L-glutamic acid (PubChem CID: 33032); Monosodium glutamate (PubChem CID: 23672308); Oxidized glutathione (PubChem CID: 65359); Reduced L-glutathione (PubChem CID: 124886); Ribonucleotide; S807 (N-(heptan-4-yl)benzo[d][1,3]dioxole-5-carboxamide) (PubChem CID: 22831877); Sucralose (PubChem CID: 71485); TAS1R1/TAS1R3; Taste receptor; γ-glutamylcysteine (PubChem CID: 123938).