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

## TL;DR

This study shows how glutathione interacts with taste receptors to enhance umami and sweet flavors, revealing new molecular mechanisms.

## Contribution

The paper identifies glutathione as a partial agonist of umami and sweet taste receptors and maps its binding sites.

## Key findings

- GSH is a partial agonist of the umami taste receptor hTAS1R1/rTAS1R3 and synergizes with L-glutamic acid.
- GSH binds to the Venus Flytrap domain of hTAS1R1 near the L-Glu binding site.
- GSH is a weak agonist of the sweet taste receptor and synergizes with sucralose via the rTAS1R3 subunit.

## Abstract

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.

Unlabelled Image

•Reduced L-glutathione (GSH) is a partial agonist of hTAS1R1/rTAS1R3.•GSH synergizes with L-Glu but not with 5′-ribonucleotides.•GSH binds to hTAS1R1-VFT at a binding site adjacent to that of L-Glu.•GSH is a weak agonist of hTAS1R2/hTAS1R3 and hTAS1R2/rTAS1R3.•GSH synergizes with sucralose in affecting of rTAS1R3-VFT.

Reduced L-glutathione (GSH) is a partial agonist of hTAS1R1/rTAS1R3.

GSH synergizes with L-Glu but not with 5′-ribonucleotides.

GSH binds to hTAS1R1-VFT at a binding site adjacent to that of L-Glu.

GSH is a weak agonist of hTAS1R2/hTAS1R3 and hTAS1R2/rTAS1R3.

GSH synergizes with sucralose in affecting of rTAS1R3-VFT.