Indole-3-propionic Acid Is an Endogenous Agonist of TAS2R38

Area of Science:

• Biochemistry
• Molecular Biology
• Metabolomics

Background:

• Bitter taste receptor 38 (TAS2R38) has emerging roles in metabolic and immune regulation beyond taste perception.
• Understanding TAS2R38 function is limited by a lack of identified endogenous ligands.
• Aromatic amino acid metabolites are potential sources for novel TAS2R38 ligands.

Purpose of the Study:

• To discover novel endogenous agonists for TAS2R38 from food and microbiota metabolites.
• To elucidate the molecular interactions governing TAS2R38 activation.

Main Methods:

• AI-based molecular modeling to predict TAS2R38 ligand-binding pockets and interactions.
• Cell-based assays using HEK293T cells expressing TAS2R38 to validate agonist activity.
• Structure-activity relationship analysis of indole-3-propionic acid (IPA) analogs.

Main Results:

• AI modeling identified key interactions for TAS2R38 activation, including π-π stacking and hydrogen bonding.
• Indole-3-propionic acid (IPA), a tryptophan metabolite, was validated as a potent TAS2R38 agonist.
• IPA suppressed forskolin-induced cAMP accumulation with an IC50 of 1.06 μM, similar to phenylthiocarbamide (PTC).

Conclusions:

• Indole-3-propionic acid is a novel, potent agonist for bitter taste receptor 38 (TAS2R38).
• The study provides a molecular framework for designing extra-oral TAS2R agonists.
• Findings support the development of functional food ingredients targeting TAS2R38 for metabolic and immune health.