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Link to original content: https://pubmed.ncbi.nlm.nih.gov/37248411
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. 2023 Oct;19(10):1205-1214.
doi: 10.1038/s41589-023-01328-z. Epub 2023 May 29.

Chemoproteomics reveals microbiota-derived aromatic monoamine agonists for GPRC5A

Xiaohui Zhao  1 , Kathryn R Stein  1 , Victor Chen  2 , Matthew E Griffin  1 , Luke L Lairson  3 , Howard C Hang  4   5
Affiliations

Chemoproteomics reveals microbiota-derived aromatic monoamine agonists for GPRC5A

Xiaohui Zhao et al. Nat Chem Biol. 2023 Oct.

Abstract

The microbiota generates diverse metabolites to modulate host physiology and disease, but their protein targets and mechanisms of action have not been fully elucidated. To address this challenge, we explored microbiota-derived indole metabolites and developed photoaffinity chemical reporters for proteomic studies. We identified many potential indole metabolite-interacting proteins, including metabolic enzymes, transporters, immune sensors and G protein-coupled receptors. Notably, we discovered that aromatic monoamines can bind the orphan receptor GPRC5A and stimulate β-arrestin recruitment. Metabolomic and functional profiling also revealed specific amino acid decarboxylase-expressing microbiota species that produce aromatic monoamine agonists for GPRC5A-β-arrestin recruitment. Our analysis of synthetic aromatic monoamine derivatives identified 7-fluorotryptamine as a more potent agonist of GPRC5A. These results highlight the utility of chemoproteomics to identify microbiota metabolite-interacting proteins and the development of small-molecule agonists for orphan receptors.

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