Hyun Bong Park, Deguang Song, Mytien Nguyen, Noah W Palm, Jason M Crawford
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引用次数: 0
Abstract
Gut microbes secrete specialized small molecules that broadly influence human physiology. Despite their potential significance, the variety of functional small molecules known in the gut is relatively limited. Here, we screened the supernatants from human fecal-derived bacterial cultures to explore their agonist effects on the human G protein-coupled receptors (GPCRs), melatonin receptor types 1A and 1B (MTNR1A, MTNR1B). Chemical analysis of the supernatant-soluble molecules of Clostridium sporogenes, a prominent gut commensal identified in the screen, led to the characterization of agonists for these two melatonin receptors. Specifically, through bioactivity-assisted isolation and characterization, we identified three small molecules, 1-3, including two previously uncharacterized metabolites, which were synthesized to confirm their structures. While the structure of 1 features a urea core symmetrically disubstituted with tryptamine moieties, 2 and 3 harbor a monomeric tryptamine functionalized with methyl carbamate and N-acetyl groups, respectively. These structural characterization efforts illuminated downstream functional consequences of tryptamine metabolism in C. sporogenes. Additional GPCR screening analyses revealed that 2 activates melatonin receptors and the purinergic P2RY11 receptor, whereas 1 serves as an agonist for the semiorphan receptor GPR55. Interestingly, 1 also exhibits significant inhibitory activity against inflammatory soluble epoxide hydrolase with a half-maximal inhibitory concentration of 420 nM. Single-cell RNA sequencing analysis of the gut tissue from mice orally treated with 1 relative to the solvent vehicle control revealed that 1 specifically decreased the frequency of GPR55- and granzyme K-expressing effector-like CD8 T cells in the intraepithelial lymphocyte population. Overall, this study broadens our understanding of tryptamine-derived signaling at the human-microbe interface.
期刊介绍:
ACS Chemical Biology provides an international forum for the rapid communication of research that broadly embraces the interface between chemistry and biology.
The journal also serves as a forum to facilitate the communication between biologists and chemists that will translate into new research opportunities and discoveries. Results will be published in which molecular reasoning has been used to probe questions through in vitro investigations, cell biological methods, or organismic studies.
We welcome mechanistic studies on proteins, nucleic acids, sugars, lipids, and nonbiological polymers. The journal serves a large scientific community, exploring cellular function from both chemical and biological perspectives. It is understood that submitted work is based upon original results and has not been published previously.