Chemoproteomic Analysis of Microbiota Metabolite–Protein Targets and Mechanisms

Abstract

The microbiota have emerged as an important factor in host physiology, disease, and response to therapy. These diverse microbes (bacteria, virus, fungi, and protists) encode unique functions and metabolites that regulate intraspecies and interspecies interactions. While the mechanisms of some microbiota species and metabolites have been elucidated, the diversity and abundance of different microbiota species and their associated pathways suggest many more metabolites and mechanisms of action remain to be discovered. In this Perspective, we highlight how the advances in chemical proteomics have provided new opportunities to elucidate the molecular targets of specific microbiota metabolites and reveal new mechanisms of action. The continued development of specific microbiota metabolite reporters and more precise proteomic methods should reveal new microbiota mechanisms of action, therapeutic targets, and biomarkers for a variety of human diseases.

Monitoring host–pathogen interactions using chemical proteomics

“…[47][48][49] As many components are distinct in microbial pathogens from eukaryotic cells, substantial progress in hostpathogen interaction studies has been made using metabolic labelling. [50][51][52][53][54][55][56][57][58] In both approaches, chemical probes may directly be modified with a reporter group such as a fluorophore or an affinity…”

Chemoproteomic Approaches for Unraveling Prokaryotic Biology

“…This review highlights specific biological processes in bacteria and contributions of chemical proteomics to understanding these processes. The discussion of works on chemoproteomic profiling of mammalian proteins and its application to studying interactions with bacterial biomolecules, [11] serine hydrolases, [12] and reactive sites in the human proteome [13] have been reviewed elsewhere. Rather, this review highlights seminal technologies for chemoproteomic profiling of bacterial proteins in specific processes and the mechanistic biological studies that these technologies have enabled.…”

Chemical proteomic analysis of bile acid-protein targets in Enterococcus faecium

“…For example, activity-based probes for bile acid hydrolases (BSH) with different reactive warheads such as acyloxymethylketone 15 , α-fluoromethyl ketone 16 and β-lactam or acrylamide 17 have been developed to profile the gut microbiota-associated bile salt hydrolase (BSH) activity. Alternatively, photoaffinity reporters for bile acids and other microbiota metabolites can be employed to characterize other protein targets in mammalian cells and microbes 18 . Of note, photoaffinity reporters were developed for primary bile acid cholic acid and enabled the identification of cholic acid-binding proteins in mammalian cell lines 19 and E. coli 20 .…”

“…Alternatively, photoaffinity reporters for bile acids and other microbiota metabolites can be employed to characterize other protein targets in mammalian cells and microbes. 18 Of note, photoaffinity reporters were developed for primary bile acid cholic acid and enabled the identification of cholic acidbinding proteins in mammalian cell lines 19 and E. coli. 20 In addition, our chemoproteomic analysis in Salmonella revealed anti-infective bile acids such as chenodeoxycholic acid can bind and inactivate a transcriptional regulator of Salmonella virulence HilD.…”

“…Alternatively, photoaffinity reporters for bile acids and other microbiota metabolites can be employed to characterize other protein targets in mammalian cells and microbes. 18 Of note, photoaffinity reporters were developed for primary bile acid cholic acid and enabled the identification of cholic acid-binding proteins in mammalian cell lines 19 and E . coli.…”