Metabolism as a signal generator in bacteria

Bacteria constantly monitor their environment to adapt their inner makeup. Beyond providing chemical sustenance, meta-bolism provides most of the feedback on the cellular environ-ment via metabolite binding to regulatory proteins or mRNA. Although first metabolite-protein interactions were discovered more than 60 years ago, identification of new interactions is still technically challenging and time-consuming. Here, we compiled and quantified the current knowledge on metabolite -protein interactions and review recent advances in the identi-fication of interactions and in understanding how metabolites act as signals to transcription factors, two-component systems, protein kinases, and riboswitches. New systematic methods of metabolite-protein identification and omics integration will accelerate the pace of discovery, a remaining challenge is understanding of functionality and the coordination of local and global metabolic signals across different regulatory layers.