Metabolic Coordination through Metabolite-Protein Interactions

How do bacteria know what goes on in their environment and how to they make appropriate decisions? While some bona fide extracellular sensors are known, there are far more environmental conditions and cellular responses than could possibly be dealt with through dedicated sensors. Instead, most microbial responses are based on intracellular changes to environmental changes. One of the first affected networks to just about any extracellular change is metabolism that passively responds to nutritional or chemical/physical challenges. Since fluxes and intracellular metabolite levels respond within seconds, allosteric binding of metabolites to regulatory proteins and enzymes is a highly effective and rapid sensing mechanism. Different from well-establish methods to assess physical interaction between proteins and between proteins and nucleic acids, however, methods to assess metabolite-protein interactions are still in its infancy. In this talk I will focus first on reconstructing the regulatory network of metabolite-enzyme interactions from databases, which currenty consists of 1500 unique regulatory interactions (1). I will then describe out efforts to experimentally map this network out further. The current results indicate that the known interactions are only the tip of the iceberg (2). Beyond knowing the interaction topology, I will conclude this talk on the even more challenging and conceptual problem: understanding which of the many regulation mechanisms actually matter for a given adaptation to elicit an appropriate physiological system response.

1. Reznik, Christodoulou, Goldford, Briars, Sauer, Segre & Noor. Cell Reports 20: 2666-2677 (2017).

2. Piazza, Kochanowski, Cappelletti, Fuhrer, Noor, Sauer & Picotti. Cell 72:358-372 (2018).