Limitation of phosphate assimilation maintains cytoplasmic magnesium homeostasis.

Phosphorus (P) is an essential component of core biological molecules. In bacteria, P is acquired mainly as inorganic orthophosphate (Pi) and assimilated into adenosine triphosphate (ATP) in the cytoplasm. Although P is essential, excess cytosolic Pi hinders growth. We now report that bacteria limit Pi uptake to avoid disruption of Mg-dependent processes that result, in part, from Mg chelation by ATP. We establish that the MgtC protein inhibits uptake of the ATP precursor Pi when serovar Typhimurium experiences cytoplasmic Mg starvation. This response prevents ATP accumulation and overproduction of ribosomal RNA that together ultimately hinder bacterial growth and result in loss of viability. Even when cytoplasmic Mg is not limiting, excessive Pi uptake increases ATP synthesis, depletes free cytoplasmic Mg, inhibits protein synthesis, and hinders growth. Our results provide a framework to understand the molecular basis for Pi toxicity. Furthermore, they suggest a regulatory logic that governs P assimilation based on its intimate connection to cytoplasmic Mg homeostasis.