Pyrimidine homeostasis is accomplished by directed overflow metabolism

Here, the authors identify a previously unknown regulatory strategy used by Escherichia coli to control end-product levels of the pyrimidine biosynthetic pathway: this involves feedback regulation of the near-terminal pathway enzyme UMP kinase, with accumulation of UMP prevented by its degradation to uridine through UmpH, a phosphatase with a previously unknown function. A metabolic purine safety valve The control of the concentrations and fluxes of the thousand or so metabolites in a living cell such as Escherichia coli occurs via regulation of enzyme concentrations, activities and substrate occupancies. De novo pyrimidine biosynthesis has been reported to be regulated at the first committed pathway step (catalysed by aspartate transcarbamoylase) and at the previous (carbamoyl phosphate synthetase) step. Here the authors identify a novel regulatory strategy — an overflow pathway from UMP to uracil — that E. coli cells use to avoid the accumulation of an excess of the end products of pyrimidine biosynthesis. The process is analogous to that seen in central carbon metabolism, where excessive sugar catabolism leads to buildup of pyruvate that can be excreted as lactate, ethanol or acetate. Cellular metabolism converts available nutrients into usable energy and biomass precursors. The process is regulated to facilitate efficient nutrient use and metabolic homeostasis. Feedback inhibition of the first committed step of a pathway by its final product is a classical means of controlling biosynthesis 1 , 2 , 3 , 4 . In a canonical example, the first committed enzyme in the pyrimidine pathway in Escherichia coli is allosterically inhibited by cytidine triphosphate 1 , 4 , 5 . The physiological consequences of disrupting this regulation, however, have not been previously explored. Here we identify an alternative regulatory strategy that enables precise control of pyrimidine pathway end-product levels, even in the presence of dysregulated biosynthetic flux. The mechanism involves cooperative feedback regulation of the near-terminal pathway enzyme uridine monophosphate kinase 6 . Such feedback leads to build-up of the pathway intermediate uridine monophosphate, which is in turn degraded by a conserved phosphatase, here termed UmpH, with previously unknown physiological function 7 , 8 . Such directed overflow metabolism allows homeostasis of uridine triphosphate and cytidine triphosphate levels at the expense of uracil excretion and slower growth during energy limitat