Pyrimidine homeostasis is accomplished by directed overflow metabolism

Abstract

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 biosynthesis1–4. In a canonical example, the first committed enzyme in the pyrimidine pathway in Escherichia coli is allosterically inhibited by cytidine triphosphate1,4,5. 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 kinase6. 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 function7,8. Such directed overflow metabolism allows homeostasis of uridine triphosphate and cytidine triphosphate levels at the expense of uracil excretion and slower growth during energy limitation. Disruption of the directed overflow regulatory mechanism impairs growth in pyrimidine-rich environments. Thus, pyrimidine homeostasis involves dual regulatory strategies, with classical feedback inhibition enhancing metabolic efficiency and directed overflow metabolism ensuring end-product homeostasis.

Control of bacterial metabolism by quorum sensing

“…As the pentose phosphate pathway is the main source of bacterial NADPH, higher concentrations of NADP + would be expected in QS mutants, in agreement with the fact that the expression levels of pathway genes were higher in QS mutants than in wild type [22,38]. It is important to note that bacteria maintain a homeostatic level of ribose-5-phosphate to control nucleotide concentrations; intracellular ribose-5-phosphate is the primary regulator of de novo purine and pyrimidine biosynthesis [55][56][57][58]. Therefore, the higher levels of ribose-5-phosphate in QS mutants may explain imbalances in the nucleotide concentrations of such mutants [38].…”

A family of metal-dependent phosphatases implicated in metabolite damage-control

“…Many such enzymes are known to rid cells of unwanted and potentially harmful metabolites or side products, in related metabolic damagecontrol processes termed 'damage pre-emption' 9 (or 'housecleaning' 10 ) and 'directed overflow' 11 . Damage pre-emption processes remove side-products formed spontaneously or by enzyme errors 9,10 , whereas directed overflow eliminates excesses of normal metabolites 11,12 . The association of yeast YMR027W and human C6orf211 with response to DNA damage fits with a damage pre-emption function 10 .…”

Eco-evolutionary feedbacks drive species interactions

“…We hypothesized that the PRPP pools were depleted as a result of an increase in the synthesis of OMP stimulated by exogenous OA. PRPP depletion would result in a marked decrease in purine synthesis, which would lead to an imbalance between purine and pyrimidine nucleotides (Shimosaka et al, 1984), causing arrest of DNA synthesis (Sheikh et al, 1993) and a lack of energetic nucleotides (ADP, ATP) (Reaves et al, 2013).…”