a, In this general metabolic pathway, a starting material (A) is converted to an end product (E) via intermediates (B to D). When demand for E is normal, regulation of the pathway occurs by feedback inhibition of the first step — E inhibits the conversion of A to B. The sizes of the letters indicate the amount of each compound that accumulates. b, At very low demand, feedback inhibition is ineffective (broken line). Production of E is therefore excessive, and so it and the intermediates B to D accumulate. c, Reaves et al.1 report that homeostasis of end products can be maintained when demand is very low if any excess is degraded and the resulting products are excreted. The authors discovered such a mechanism in the metabolic pathway that produces CTP, a pyrimidine nucleotide.