Metabolites are consumed by enzymes to produce other vital molecules as well as to control metabolite levels. But how do cells avoid consuming too much? Researchers from the MPI of Biochemistry, with the University of Nevada, Las Vegas, and the de Duve Institute in Brussels, have deciphered such molecular regulation in tryptophan metabolism. The essential amino acid tryptophan binds to a second site on the enzyme TDO2, distinct from where it is consumed. This sequesters a region needed by two effectors, the kinase CK2 and the ubiquitin ligase CUL1–β-TrCP, which act sequentially to signal TDO2 degradation. The findings are now published in Molecular Cell.