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.

The essential amino acid tryptophan is a key building block for proteins and also serves as a precursor for serotonin, melatonin, niacin (vitamin B3) and NAD+. These molecules are vital for the nervous and immune systems and the cell’s energy supply. As tryptophan can only be obtained through dietary supply, the body must maintain tryptophan levels within a physiological range.

The enzyme tryptophan 2,3-dioxygenase (TDO2) carries out the first and rate-limiting step of the kynurenine pathway. While the cell requires the downstream products of TDO2, it must also avoid consuming too much tryptophan.