This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: 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.
Researchers have known since the 1950s that TDO2 is stable when there is sufficient tryptophan and is rapidly broken down when tryptophan supply is limiting. It has recently been shown that this feedback mechanism relies on the ubiquitin-proteasome system, the cellular system that marks and degrades unwanted proteins. How tryptophan controls this system has now been elucidated.
Alina Thielen, the first author of the study, explains, "To identify the molecular mechanism underlying TDO2 degradation, we conducted a genome-wide CRISPRi screen. This enabled us to discover the two proteins controlling the degradation process: the kinase CK2 and the E3 ligase CUL1–β-TrCP. To understand their mechanism of action, we performed biochemical reactions with purified proteins in a test tube and used cryo-electron microscopy to examine the structure of TDO2 with and without tryptophan occupying the second binding site." The kinase and E3 ligase proteins act sequentially on TDO2 to mark it for degradation.
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