ArticleProceedings of the National Academy of Sciences of the United States of America2021
Tryptophanemia is controlled by a tryptophan-sensing mechanism ubiquitinating tryptophan 2,3-dioxygenase.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 18 citations in OpenAlex.
- Compensatory pathways in tryptophan metabolism and immune regulation following IDO inhibition.Molecular biology reports · 2026Review
- Cysteine availability tunes ubiquitin signaling via inverse stability of LRRC58 E3 ligase and its substrate CDO1.Nature communications · 2026Article
- Advances in Mammalian Metallomics: New Insights into Metal Dynamics and Biological Significance.International journal of molecular sciences · 2025Review
- Off-target depletion of plasma tryptophan by allosteric inhibitors of BCKDK.Molecular metabolism · 2025Article
- Unlocking the potential of the 3-hydroxykynurenine/kynurenic acid ratio: a promising biomarker in adolescent major depressive disorder.European archives of psychiatry and clinical neuroscience · 2025Article
- SKP1-CUL1-F-box: Key molecular targets affecting disease progression.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Review
- Value of serum tryptophan in stratified management of 90-day mortality risk in patients with hepatitis B virus-related acute-on-chronic liver failure: a multicenter retrospective study.Nan fang yi ke da xue xue bao = Journal of Southern Medical University · 2025Article
- Host 5-HT affects Plasmodium transmission in mosquitoes via modulating mosquito mitochondrial homeostasis.PLoS pathogens · 2024Article
- Nutrient sensors and their crosstalk.Experimental & molecular medicine · 2023Review
- Human cytosolic transaminases: side activities and patterns of discrimination towards physiologically available alternative substrates.Cellular and molecular life sciences : CMLS · 2022Article
- Systemic tryptophan homeostasis.Frontiers in molecular biosciences · 2022Review
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Maintaining stable tryptophan levels is required to control neuronal and immune activity. We report that tryptophan homeostasis is largely controlled by the stability of tryptophan 2,3-dioxygenase (TDO), the hepatic enzyme responsible for tryptophan catabolism. High tryptophan levels stabilize the active tetrameric conformation of TDO through binding noncatalytic exosites, resulting in rapid catabolism of tryptophan. In low tryptophan, the lack of tryptophan binding in the exosites destabilizes the tetramer into inactive monomers and dimers and unmasks a four-amino acid degron that triggers TDO polyubiquitination by SKP1-CUL1-F-box complexes, resulting in proteasome-mediated degradation of TDO and rapid interruption of tryptophan catabolism. The nonmetabolizable analog alpha-methyl-tryptophan stabilizes tetrameric TDO and thereby stably reduces tryptophanemia. Our results uncover a mechanism allowing a rapid adaptation of tryptophan catabolism to ensure quick degradation of excess tryptophan while preventing further catabolism below physiological levels. This ensures a tight control of tryptophanemia as required for both neurological and immune homeostasis.
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