The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index.
Trace derivatives of kynurenine potently activate the aryl hydrocarbon receptor (AHR)
Open accessAbstract
Cellular metabolites act as important signaling cues, but are subject to complex unknown chemistry. Kynurenine is a tryptophan metabolite that plays a crucial role in cancer and the immune system. Despite its atypical, non-ligand-like, highly polar structure, kynurenine activates the aryl hydrocarbon receptor (AHR), a PER, ARNT, SIM (PAS) family transcription factor that responds to diverse environmental and cellular ligands. The activity of kynurenine is increased 100-1000-fold by incubation or long-term storage and relies on the hydrophobic ligand-binding pocket of AHR, with identical structural signatures for AHR induction before and after activation. We purified trace-active derivatives of kynurenine and identified two novel, closely related condensation products, named trace-extended aromatic condensation products (TEACOPs), which are active at low picomolar levels. The synthesized compound for one of the predicted structures matched the purified compound in both chemical structure and AHR pharmacology. Our study provides evidence that kynurenine acts as an AHR pro-ligand, which requires novel chemical conversions to act as a receptor agonist.
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“On the basis of these novel approaches, recent docking studies not only allowed prediction of the binding modes of several AhR ligands but also led to the discovery of novel AhR agonists and SAhRMs25,27–30.”
From Modeling the binding of diverse ligands within the Ah receptor ligand binding domain (2019) · cites this paper as [29]
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“They may rather function as “pro-ligands” through further conversion to “real” AHR ligands with much higher binding potencies, as exemplified by kynurenine and its trace derivatives52.”
From Structural basis for the ligand-dependent activation of heterodimeric AHR-ARNT complex (2025) · cites this paper as [52]
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Citations
Cites
Zelante, T., Iannitti, R. G., Cunha, C., De Luca, A., Giovannini, G., Pieraccini, G., Zecchi, R., D’Angelo, C., Massi-Benedetti, C., Fallarino, F., et al. (2013) · Immunity · doi:10.1016/j.immuni.2013.08.003 · Cited by 2,614
An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor
Opitz, C. A., Litzenburger, U. M., Sahm, F., Ott, M., Tritschler, I., Trump, S., Schumacher, T., Jestaedt, L., Schrenk, D., Weller, M., et al. (2011) · Nature · doi:10.1038/nature10491 · Cited by 1,898 · cited 2×
“As observed previously (14), kynurenine induces a maximum AHR activation that is 40% higher than that induced by FICZ (Fig.”
BackgroundAn Interaction between Kynurenine and the Aryl Hydrocarbon Receptor Can Generate Regulatory T Cells
Mezrich, J. D., Fechner, J. H., Zhang, X., Johnson, B. P., Burlingham, W. J., & Bradfield, C. A. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0903670 · Cited by 1,667 · cited 3×
“Kynurenine is metabolized to different compounds by diverse enzymes in the kynurenine pathway (1), and many of these metabolic intermediates (other than kynurenine) are not active in AHR activation assays (7).”
BackgroundResultSelf-citationRothhammer, V., Mascanfroni, I. D., Bunse, L., Takenaka, M. C., Kenison, J. E., Mayo, L., Chao, C.-C., Patel, B., Yan, R., Blain, M., et al. (2016) · Nature Medicine · doi:10.1038/nm.4106 · Cited by 1,559
Lamas, B., Richard, M. L., Leducq, V., Pham, H.-P., Michel, M.-L., Da Costa, G., Bridonneau, C., Jegou, S., Hoffmann, T. W., Natividad, J. M., et al. (2016) · Nature Medicine · doi:10.1038/nm.4102 · Cited by 1,482
AH RECEPTOR SIGNALING PATHWAYS
Schmidt, J. V., & Bradfield, C. A. (1996) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.12.1.55 · Cited by 899 · cited 1×
“with diverse shape and chemical properties have been reported to bind AHR (28, 29).”
BackgroundSelf-citationEndogenous kynurenines as targets for drug discovery and development
Stone, T. W., & Darlington, L. G. (2002) · Nature Reviews Drug Discovery · doi:10.1038/nrd870 · Cited by 768 · cited 3×
“Disorders of kynurenine metabolism are associated with a variety of human health issues, including cancer, hypertension, chronic inflammation, and neurodegenerative disorders (1, 5, 6).”
BackgroundThe Search for Endogenous Activators of the Aryl Hydrocarbon Receptor
Nguyen, L. P., & Bradfield, C. A. (2007) · Chemical Research in Toxicology · doi:10.1021/tx7001965 · Cited by 718 · cited 1×
“with diverse shape and chemical properties have been reported to bind AHR (28, 29).”
BackgroundSelf-citationNguyen, N. T., Kimura, A., Nakahama, T., Chinen, I., Masuda, K., Nohara, K., Fujii‐Kuriyama, Y., & Kishimoto, T. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1014465107 · Cited by 702
Aryl hydrocarbon receptor control of a disease tolerance defence pathway
Bessede, A., Gargaro, M., Pallotta, M. T., Matino, D., Servillo, G., Brunacci, C., Bicciato, S., Mazza, E. M. C., Macchiarulo, A., Vacca, C., et al. (2014) · Nature · doi:10.1038/nature13323 · Cited by 693
Cited by
Sorted by citations
Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond
Platten, M., Nollen, E. A. A., Röhrig, U. F., Fallarino, F., & Opitz, C. A. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0016-5 · Cited by 1,586
Rothhammer, V., & Quintana, F. J. (2019) · Nature Reviews Immunology · doi:10.1038/s41577-019-0125-8 · Cited by 1,197
Inflammatory bowel diseases (IBD) and the microbiome-searching the crime scene for clues
Lee, M., & Chang, E. B. (2021) · Gastroenterology · doi:10.1053/j.gastro.2020.09.056 · Cited by 645
Rosser, E. C., Piper, C. J. M., Matei, D. E., Blair, P. A., Rendeiro, A. F., Orford, M., Alber, D. G., Krausgruber, T., Catalan, D., Klein, N., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.03.003 · Cited by 579
“In addition, L-kynurenine and kynurenic acid, which are produced following metabolism of tryptophan by indoleamine 2,3-dioxygenase (IDO), can also activate AhR in immune cells (Quintana et al., 2008; Seok et al., 2018).”
BackgroundAHR in the intestinal microenvironment: safeguarding barrier function
Stockinger, B., Shah, K., & Wincent, E. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00430-8 · Cited by 427
Metadata
- Authors
- Seok, S.-H., Ma, Z.-X., Feltenberger, J. B., Chen, H., Chen, H., Scarlett, C., Lin, Z., Satyshur, K. A., Cortopassi, M., Jefcoate, C. R., Ge, Y., Tang, W., Bradfield, C. A., & Xing, Y.
- Affiliations
- University of Wisconsin–Madison (US)
- Corresponding author
- Xing, Yongna
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 293
- Issue
- 6
- Pages
- 1994-2005
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC5808761
- OpenAlex
- W2779643604
- Cited by
- 157
- References
- 48
- Citations by year
- 2026: 15 · 2025: 27 · 2024: 16 · 2023: 19 · 2022: 16 · 2021: 16 · 2020: 22 · 2019: 16 · 2018: 10
- FWCI
- 4.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- DH National Institute for Health Research (NIHR) (R01 GM096060, R35028377)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- kynurenine, aryl hydrocarbon receptor, tryptophan metabolism, AhR activation, binding pocket, condensation products, transcription factor activation
- MeSH terms
- Animals, Binding Sites, Kinetics, Kynurenine, Ligands, Molecular Structure, Receptors, Aryl Hydrocarbon, Mice
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