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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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Cites
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“Disorders of kynurenine metabolism are associated with a variety of human health issues, including cancer, hypertension, chronic inflammation, and neurodegenerative disorders (1, 5, 6).”
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“Our recent advance in understanding the structural basis of AHR signaling revealed a versatile allosteric structural pathway from the AHR-LBD to the N-terminal nuclear localization signal and DNA-reading head (44).”
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“1 DREs-driven luciferase reporter vector (14 ng) (30) and TK-Renilla luciferase vector (3 ng) (Invitrogen).”
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Tryptophan metabolism to kynurenine is a potential novel contributor to hypotension in human sepsis*
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“Disorders of kynurenine metabolism are associated with a variety of human health issues, including cancer, hypertension, chronic inflammation, and neurodegenerative disorders (1, 5, 6).”
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Changing the Face of Kynurenines and Neurotoxicity: Therapeutic Considerations
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Ultraviolet Photoproducts of Tryptophan Can Act as Dioxin Agonists
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“We compared the ability of kynurenine and FICZ, another tryptophan derivative that acts as a potent AHR ligand (20, 21), to activate themouseAHR (mAHRB1-allele, simplified asAHR ormAHR if not specified) using a luciferase reporter gene assay (30).”
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Identification of the Ah-Receptor Structural Determinants for Ligand Preferences
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“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).”
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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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