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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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“As observed previously (14), kynurenine induces a maximum AHR activation that is 40% higher than that induced by FICZ (Fig.”
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“with diverse shape and chemical properties have been reported to bind AHR (28, 29).”
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BackgroundAHR in the intestinal microenvironment: safeguarding barrier function
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“, Agent orange contaminant) 6-Formylindolo[3,2-b]carbazole FICZ 10−11–10−10 [29,30] Endogenous Natural Ultraviolet derivative of tryptophan Benzo[a]pyrene BaP 10−9–10−8 [28,31] Exogenous Synthetic Product of burning of organic compounds and cigarette smoke 3-Methylcholanthrene 3-MC 10−9–10−6 [27,28,30] Exogenous Synth…”
BackgroundSingle cell analysis of kynurenine and System L amino acid transport in T cells
Sinclair, L. V., Neyens, D., Ramsay, G., Taylor, P. M., & Cantrell, D. A. (2018) · Nature Communications · doi:10.1038/s41467-018-04366-7 · Cited by 200
“Hence, trace element condensation products of kynurenine can be potent AHR agonists (in the picomolar range) 16 .”
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“In addition, the chemical structure of kynurenine does not make it an optimal ligand, as it is highly polar and also too small for good binding in the AHR ligand binding site, which rather accommodates ligands with more than one aromatic ring (18).”
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“…the human AHR) is less responsive to TCDD than the variant with Ala at this position but both exhibit similar sensitivity to FICZ (Cho et al. 2015; Seok et al. 2018; Smith et al. 2018) and FICZ accelerates wound healing similarly in C57BL/6 (Ala375) and DBA/2 (Val375) mice (Morino-Koga et al.…”
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“Similarly, the Trp metabolite Kyn is the source of trace-extended aromatic condensation products (TEACOPs), which are highly potent AHR agonists 68 .”
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“Kynurenine (and its metabolites), FICZ and ITE are high affinity endogenous agonists that cause AhR activation in pM to nM concentrations [2,7,44].”
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“In addition, kynurenic acid was reported to activate AhR in immune cells ( 34 ), while restoring AhR signaling exert beneficial effects on metabolic syndrome ( 35 ).”
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“Recently, two trace-active derivatives of Kyn named trace-extended aromatic condensation products (TEACOPs) have been identified and considered as high affinity AHR ligands [61].”
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“Known agonists of AHR include Kyn, a low-affinity ligand whose physiological relevance is doubtful (42), and indole derivatives originating from bacterial degradation of Trp.”
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“Kynurenine enters the cells via AHR (aryl hydrocarbon receptor) [13].”
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“Over the decades, it has become clear that certain KYN metabolites, such as KYN, KYNA, AA, XA, and CA function as ligands for the AhR, a key transcription factor involved in immune regulation [286–288].”
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“However, there are also structural chemistry data that suggest Lkynurenine to be a weak binding agonist to AhR, and that more potent AhR agonists can be formed from L-kynurenine through aromatic condensation [55].”
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“Recent evidence has cast doubt upon the veracity of kynurenine as a bone fide AHR ligand, rather in vitro/modeling data is presented suggesting that kynurenine is a proligand which can undergo condensation reactions to generate so-called trace-extended aromatic condensation products (TEACOPs) with greatly enhanced AHR…”
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“Kynurenine activity as an AhR agonist is cell context– dependent (26 –36), and a recent study showed that, under storage conditions, the AhR activity of kynurenine can be increased by up to a 1000-fold because of formation of potent polycyclic condensation products (35).”
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“For example, kynurenine is spontaneously converted to trace condensation products called TEACOPs that are potent activators of the aryl hydrocarbon receptor (AHR), a transcription factor that controls the development of Treg cells [53].”
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Grobben, Y. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1440269 · Cited by 34
Tryptophan and Its Metabolites in Lung Cancer: Basic Functions and Clinical Significance
Li, C., & Zhao, H. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.707277 · Cited by 31
“Interestingly, KYN can directly bind and activate the AhR, with a high affinity at low picomolar levels (95).”
BackgroundA microbially produced AhR ligand promotes a Tph1-driven tolerogenic program in multiple sclerosis
Zelante, T., Paolicelli, G., Fallarino, F., Gargaro, M., Vascelli, G., Zuani, M. D., Frič, J., Lázničková, P., Kohoutková, M. H., Macchiarulo, A., et al. (2024) · Scientific Reports · doi:10.1038/s41598-024-57400-8 · Cited by 31
“The AhR mutation H285A, is known to also disrupt FICZ and L-Kyn binding to the the AhR ligand-binding pocket 24 .”
BackgroundDiscrete interplay of gut microbiota L-tryptophan metabolites in host biology and disease
Ranhotra, H. S. (2023) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-023-04867-0 · Cited by 28
“Seok et al.observed that the AhR activity of kynurenine increases 100–1000-fold with incubation or during long-term storage [129].”
Kynurenine Relaxes Arteries of Normotensive Women and Those With Preeclampsia
Worton, S. A., Pritchard, H. A. T., Greenwood, S. L., Alakrawi, M., Heazell, A. E. P., Wareing, M., Greenstein, A. S., & Myers, J. (2021) · Circulation Research · doi:10.1161/circresaha.120.317612 · Cited by 27
Boyt, D., Boland, L. K., Burand, A. J., Brown, A. J., & Ankrum, J. A. (2020) · Journal of The Royal Society Interface · doi:10.1098/rsif.2019.0815 · Cited by 26
Vázquez-Gómez, G., Petráš, J., Dvořák, Z., & Vondráček, J. (2023) · Biochemical Pharmacology · doi:10.1016/j.bcp.2023.115797 · Cited by 26
Huerta‐Yépez, S., Tirado-Rodriguez, A. B., Montecillo-Aguado, M. R., Yang, J., Hammock, B. D., & Hankinson, O. (2020) · Scientific Reports · doi:10.1038/s41598-020-64146-6 · Cited by 26
Decreased IDO1-dependent tryptophan metabolism in aged lung during influenza
Cho, S. J., Hong, K. S., Schenck, E. J., Lee, S. F., Harris, R. M., Yang, J., Choi, A. M. K., & Stout-Delgado, H. W. (2020) · European Respiratory Journal · doi:10.1183/13993003.00443-2020 · Cited by 23
“Recent work has illustrated that kynurenine can bind to aryl hydrocarbon receptor and result in heightened kynurenine activity [21].”
BackgroundCirac, A., Tsaktanis, T., Beyer, T., Linnerbauer, M., Andlauer, T. F. M., Grummel, V., Nirschl, L., Lößlein, L., Quintana, F. J., Hemmer, B., et al. (2021) · Neurology Neuroimmunology & Neuroinflammation · doi:10.1212/nxi.0000000000001043 · Cited by 23
The aryl hydrocarbon receptor as a model PAS sensor
Vazquez-Rivera, E., Rojas, B. L., Parrott, J. C., Shen, A. L., Xing, Y., Carney, P. R., & Bradfield, C. A. (2021) · Toxicology Reports · doi:10.1016/j.toxrep.2021.11.017 · Cited by 22
Self-citationThe kynurenine pathway; A new target for treating maternal features of preeclampsia?
Worton, S. A., Greenwood, S. L., Wareing, M., Heazell, A. E. P., & Myers, J. (2019) · Placenta · doi:10.1016/j.placenta.2019.04.007 · Cited by 22
Pirzadeh, M., Khalili, N., & Rezaei, N. (2020) · International Reviews of Immunology · doi:10.1080/08830185.2020.1851371 · Cited by 20
Saito, N., Kanno, Y., Yamashita, N., Degawa, M., Yoshinari, K., & Nemoto, K. (2021) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b20-00961 · Cited by 22
Summers, B. S., Broome, S. T., Pang, T. W. R., Mundell, H. D., Belic, N. K., Tom, N., Ng, M. L., Yap, M. L., Sen, M. K., Sedaghat, S., et al. (2024) · International Journal of Tryptophan Research · doi:10.1177/11786469241248287 · Cited by 27
“94 AhR activation regulates a diverse set of biological processes including metabolising environmental toxins, cellular oxidation/antioxidation and immune regulation in the CNS. 95 Immune regulation mediated by AhR can result in both anti-and pro-inflammatory effects, 95-97 as previously reviewed.”
BackgroundThe aryl hydrocarbon receptor: A diagnostic and therapeutic target in glioma
Lim, T. X., Ahamed, M., & Reutens, D. C. (2021) · Drug Discovery Today · doi:10.1016/j.drudis.2021.09.021 · Cited by 20
Regulation of host immune responses by Lactobacillus through aryl hydrocarbon receptors
Huang, Z., Xie, L., & Huang, Z. (2023) · Medicine in Microecology · doi:10.1016/j.medmic.2023.100081 · Cited by 19
IDO-triggered swellable polymeric micelles for IDO inhibition and targeted cancer immunotherapy.
Park, J., Nah, Y., & Kim, W. J. (2023) · Journal of Controlled Release · doi:10.1016/j.jconrel.2023.09.050 · Cited by 19
Immunomodulatory actions of a kynurenine-derived endogenous electrophile
Carreño, M., Pires, M. F., Woodcock, S. R., Brzóska, T., Ghosh, S., Salvatore, S. R., Chang, F., Khoo, N. K. H., Dunn, M., Connors, N., et al. (2022) · Science Advances · doi:10.1126/sciadv.abm9138 · Cited by 18
Lu, Z., Hsu, C., Younis, N. K., Mustafa, M. A., Matveeva, E. A., Al-Juboory, Y. H. O., Adil, M., Athab, Z. H., & Abdulraheem, M. N. (2024) · Apmis · doi:10.1111/apm.13401 · Cited by 19
“Tryptophan metabolism through indolea-mine 2,3-dioxygenase (IDO) yields L-kynurenine and kynurenic acid, both of which have the potential to activate AhR within immune cells [172, 173].”
BackgroundExploring tryptophan metabolism in cardiometabolic diseases
Mouttoulingam, N., & Taleb, S. (2024) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2024.11.009 · Cited by 17
Liu, L., Xu, J., Xu, X., Mao, T., Niu, W., Wu, X., Lu, L., & Zhou, H. J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232415578 · Cited by 17
“KYN is a moderate-affinity ligand of AHR and is sufficient to activate the transcriptional activity of genes downstream of AHR [48,49].”
BackgroundAryl hydrocarbon receptor role in chronic inflammatory skin diseases: a narrative review
Dec, M., & Arasiewicz, H. (2024) · Advances in Dermatology and Allergology · doi:10.5114/ada.2023.135617 · Cited by 18
“…modest affinity, the physiological implications of which remain uncertain and indole derivatives originating from bacterial degradation of Trp. Guenin-Macé et al. made metabolomic analysis and among bacterial metabolites of Trp detected indole-3-acetic acid (IAA)- recognized AHR agonist [58, 59].”
BackgroundInhibition of tryptophan 2,3-dioxygenase impairs DNA damage tolerance and repair in glioma cells
Reed, M. R., Maddukuri, L., Ketkar, A. D., Byrum, S. D., Zafar, M. K., Bostian, A. C. L., Tackett, A. J., & Eoff, R. L. (2021) · NAR Cancer · doi:10.1093/narcan/zcab014 · Cited by 16
The effect of environmental pollution on immune evasion checkpoints of SARS-CoV-2
Engin, A. B., Engin, A., & Engin, A. (2020) · Environmental Toxicology and Pharmacology · doi:10.1016/j.etap.2020.103520 · Cited by 16
Further characterization of tryptophan metabolism and its dysregulation in fibroids
Chuang, T., Quintanilla, D., Boos, D., & Khorram, O. (2022) · F&S Science · doi:10.1016/j.xfss.2022.04.005 · Cited by 15
Maguire, M., Larsen, M. C., Vezina, C. M., Quadro, L., Kim, Y., Tanumihardjo, S. A., & Jefcoate, C. R. E. (2020) · PLoS ONE · doi:10.1371/journal.pone.0228436 · Cited by 13
“Cyp1b1 metabolizes diverse natural substrates in different cell types, including estradiol in vascular cells [20, 21], arachidonic acid in macrophage [22] and natural ligands for the AhR [23, 24].”
BackgroundSelf-citationChemical sensing in development and function of intestinal lymphocytes
Cervantes‐Barragán, L., & Colonna, M. (2018) · Current Opinion in Immunology · doi:10.1016/j.coi.2018.01.004 · Cited by 12
Larsen, M. C., Almeldin, A., Tong, T., Rondelli, C. M., Maguire, M., Jaskula‐Sztul, R., & Jefcoate, C. R. E. (2020) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2020.115111 · Cited by 13
Self-citationAi, Y., Wang, B., Xiao, S., Luo, S., & Wang, Y. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222212428 · Cited by 11
“Moreover, kynurenine is an endogenous ligand that promotes tumor proliferation; it can bind to and activate aryl hydrocarbon receptor (AHR) to exert biological effects, both of which contribute to the occurrence and development of tumors [25].”
BackgroundTDO2 promotes bladder cancer progression via AhR-mediated SPARC/FILIP1L signaling
Ding, X., Jin, Y., Shi, X., Wang, Y., Jin, Z., Yin, L., Gao, S., Lei, Y., & Yang, J. (2024) · Biochemical Pharmacology · doi:10.1016/j.bcp.2024.116172 · Cited by 10
Gao, S., Leng, Y., Qiu, Z., Li, K., Li, J., Peng, J., Xie, W., Lei, S., & Xia, Z. (2025) · Advanced Science · doi:10.1002/advs.202409296 · Cited by 10
Tryptophan Metabolism Through the Kynurenine Pathway in Glial Cells
Argolo, D. S., de Oliveira, L. M. G., Guillemin, G. J., Barreto, G. E., Butt, A. M., Costa, S. L., & Costa, M. D. F. D. (2025) · Neuroglia · doi:10.3390/neuroglia6010014 · Cited by 11
“It is well established that KYN concentrations below the picomolar level are sufficient to bind to AhRs [64].”
The role of aryl hydrocarbon receptor in antiviral immunity: a focus on RNA viruses
Grycová, A., Vyhlídalová, B., & Dvořák, Z. (2025) · Critical Reviews in Microbiology · doi:10.1080/1040841x.2025.2497789 · Cited by 11
“…which spontaneously converts in solution to yield trace-extended aromatic condensation products (teAcOPs) that are picomolar agonists of the AhR (Seok et al. 2018). it is known that iDO-1 is regulated by iFN-β, iFN-γ and other cytokines, and by nitric oxide, which participate in host response…”
Mosa, F. E. S., El‐Kadi, A. O. S., & Barakat, K. (2022) · Journal of Molecular Graphics and Modelling · doi:10.1016/j.jmgm.2022.108339 · Cited by 10
Palzkill, V. R., Tan, J., Yang, Q., Morcos, J., Laitano, O., & RYAN, T. E. (2023) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00530.2023 · Cited by 9
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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