Trace derivatives of kynurenine potently activate the aryl hydrocarbon receptor (AHR).
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.
['Seok|Seung-Hyeon|SH|', 'Ma|Zhi-Xiong|ZX|', 'Feltenberger|John B|JB|', 'Chen|Hongbo|H|', 'Chen|Hui|H|', 'Scarlett|Cameron|C|', 'Lin|Ziqing|Z|', 'Satyshur|Kenneth A|KA|', 'Cortopassi|Marissa|M|', 'Jefcoate|Colin R|CR|', 'Ge|Ying|Y|', 'Tang|Weiping|W|', 'Bradfield|Christopher A|CA|', 'Xing|Yongna|Y|']
D000818:Animals D001665:Binding Sites D007700:Kinetics D007737:Kynurenine D008024:Ligands D051379:Mice D015394:Molecular Structure D018336:Receptors, Aryl Hydrocarbon
kynurenine pro-ligand Ah receptor aryl hydrocarbon receptor (AhR) (AHR) chemical biology dioxin ligand-binding protein structural determinants structure-function