From the McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin 53705.
the School of Pharmacy, Medicinal Chemistry Center, University of Wisconsin, Madison, Wisconsin 53705.
J Biol Chem. 2018 Feb 9;293(6):1994-2005. doi: 10.1074/jbc.RA117.000631. Epub 2017 Dec 26.
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.
细胞代谢物作为重要的信号提示物，但受到复杂的未知化学的影响。犬尿氨酸是一种色氨酸代谢物，在癌症和免疫系统中起着关键作用。尽管犬尿氨酸具有非典型的、非配体样的、高度极性的结构，但它可以激活芳香烃受体（AHR），AHR 是一个 PER、ARNT、SIM（PAS）家族转录因子，对各种环境和细胞配体做出反应。犬尿氨酸的活性在孵育或长期储存时会增加 100-1000 倍，这依赖于 AHR 的疏水配体结合口袋，在激活前后，AHR 诱导具有相同的结构特征。我们纯化了痕量活性的犬尿氨酸衍生物，并鉴定出两种新型的、密切相关的缩合产物，命名为痕量扩展芳香缩合产物（TEACOPs），它们在低皮摩尔水平具有活性。一种预测结构的合成化合物在化学结构和 AHR 药理学方面与纯化化合物相匹配。我们的研究提供了证据表明，犬尿氨酸作为 AHR 前配体，需要新的化学转化才能作为受体激动剂发挥作用。
