A ligand for the aryl hydrocarbon receptor isolated from lung
A ligand for the aryl hydrocarbon receptor isolated from lung
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DOI：
10.1073/pnas.232562899
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发表时间：
2002-11-12
影响因子：
11.1
通讯作者：
DeLuca, HF
中科院分区：
文献类型：
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作者：
Song, JS;Clagett-Dame, M;DeLuca, HF
芳烃受体 (AHR) 是一种配体诱导型转录因子，因其介导多环和卤代芳香烃环境毒物（如 3-甲基胆蒽和 2,3,7,8-四氯二苯并对二恶英）的作用而闻名。我们在这里报告了该受体的内源配体的成功鉴定；从 35 公斤猪肺中分离出约 20 杯纯净物。通过广泛的物理测量和量子力学计算，其结构被推断为2-(1'H-吲哚-3'-羰基)-噻唑-4-甲酸甲酯。在报告基因测定中，该配体激活 AHR 的效力比 β-萘黄酮（一种典型的合成 AHR 配体）高五倍。 2-(1'1H-吲哚-3'-羰基)-噻唑-4-甲酸甲酯与 2,3,7,8[H-3]四氯二苯并-对-二恶英竞争与人类、鼠类和鱼类 AHR 的结合，从而表明 AHR 激活是由直接受体结合引起的，并且这种内源性配体的识别从早期脊椎动物（鱼）到人类都是保守的。
The aryl hydrocarbon receptor (AHR) is a ligand-inducible transcription factor that is best known because it mediates the actions of polycyclic and halogenated aromatic hydrocarbon environmental toxicants such as 3-methylcholanthrene and 2,3,7,8-tetrachlo-rodibenzo-p-dioxin. We report here the successful identification of an endogenous ligand for this receptor; approximate to20 mug was isolated in pure form from 35 kg of porcine lung. Its structure was deduced as 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester from extensive physical measurements and quantum mechanical calculations. In a reporter gene assay, this ligand activates the AHR with a potency five times greater than that of beta-naphthoflavone, a prototypical synthetic AHR ligand. 2-(1'1H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester competes with 2,3,7,8[H-3]tetrachlorodibenzo-p-dioxin for binding to human, murine, and fish AHRs, thus showing that AHR activation is caused by direct receptor binding, and that recognition of this endogenous ligand is conserved from early vertebrates (fish) to humans.