D-Amino Acid Oxidase Generates Agonists of the Aryl Hydrocarbon Receptor from D-Tryptophan
D-Amino Acid Oxidase Generates Agonists of the Aryl Hydrocarbon Receptor from D-Tryptophan
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DOI：
10.1021/tx900043s
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发表时间：
2009-12-01
影响因子：
4.1
通讯作者：
Bradfield, Christopher A.
中科院分区：
文献类型：
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作者：
Nguyen, Linh P.;Hsu, Erin L.;Bradfield, Christopher A.
芳香烃受体（AHR）是众所周知的，其作用是介导的毒性和适应性反应的异生化合物。最近的研究还表明，AHR配体是内源性产生的，可能是正常发育所必需的。以前，我们表明，内源性酶，天冬氨酸氨基转移酶（AST），产生AHR前激动剂，吲哚-3-阿魏酸（I3 P），通过脱氨基其底物L-色氨酸。我们假设其他能够产生I3 P的酶途径可能在体内产生AHR激动剂。我们现在证明，酶D-氨基酸氧化酶（DAAO）催化AHR激动剂的生产，通过D-色氨酸的酶转化为I3 P。此外，我们提供的证据表明，非酶的氧化和缩合的I3 P是一个关键步骤，在受体激动剂的DAAO和AST的生成。该方法的产物包括两种新的激动剂，1，3-二（1H-吲哚-3-基）丙-2-酮和1-（1H-吲哚-3-基）-3-（3 H-吲哚-3-亚基）丙-2-酮[在所附论文中表征，Chowdhury等人（2009）Chem.Res.Toxicol.，DOI：10.1021/tx 9000418]，这两者都可以在纳摩尔范围内的浓度下有效地激活AHR。这些结果表明，内源性AHR活性可以通过多种酶促途径，包括DAAO和AST催化的途径，由氨基酸前体产生I3 P来调节。
The aryl hydrocarbon receptor (AHR) is well-known for its role in mediating the toxic and adaptive responses to xenobiotic compounds. Recent studies also indicate that AHR ligands are endogenously produced and may be essential for normal development. Previously, we showed that the endogenous enzyme, aspartate aminotransferase (AST), generates the AHR proagonist, indole-3-pyruvic acid (I3P), by deamination of its substrate L-tryptophan. We hypothesized that other enzymatic pathways capable of producing I3P may generate AHR agonists in vivo. We now demonstrate that the enzyme D-amino acid oxidase (DAAO) catalyzes the production of AHR agonists through the enzymatic conversion of D-tryptophan to I3P. Moreover, we provide evidence that the nonenzymatic oxidation and condensation of I3P is a critical step in the generation of receptor agonists by DAAO and AST. Products of this process include two novel agonists, 1,3-di(1H-indol-3-yl)propan-2-one and 1-(1H-indol-3-yl)-3-(3H-indol-3-ylidene) propan-2-one [characterized in the accompanying paper, Chowdhury et al. (2009) Chem. Res. Toxicol., DOI: 10.1021/tx9000418], both of which can potently activate the AHR at concentrations in the nanomolar range. These results show that endogenous AHR activity can be modulated by I3P production from amino acid precursors through Multiple enzymatic pathways, including those catalyzed by DAAO and AST.