| D-amino acid oxidase generates agonists of the aryl hydrocarbon receptor from D-tryptophan. | |
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MedLine Citation:
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PMID: 19860415 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Linh P Nguyen; Erin L Hsu; Goutam Chowdhury; Miroslav Dostalek; F Peter Guengerich; Christopher A Bradfield |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural |
Journal Detail:
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Title: Chemical research in toxicology Volume: 22 ISSN: 1520-5010 ISO Abbreviation: Chem. Res. Toxicol. Publication Date: 2009 Dec |
Date Detail:
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Created Date: 2009-12-21 Completed Date: 2010-03-09 Revised Date: 2011-03-03 |
Medline Journal Info:
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Nlm Unique ID: 8807448 Medline TA: Chem Res Toxicol Country: United States |
Other Details:
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Languages: eng Pagination: 1897-904 Citation Subset: IM |
Affiliation:
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McArdle Laboratory, Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Cell Line, Tumor D-Amino-Acid Oxidase / genetics, metabolism* Humans Indoles / chemistry*, isolation & purification Receptors, Aryl Hydrocarbon / agonists*, metabolism Tryptophan / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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P30 CA014520/CA/NCI NIH HHS; P30 CA014520-339026/CA/NCI NIH HHS; P30 ES000267/ES/NIEHS NIH HHS; R37 CA090426/CA/NCI NIH HHS; R37 ES005703/ES/NIEHS NIH HHS; R37 ES005703-21/ES/NIEHS NIH HHS; T32 CA009135/CA/NCI NIH HHS; T32 ES007015/ES/NIEHS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/1,3-di(1H-indol-3-yl)propan-2-one; 0/1-(1H-indol-3-yl)-3-(3H-indol-3-ylidene)propan-2-one; 0/Indoles; 0/Receptors, Aryl Hydrocarbon; 392-12-1/indol-3-yl pyruvic acid; 73-22-3/Tryptophan; EC 1.4.3.3/D-Amino-Acid Oxidase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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