D-amino acid oxidase generates agonists of the aryl hydrocarbon receptor from D-tryptophan

Linh P. Nguyen, Erin L Hsu, Goutam Chowdhury, Miroslav Dostalek, F. Peter Guengerich, Christopher A. Bradfield

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26 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1897-1904
Number of pages8
JournalChemical Research in Toxicology
Volume22
Issue number12
DOIs
StatePublished - Dec 21 2009

ASJC Scopus subject areas

  • Toxicology

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    Nguyen, L. P., Hsu, E. L., Chowdhury, G., Dostalek, M., Guengerich, F. P., & Bradfield, C. A. (2009). D-amino acid oxidase generates agonists of the aryl hydrocarbon receptor from D-tryptophan. Chemical Research in Toxicology, 22(12), 1897-1904. https://doi.org/10.1021/tx900043s