Aspartate Aminotransferase Generates Proagonists of the Aryl Hydrocarbon Receptor

Bittinger, Mark; Nguyen, Linh P.; Bradfield, Christopher A.

doi:10.1124/mol.64.3.550

Cited by 97 publications

(91 citation statements)

References 27 publications

(22 reference statements)

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“…We next investigated the mechanism of inhibition of HIF-1α by indolepyruvate. Several studies suggest tryptophan catabolites, including breakdown products of indolepyruvate, act as endogenous ligands for the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor (35,36). AhR was of particular interest because AhR dimerizes with aryl hydrocarbon receptor nuclear translocator (ARNT) (36,37), the binding partner of HIF-1α; thus, an increase in AhR activation could cause a decrease in HIF-1α-ARNT complexes, reducing the production of HIF-1α-dependent target genes.…”

Section: Indolepyruvate Alters the Glycolytic State Of The Cell Follomentioning

confidence: 99%

Trypanosoma bruceimetabolite indolepyruvate decreases HIF-1α and glycolysis in macrophages as a mechanism of innate immune evasion

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The parasite Trypanasoma brucei causes African trypanosomiasis, known as sleeping sickness in humans and nagana in domestic animals. These diseases are a major burden in the 36 sub-Saharan African countries where the tsetse fly vector is endemic. Untreated trypanosomiasis is fatal and the current treatments are stagedependent and can be problematic during the meningoencephalitic stage, where no new therapies have been developed in recent years and the current drugs have a low therapeutic index. There is a need for more effective treatments and a better understanding of how these parasites evade the host immune response will help in this regard. The bloodstream form of T. brucei excretes significant amounts of aromatic ketoacids, including indolepyruvate, a transamination product of tryptophan. This study demonstrates that this process is essential in bloodstream forms, is mediated by a specialized isoform of cytoplasmic aminotransferase and, importantly, reveals an immunomodulatory role for indolepyruvate. Indolepyruvate prevents the LPS-induced glycolytic shift in macrophages. This effect is the result of an increase in the hydroxylation and degradation of the transcription factor hypoxia-inducible factor-1α (HIF-1α). The reduction in HIF-1α levels by indolepyruvate, following LPS or trypanosome activation, results in a decrease in production of the proinflammatory cytokine IL-1β. These data demonstrate an important role for indolepyruvate in immune evasion by T. brucei.immunometabolism | innate immunity | immune evasion |

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Section: Indolepyruvate Alters the Glycolytic State Of The Cell Follomentioning

confidence: 99%

Trypanosoma bruceimetabolite indolepyruvate decreases HIF-1α and glycolysis in macrophages as a mechanism of innate immune evasion

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…23,25 Candidate endogenous ligands of the AhR include ketocholesterol, bilirubin, indigo, lipoxin A 4 , and tryptophan derivatives such as ITE. 22,[27][28][29][30][31][32] However, the AhR is betterknown for its ligation by a diverse group of xenobiotics, the most potent of which is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). 22 Agonist binding induces nuclear translocation of the AhR, which allows it to regulate expression of a variety of genes, including those of the cytochrome P450 family of drug-metabolizing enzymes.…”

mentioning

confidence: 99%

The Aryl Hydrocarbon Receptor Ligand ITE Inhibits TGFβ1-Induced Human Myofibroblast Differentiation

Lehmann

Xia

Kulkarni

et al. 2011

The American Journal of Pathology

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Fibrosis can occur in any human tissue when the normal wound healing response is amplified. Such amplification results in fibroblast proliferation, myofibroblast differentiation, and excessive extracellular matrix deposition. Occurrence of these sequelae in organs such as the eye or lung can result in severe consequences to health. Unfortunately, medical treatment of fibrosis is limited by a lack of safe and effective therapies. These therapies may be developed by identifying agents that inhibit critical steps in fibrotic progression; one such step is myofibroblast differentiation triggered by transforming growth factor-␤1 (TGF␤1). In this study, we demonstrate that TGF␤1-induced myofibroblast differentiation is blocked in human fibroblasts by a candidate endogenous aryl hydrocarbon receptor (AhR) ligand 2-(1=H-indole-3=-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). Our data show that ITE disrupts TGF␤1 signaling by inhibiting the nuclear translocation of Smad2/3/4. Although ITE functions as an AhR agonist, and biologically persistent AhR agonists, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, cause severe toxic effects, ITE exhibits no toxicity. Interestingly, ITE effectively inhibits TGF␤1-driven myofibroblast differentiation in AhR ؊/؊ fibroblasts: Its ability to inhibit TGF␤1 signaling is AhR independent. As supported by the results of this study, the small molecule ITE inhibits myofibroblast differentiation and may be useful clinically as an antiscarring agent.

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“…I3P from l-Trp is produced by aspartate aminotransferase (40), and I3P from d-Trp is produced by d-amino acid oxidase (40). The toxicity of d-Trp was higher than that of l-Trp; the amount of d-Trp that did not reduce bodyweight gain was 0.15 g/kg of body weight, whereas that of l-Trp was 2 g/kg of body weight (3).…”

Section: Discussionmentioning

confidence: 99%

“…The toxicity of l-Trp and d-Trp could be mediated by I3P, which produces numerous aryl hydrocarbon receptor (AHR)-activating compounds (40,41). I3P from l-Trp is produced by aspartate aminotransferase (40), and I3P from d-Trp is produced by d-amino acid oxidase (40).…”

Section: Discussionmentioning

confidence: 99%

The Urinary Ratio of 3-Hydroxykynurenine/3-Hydroxyanthranilic Acid Is an Index to Predicting the Adverse Effects of D-Tryptophan in Rats

Shibata

Ohno

Sano

et al. 2014

J Nutr Sci Vitaminol

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SummaryThe adverse effects of d-tryptophan and the possibility of it being a surrogate index for predicting adverse effects in rats were investigated. Male rats were fed one of several test diets (20% casein diets with 0% (control), 0.1%, 0.2%, 0.3%, 0.4%, and 0.5% d-tryptophan) for 21 d, and 24-h urine samples on the final day of the experiment were collected. Analyses of food intake and body-weight changes revealed adverse effects to be observed in the group fed the 0.3% d-tryptophan diet. We propose urinary levels of 3-hydroxykynurenine/3-hydroxyanthranilic acid to be surrogate indicators for predicting the adverse effects of d-tryptophan from the break point of body-weight gains and urinary levels of d-tryptophan metabolites. The reaction 3-hydroxykynurenine→3-hydroxyanthranilic acid is catalyzed by the pyridoxal phosphate-dependent enzyme kynureninase. Increasing urinary 3-hydrokykynurenine indicates kynureninase deficiency. Intake of d-tryptophan in rats fed the 0.3% d-tryptophan diet was 0.21 g/kg body weight and feeding of the 0.3% d-tryptophan diet did not elicit adverse effects. Thus, the safe level of d-tryptophan was less than 0.2% in the diet, 0.15 g/kg body weight, in rats.

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Aspartate Aminotransferase Generates Proagonists of the Aryl Hydrocarbon Receptor

Cited by 97 publications

References 27 publications

Trypanosoma bruceimetabolite indolepyruvate decreases HIF-1α and glycolysis in macrophages as a mechanism of innate immune evasion

Trypanosoma bruceimetabolite indolepyruvate decreases HIF-1α and glycolysis in macrophages as a mechanism of innate immune evasion

The Aryl Hydrocarbon Receptor Ligand ITE Inhibits TGFβ1-Induced Human Myofibroblast Differentiation

The Urinary Ratio of 3-Hydroxykynurenine/3-Hydroxyanthranilic Acid Is an Index to Predicting the Adverse Effects of D-Tryptophan in Rats

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