Tryptophan 2,3-Dioxygenfase and Indoleamine 2,3-Dioxygenase 1 Make Separate, Tissue-Specific Contributions to Basal and Inflammation-Induced Kynurenine Pathway Metabolism in Mice
| Autor: | Robert Schwarcz, Hiroshi Funakoshi, Toshikazu Nakamura, Paul J. Muchowski, Francesca M. Notarangelo, Korrapati V. Sathyasaikumar, Paul B. Larkin |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Lipopolysaccharides Kynurenine pathway Metabolite Biophysics Biology Biochemistry Article 03 medical and health sciences chemistry.chemical_compound Mice Immune system Animals Indoleamine-Pyrrole 2 3 -Dioxygenase Indoleamine 2 3-dioxygenase Molecular Biology Kynurenine chemistry.chemical_classification Inflammation Brain Metabolism Tryptophan Oxygenase Mice Inbred C57BL 030104 developmental biology Enzyme chemistry Liver Organ Specificity Knockout mouse |
| Popis: | Background In mammals, the majority of the essential amino acid tryptophan is degraded via the kynurenine pathway (KP). Several KP metabolites play distinct physiological roles, often linked to immune system functions, and may also be causally involved in human diseases including neurodegenerative disorders, schizophrenia and cancer. Pharmacological manipulation of the KP has therefore become an active area of drug development. To target the pathway effectively, it is important to understand how specific KP enzymes control levels of the bioactive metabolites in vivo . Methods Here, we conducted a comprehensive biochemical characterization of mice with a targeted deletion of either tryptophan 2,3-dioxygenase (TDO) or indoleamine 2,3-dioxygenase (IDO), the two initial rate-limiting enzymes of the KP. These enzymes catalyze the same reaction, but differ in biochemical characteristics and expression patterns. We measured KP metabolite levels and enzyme activities and expression in several tissues in basal and immune-stimulated conditions. Results and conclusions Although our study revealed several unexpected downstream effects on KP metabolism in both knockout mice, the results were essentially consistent with TDO-mediated control of basal KP metabolism and a role of IDO in phenomena involving stimulation of the immune system. |
| Databáze: | OpenAIRE |
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