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Biochim Biophys Acta. 2016 Nov;1860(11 Pt A):2345-2354. doi: 10.1016/j.bbagen.2016.07.002. Epub 2016 Jul 5.

Tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase 1 make separate, tissue-specific contributions to basal and inflammation-induced kynurenine pathway metabolism in mice.

Author information

1
Gladstone Institute of Neurological Disease, San Francisco, CA, USA; Neuroscience Graduate Program, University of California, San Francisco, CA, USA.
2
Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
3
Center for Advanced Research and Education (CARE), Asahikawa Medical University, 1-1-1- Higashinijo Midorigaoka, Asahikawa 078-8510, Japan.
4
Neurogen Inc., 1-1-52-201 Nakahozumi, Ibaraki 567-0034, Japan.
5
Gladstone Institute of Neurological Disease, San Francisco, CA, USA; Neuroscience Graduate Program, University of California, San Francisco, CA, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, CA, USA; The Taube-Koret Center for Huntington's Disease Research, San Francisco, CA, USA. Electronic address: paulmuchowski@kynurex.com.

Abstract

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.

KEYWORDS:

Cancer; Inflammation; Neurodegeneration; Schizophrenia; Tryptophan

PMID:
27392942
PMCID:
PMC5808460
DOI:
10.1016/j.bbagen.2016.07.002
[Indexed for MEDLINE]
Free PMC Article

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