title: 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.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA, USA; Neuroscience Graduate Program, University of California, San Francisco, CA, USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Larkin
authors.affiliation: Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Korrapati V
authors.initials: KV
authors.lastname: Sathyasaikumar
authors.affiliation: Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Notarangelo
authors.affiliation: Center for Advanced Research and Education (CARE), Asahikawa Medical University, 1-1-1- Higashinijo Midorigaoka, Asahikawa 078-8510, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Funakoshi
authors.affiliation: Neurogen Inc., 1-1-52-201 Nakahozumi, Ibaraki 567-0034, Japan.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Schwarcz
authors.affiliation: 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.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Muchowski
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000209:etiology / Q000378:metabolism; D007737:Kynurenine / Q000097:blood / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D014366:Tryptophan Oxygenase / Q000235:genetics / Q000378:metabolism*
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008070:Lipopolysaccharides; D007737:Kynurenine; D014366:Tryptophan Oxygenase
keywords: Cancer; Inflammation; Neurodegeneration; Schizophrenia; Tryptophan