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Overview of the Kynurenine Pathway of Tryptophan Metabolism

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Targeting the Broadly Pathogenic Kynurenine Pathway

Abstract

Tryptophan (TRP) is an essential amino acid that plays a critical role in synthesis of a host of modulatory biomolecules including serotonin, melatonin, tryptamine, and kynurenine (KYN). TRP can either be incorporated into proteins, converted to the neurotransmitter serotonin (5-hydroxytryptamine), or metabolized to kynurenine. The majority of dietary TRP is metabolized via the kynurenine pathway (KP). The initial and rate-limiting step in the KP involves one of three enzymes, namely, the two isoforms of indoleamine 2-3-dioxygenase (IDO1 and IDO2) and tryptophan 2,3-dioxygenase (TDO). In this chapter, we provide a broad overview of the KP and explore the gene regulation of the key enzymes involved.

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Abbreviations

3-HK:

3-Hydroxykynurenine

AhR:

Aryl hydrocarbon receptor

GR:

Glucocorticoid receptor

IDO:

Indoleamine 2,3-dioxygenase

KAT:

Kynurenine aminotransferase

KYNA:

Kynurenic acid

KYN:

Kynurenine

KMO:

Kynurenine 3-monooxygenase

KP:

Kynurenine pathway

QUIN:

Quinolinic acid

TRP:

Tryptophan

TDO:

Tryptophan 2,3-dioxygenase

STAT:

Signal transducer and activator of transcription

References

  1. Schwarcz R, Bruno JP, Muchowski PJ, Wu HQ. Kynurenines in the mammalian brain: when physiology meets pathology. Nat Rev Neurosci. 2012;13(7):465–77.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature. 2011;478(7368):197–203. doi:10.1038/nature10491.

    Article  CAS  PubMed  Google Scholar 

  3. Barouki R, Aggerbeck M, Aggerbeck L, Coumoul X. The aryl hydrocarbon receptor system. Drug Metabol Drug Interact. 2012;27(1):3–8.

    Article  CAS  PubMed  Google Scholar 

  4. Cartharius K, Frech K, Grote K, Klocke B, Haltmeier M, Klingenhoff A, et al. MatInspector and beyond: promoter analysis based on transcription factor binding sites. Bioinformatics. 2005;21(13):2933–42.

    Article  CAS  PubMed  Google Scholar 

  5. He YW, Wang HS, Zeng J, Fang X, Chen HY, Du J, et al. Sodium butyrate inhibits interferon-gamma induced indoleamine 2,3-dioxygenase expression via STAT1 in nasopharyngeal carcinoma cells. Life Sci. 2013;93(15):509–15.

    Article  CAS  PubMed  Google Scholar 

  6. Sotero-Esteva WD, Wolfe D, Ferris M, Taylor MW. An indoleamine 2,3-dioxygenase-negative mutant is defective in stat1 DNA binding: differential response to IFN-gamma and IFN-alpha. J Interferon Cytokine Res. 2000;20(7):623–32.

    Article  CAS  PubMed  Google Scholar 

  7. Xue ZT, Sjogren HO, Salford LG, Widegren B. An epigenetic mechanism for high, synergistic expression of indoleamine 2,3-dioxygenase 1 (IDO1) by combined treatment with zebularine and IFN-gamma: potential therapeutic use in autoimmune diseases. Mol Immunol. 2012;51(2):101–11.

    Article  CAS  PubMed  Google Scholar 

  8. Bankoti J, Rase B, Simones T, Shepherd DM. Functional and phenotypic effects of AhR activation in inflammatory dendritic cells. Toxicol Appl Pharmacol. 2010;246(1-2):18–28.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Mezrich JD, Nguyen LP, Kennedy G, Nukaya M, Fechner JH, Zhang X, et al. SU5416, a VEGF receptor inhibitor and ligand of the AHR, represents a new alternative for immunomodulation. PLoS One. 2012;7(9), e44547.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Vogel CF, Wu D, Goth SR, Baek J, Lollies A, Domhardt R, et al. Aryl hydrocarbon receptor signaling regulates NF-kappaB RelB activation during dendritic-cell differentiation. Immunol Cell Biol. 2013;91(9):568–75.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Soichot M, Vaast A, Vignau J, Guillemin GJ, Lhermitte M, Broly F, et al. Characterization of functional polymorphisms and glucocorticoid-responsive elements in the promoter of TDO2, a candidate gene for ethanol-induced behavioural disorders. Alcohol Alcohol. 2013;48(4):415–25.

    Article  CAS  PubMed  Google Scholar 

  12. Ott M, Litzenburger UM, Rauschenbach KJ, Bunse L, Ochs K, Sahm F, et al. Suppression of TDO-mediated tryptophan catabolism in glioblastoma cells by a steroid-responsive FKBP52-dependent pathway. Glia. 2015;63(1):78–90.

    Article  PubMed  Google Scholar 

  13. Larrea E, Riezu-Boj JI, Gil-Guerrero L, Casares N, Aldabe R, Sarobe P, et al. Upregulation of indoleamine 2,3-dioxygenase in hepatitis C virus infection. J Virol. 2007;81(7):3662–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Medana IM, Day NP, Salahifar-Sabet H, Stocker R, Smythe G, Bwanaisa L, et al. Metabolites of the kynurenine pathway of tryptophan metabolism in the cerebrospinal fluid of Malawian children with malaria. J Infect Dis. 2003;188(6):844–9.

    Article  CAS  PubMed  Google Scholar 

  15. Huttunen R, Syrjanen J, Aittoniemi J, Oja SS, Raitala A, Laine J, et al. High activity of indoleamine 2,3 dioxygenase enzyme predicts disease severity and case fatality in bacteremic patients. Shock. 2010;33(2):149–54.

    Article  CAS  PubMed  Google Scholar 

  16. Prendergast GC, Smith C, Thomas S, Mandik-Nayak L, Laury-Kleintop L, Metz R, et al. Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer. Cancer Immunol Immunother. 2014;63(7):721–35.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Peters JC. Tryptophan nutrition and metabolism: an overview. Adv Exp Med Biol. 1991;294:345–58.

    Article  CAS  PubMed  Google Scholar 

  18. Pilotte L, Larrieu P, Stroobant V, Colau D, Dolusic E, Frederick R, et al. Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase. Proc Natl Acad Sci U S A. 2012;109(7):2497–502.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature. 2011;478(7368):197–203.

    Article  CAS  PubMed  Google Scholar 

  20. Kanai M, Funakoshi H, Takahashi H, Hayakawa T, Mizuno S, Matsumoto K, et al. Tryptophan 2,3-dioxygenase is a key modulator of physiological neurogenesis and anxiety-related behavior in mice. Mol Brain. 2009;2:8.

    Article  PubMed Central  PubMed  Google Scholar 

  21. Pisar M, Forrest CM, Khalil OS, McNair K, Vincenten MC, Qasem S, et al. Modified neocortical and cerebellar protein expression and morphology in adult rats following prenatal inhibition of the kynurenine pathway. Brain Res. 2014;1576:1–17.

    Article  CAS  PubMed  Google Scholar 

  22. Savitz J, Drevets WC, Smith CM, Victor TA, Wurfel BE, Bellgowan PS, et al. Putative neuroprotective and neurotoxic kynurenine pathway metabolites are associated with hippocampal and amygdalar volumes in subjects with major depressive disorder. Neuropsychopharmacology. 2014;40(2):463–71.

    Article  PubMed  Google Scholar 

  23. Kegel ME, Bhat M, Skogh E, Samuelsson M, Lundberg K, Dahl ML, et al. Imbalanced kynurenine pathway in schizophrenia. Int J Tryptophan Res. 2014;7:15–22.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Yu P, Mosbrook DM, Tagle DA. Genomic organization and expression analysis of mouse kynurenine aminotransferase II, a possible factor in the pathophysiology of Huntington's disease. Mamm Genome. 1999;10(9):845–52.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by a grant (R01 CA123451 to SM) from the National Cancer Institute; a grant from the Fund for Medical Research and Education, Wayne State University School of Medicine (to SM); and Strategic Research Initiative Grants from the Karmanos Cancer Institute (to SM).

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Authors and Affiliations

  1. Department of Neurosurgery, Wayne State University School of Medicine, 4160 John R St, Suite 930, Detroit, 48201, MI, USA

    Sharon K. Michelhaugh, Anthony R. Guastella & Sandeep Mittal M.D., F.R.C.S.C., F.A.C.S.

  2. Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA

    Anthony R. Guastella & Sandeep Mittal M.D., F.R.C.S.C., F.A.C.S.

  3. Karmanos Cancer Institute, Detroit, MI, USA

    Sandeep Mittal M.D., F.R.C.S.C., F.A.C.S.

Authors
  1. Sharon K. Michelhaugh
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  2. Anthony R. Guastella
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  3. Sandeep Mittal M.D., F.R.C.S.C., F.A.C.S.
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Corresponding author

Correspondence to Sandeep Mittal M.D., F.R.C.S.C., F.A.C.S. .

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Editors and Affiliations

  1. Chairman, Department of Neurosurgery, Wayne State University, Detroit, Michigan, USA

    Sandeep Mittal

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Michelhaugh, S.K., Guastella, A.R., Mittal, S. (2015). Overview of the Kynurenine Pathway of Tryptophan Metabolism. In: Mittal, S. (eds) Targeting the Broadly Pathogenic Kynurenine Pathway. Springer, Cham. https://doi.org/10.1007/978-3-319-11870-3_1

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