tryptophan oxygenase


Summary: A dioxygenase with specificity for the oxidation of the indoleamine ring of TRYPTOPHAN. It is a LIVER-specific enzyme that is the first and rate limiting enzyme in the kynurenine pathway of TRYPTOPHAN catabolism.

Top Publications

  1. Munn D, Zhou M, Attwood J, Bondarev I, Conway S, Marshall B, et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science. 1998;281:1191-3 pubmed
    ..Thus, by catabolizing tryptophan, the mammalian conceptus suppresses T cell activity and defends itself against rejection. ..
  2. Paglino A, Lombardo F, Arc B, Rizzi M, Rossi F. Purification and biochemical characterization of a recombinant Anopheles gambiae tryptophan 2,3-dioxygenase expressed in Escherichia coli. Insect Biochem Mol Biol. 2008;38:871-6 pubmed publisher
    ..Our study could contribute to understanding TDO regulation in vivo and to the identification of inhibitors to be used to alter Tryptophan homeostasis in the malaria vector...
  3. Danesch U, Gloss B, Schmid W, Schutz G, Schule R, Renkawitz R. Glucocorticoid induction of the rat tryptophan oxygenase gene is mediated by two widely separated glucocorticoid-responsive elements. EMBO J. 1987;6:625-30 pubmed
    Transcription of the gene coding for tryptophan oxygenase (TO) in rat liver is induced 10-fold by glucocorticoids...
  4. Mellor A, Chandler P, Lee G, Johnson T, Keskin D, Lee J, et al. Indoleamine 2,3-dioxygenase, immunosuppression and pregnancy. J Reprod Immunol. 2002;57:143-50 pubmed
    ..Here we review evidence that cells expressing IDO contribute to immunosuppression by inhibiting T-cell responses to tumor antigens and tissue allografts, as well as fetal tissues. ..
  5. Chauhan N, Basran J, Efimov I, Svistunenko D, Seward H, Moody P, et al. The role of serine 167 in human indoleamine 2,3-dioxygenase: a comparison with tryptophan 2,3-dioxygenase. Biochemistry. 2008;47:4761-9 pubmed publisher
    ..The data reveal significant differences between the IDO and TDO enzymes, and the implications of these results are discussed in terms of our current understanding of IDO and TDO catalysis. ..
  6. Takikawa O, Kuroiwa T, Yamazaki F, Kido R. Mechanism of interferon-gamma action. Characterization of indoleamine 2,3-dioxygenase in cultured human cells induced by interferon-gamma and evaluation of the enzyme-mediated tryptophan degradation in its anticellular activity. J Biol Chem. 1988;263:2041-8 pubmed
    ..These findings indicated that the growth inhibition by interferon-gamma was in part explained by the tryptophan depletion in the medium caused by the enzyme induction. ..
  7. Thackray S, Mowat C, Chapman S. Exploring the mechanism of tryptophan 2,3-dioxygenase. Biochem Soc Trans. 2008;36:1120-3 pubmed publisher
    ..In the present paper, we briefly discuss the function, structure and possible catalytic mechanism of these enzymes. ..
  8. Thackray S, Bruckmann C, Anderson J, Campbell L, Xiao R, Zhao L, et al. Histidine 55 of tryptophan 2,3-dioxygenase is not an active site base but regulates catalysis by controlling substrate binding. Biochemistry. 2008;47:10677-84 pubmed publisher
    ..8 mM oxidized, 4.1 microM reduced), H55A TDO (11.8 microM oxidized, 3.7 microM reduced), and H55S TDO (18.4 microM oxidized, 5.3 microM reduced). ..
  9. Capece L, Lewis Ballester A, Batabyal D, Di Russo N, Yeh S, Estrin D, et al. The first step of the dioxygenation reaction carried out by tryptophan dioxygenase and indoleamine 2,3-dioxygenase as revealed by quantum mechanical/molecular mechanical studies. J Biol Inorg Chem. 2010;15:811-23 pubmed publisher

More Information


  1. Sheoran A, King A, Velasco A, Pero J, Garneau Tsodikova S. Characterization of TioF, a tryptophan 2,3-dioxygenase involved in 3-hydroxyquinaldic acid formation during thiocoraline biosynthesis. Mol Biosyst. 2008;4:622-8 pubmed publisher
    ..The TioF reaction products generated during this study will be used as substrates for subsequent analysis of the other enzymes involved in 3HQA biosynthesis. ..
  2. Miller C, Llenos I, Cwik M, Walkup J, Weis S. Alterations in kynurenine precursor and product levels in schizophrenia and bipolar disorder. Neurochem Int. 2008;52:1297-303 pubmed publisher
    ..Nicotinamide, a pathway end product, did not differ between groups but was associated with cause of death (suicide) within the bipolar group (p=0.03). ..
  3. Fukumura E, Sugimoto H, Misumi Y, Ogura T, Shiro Y. Cooperative binding of L-trp to human tryptophan 2,3-dioxygenase: resonance Raman spectroscopic analysis. J Biochem. 2009;145:505-15 pubmed publisher
    ..These data and the inter-subunit contacts reported in the bacterial TDO structure suggest that the Y42 of rhTDO is responsible for the cooperative binding of l-Trp by participating in the active site of the adjacent subunit. ..
  4. MacKenzie C, Hadding U, Daubener W. Interferon-gamma-induced activation of indoleamine 2,3-dioxygenase in cord blood monocyte-derived macrophages inhibits the growth of group B streptococci. J Infect Dis. 1998;178:875-8 pubmed
    ..Control of the extracellular as well as intracellular L-tryptophan levels may thus be one of the effector mechanisms with which the immune system defends the host against GBS dissemination and disease. ..
  5. Guillemin G, Williams K, Smith D, Smythe G, Croitoru Lamoury J, Brew B. Quinolinic acid in the pathogenesis of Alzheimer's disease. Adv Exp Med Biol. 2003;527:167-76 pubmed
    ..Interestingly, IL-1beta has been found in association with plaques in AD. All together these data imply that QUIN may be, locally, one of the factors involved in the pathogenesis of neuronal damage in AD. ..
  6. Ohira K, Hagihara H, Toyama K, Takao K, Kanai M, Funakoshi H, et al. Expression of tryptophan 2,3-dioxygenase in mature granule cells of the adult mouse dentate gyrus. Mol Brain. 2010;3:26 pubmed publisher
    ..These findings indicate that TDO might be required at a late-stage of granule cell development, such as during axonal and dendritic growth, synaptogenesis and its maturation. ..
  7. Mellor A, Munn D. Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation?. Immunol Today. 1999;20:469-73 pubmed
    ..Here, Andrew Mellor and David Munn discuss evidence that cells that synthesize IDO protect the mammalian fetus from maternal T-cell attack and argue that this mechanism might have wider implications for the control of T-cell responses. ..
  8. Kamimura S, Eguchi K, Yonezawa M, Sekiba K. Localization and developmental change of indoleamine 2,3-dioxygenase activity in the human placenta. Acta Med Okayama. 1991;45:135-9 pubmed
    ..The indoleamine 2,3-dioxygenase activity was significantly lower in placenta with retarded intrauterine development. These results suggest the importance of placental indoleamine 2,3-dioxygenase during fetal development. ..
  9. Guillemin G, Brew B, Noonan C, Takikawa O, Cullen K. Indoleamine 2,3 dioxygenase and quinolinic acid immunoreactivity in Alzheimer's disease hippocampus. Neuropathol Appl Neurobiol. 2005;31:395-404 pubmed
    ..Our data imply that QUIN may be involved in the complex and multifactorial cascade leading to neuro-degeneration in AD. These results may open a new therapeutic door for AD patients. ..
  10. Chung L, Li X, Sugimoto H, Shiro Y, Morokuma K. Density functional theory study on a missing piece in understanding of heme chemistry: the reaction mechanism for indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase. J Am Chem Soc. 2008;130:12299-309 pubmed publisher
    ..Effects of ionization of the imidazole and negatively charged oxyporphyrin complex on the key dioxygen activation process are also studied. ..
  11. Basran J, Rafice S, Chauhan N, Efimov I, Cheesman M, Ghamsari L, et al. A kinetic, spectroscopic, and redox study of human tryptophan 2,3-dioxygenase. Biochemistry. 2008;47:4752-60 pubmed publisher
    ..These new findings illustrate that significant mechanistic differences exist across the heme dioxygenase family, and the data are discussed within this broader framework. ..
  12. Dick R, Murray B, Reid M, Correia M. Structure--function relationships of rat hepatic tryptophan 2,3-dioxygenase: identification of the putative heme-ligating histidine residues. Arch Biochem Biophys. 2001;392:71-8 pubmed
    ..Whether these His residues are both provided by the same TDO subunit or a different TDO subunit remains to be determined. ..
  13. Fridell Y, Searles L. Vermilion as a small selectable marker gene for Drosophila transformation. Nucleic Acids Res. 1991;19:5082 pubmed
  14. Malina H, Martin X. Indoleamine 2,3-dioxygenase: antioxidant enzyme in the human eye. Graefes Arch Clin Exp Ophthalmol. 1996;234:457-62 pubmed
    ..IDO activity was 351 (+/-67.3) nmol/g tissue/h. Free tryptophan is degradated in the human eye by IDO, an antioxidative enzyme. IDO may be an antioxidant mechanism in the eye. ..
  15. Grohmann U, Fallarino F, Bianchi R, Belladonna M, Vacca C, Orabona C, et al. IL-6 inhibits the tolerogenic function of CD8 alpha+ dendritic cells expressing indoleamine 2,3-dioxygenase. J Immunol. 2001;167:708-14 pubmed
    ..The activity of IL-6 includes down-regulation of IFN-gammaR expression in the CD8(+) DC subset and correlates to a reduced ability of these cells to metabolize tryptophan and initiate T cell apoptosis in vitro. ..
  16. Lorenzen M, Brown S, Denell R, Beeman R. Cloning and characterization of the Tribolium castaneum eye-color genes encoding tryptophan oxygenase and kynurenine 3-monooxygenase. Genetics. 2002;160:225-34 pubmed
    ..The Tribolium orthologs of the Drosophila eye-color genes vermilion (tryptophan oxygenase) and cinnabar (kynurenine 3-monooxygenase) were cloned and characterized...
  17. Chauhan N, Thackray S, Rafice S, Eaton G, Lee M, Efimov I, et al. Reassessment of the reaction mechanism in the heme dioxygenases. J Am Chem Soc. 2009;131:4186-7 pubmed publisher
    ..These observations suggest that deprotonation of the indole N(1) is not essential for catalysis, and an alternative reaction mechanism, based on the known chemistry of indoles, is presented. ..
  18. Chon S, Hassanain H, Gupta S. Cooperative role of interferon regulatory factor 1 and p91 (STAT1) response elements in interferon-gamma-inducible expression of human indoleamine 2,3-dioxygenase gene. J Biol Chem. 1996;271:17247-52 pubmed
    ..The results indicate that the response of INDO gene to IFN-gamma depends on a cooperative role of IFN-gamma-responsive factors binding to the ISRE and GAS elements. ..
  19. Finger E, Bluestone J. When ligand becomes receptor--tolerance via B7 signaling on DCs. Nat Immunol. 2002;3:1056-7 pubmed
  20. Zhang Y, Kang S, Mukherjee T, Bale S, Crane B, Begley T, et al. Crystal structure and mechanism of tryptophan 2,3-dioxygenase, a heme enzyme involved in tryptophan catabolism and in quinolinate biosynthesis. Biochemistry. 2007;46:145-55 pubmed publisher
    ..Modeling of the putative (S)-tryptophan hydroperoxide intermediate into the active site, as well as substrate analogue and mutagenesis studies, are consistent with a Criegee mechanism for the reaction...
  21. 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;109:2497-502 pubmed publisher
    ..Our results describe a mechanism of tumoral immune resistance based on TDO expression and establish proof-of-concept for the use of TDO inhibitors in cancer therapy. ..
  22. Tankiewicz A, Pawlak D, Buczko W. [Enzymes of the kynurenine pathway]. Postepy Hig Med Dosw. 2001;55:715-31 pubmed
    ..Attention was paid to the potential use of those biochemical parameter as biomarkers of many disease activity. ..
  23. Maezono K, Tashiro K, Nakamura T. Deduced primary structure of rat tryptophan-2,3-dioxygenase. Biochem Biophys Res Commun. 1990;170:176-81 pubmed
    ..It has twelve histidine residues around its hydrophobic region, which has homology with some heme proteins and oxygenase, suggesting that this hydrophobic region might to be the core of TO for the activity. ..
  24. Terness P, Bauer T, Rose L, Dufter C, Watzlik A, Simon H, et al. Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites. J Exp Med. 2002;196:447-57 pubmed
  25. Gupta R, Fu R, Liu A, Hendrich M. EPR and Mössbauer spectroscopy show inequivalent hemes in tryptophan dioxygenase. J Am Chem Soc. 2010;132:1098-109 pubmed publisher
  26. Daubener W, MacKenzie C, Hadding U. Establishment of T-helper type 1- and T-helper type 2-like human Toxoplasma antigen-specific T-cell clones. Immunology. 1995;86:79-84 pubmed
    ..We therefore conclude that Toxoplasma-antigen is able to activate T-helper type 1 (Th1)- and Th2-like human T cells, and only IFN-gamma-producing cells are capable of inducing anti-parasitic effector mechanisms. ..
  27. Mellor A, Sivakumar J, Chandler P, Smith K, Molina H, Mao D, et al. Prevention of T cell-driven complement activation and inflammation by tryptophan catabolism during pregnancy. Nat Immunol. 2001;2:64-8 pubmed
    ..These data show that IDO activity protects the fetus by suppressing T cell-driven local inflammatory responses to fetal alloantigens. ..
  28. Munn D, Shafizadeh E, Attwood J, Bondarev I, Pashine A, Mellor A. Inhibition of T cell proliferation by macrophage tryptophan catabolism. J Exp Med. 1999;189:1363-72 pubmed
    ..We speculate that expression of IDO by certain antigen presenting cells in vivo allows them to suppress unwanted T cell responses. ..
  29. Heyes M, Chen C, Major E, Saito K. Different kynurenine pathway enzymes limit quinolinic acid formation by various human cell types. Biochem J. 1997;326 ( Pt 2):351-6 pubmed
    ..Kynurenine 3-hydroxylase and, in some cells, kynureninase and 3-hydroxyanthranilate 3,4-dioxygenase are important determinants of whether a cell can make quinolinate. ..
  30. Terentis A, Thomas S, Takikawa O, Littlejohn T, Truscott R, Armstrong R, et al. The heme environment of recombinant human indoleamine 2,3-dioxygenase. Structural properties and substrate-ligand interactions. J Biol Chem. 2002;277:15788-94 pubmed
    ..Together these data indicate that the strong proximal Fe-His bond and the strong H-bonding and/or steric interactions between l-Trp and dioxygen in the distal pocket are likely crucial for the enzymatic activity of hIDO. ..
  31. Mellor A, Keskin D, Johnson T, Chandler P, Munn D. Cells expressing indoleamine 2,3-dioxygenase inhibit T cell responses. J Immunol. 2002;168:3771-6 pubmed
    ..These outcomes suggest that genetically enhanced IDO activity inhibited T cell proliferation in vitro and in vivo. Genetic manipulation of IDO activity may be of therapeutic utility in suppressing undesirable T cell responses. ..
  32. Wirleitner B, Neurauter G, Schröcksnadel K, Frick B, Fuchs D. Interferon-gamma-induced conversion of tryptophan: immunologic and neuropsychiatric aspects. Curr Med Chem. 2003;10:1581-91 pubmed
    ..These observations provide a basis for the better understanding of mood disorder and related symptoms in chronic diseases. ..
  33. Batabyal D, Yeh S. Human tryptophan dioxygenase: a comparison to indoleamine 2,3-dioxygenase. J Am Chem Soc. 2007;129:15690-701 pubmed
  34. Suzuki T, Kawamichi H, Imai K. Amino acid sequence, spectral, oxygen-binding, and autoxidation properties of indoleamine dioxygenase-like myoglobin from the gastropod mollusc Turbo cornutus. J Protein Chem. 1998;17:817-26 pubmed
    ..5 and 6.3 in the presence of tryptophan. We suggest that a noncatalytic binding site for tryptophan, in which several dissociation groups with pKa > or = 7.6 are involved, remains in Turbo myoglobin as a relic of molecular evolution. ..
  35. Besansky N, Mukabayire O, Benedict M, Rafferty C, Hamm D, McNitt L. The Anopheles gambiae tryptophan oxygenase gene expressed from a baculovirus promoter complements Drosophila melanogaster vermilion. Insect Biochem Mol Biol. 1997;27:803-5 pubmed
    An Anopheles gambiae cDNA encoding tryptophan oxygenase was placed under the control of the constitutive baculovirus promoter, ie-1...
  36. Takikawa O, Yoshida R, Kido R, Hayaishi O. Tryptophan degradation in mice initiated by indoleamine 2,3-dioxygenase. J Biol Chem. 1986;261:3648-53 pubmed
    ..These findings indicated that indoleamine 2,3-dioxygenase actively oxidized tryptophan in mice and that its induction resulted in an increase in tryptophan degradation. ..
  37. Kanai M, Nakamura T, Funakoshi H. Identification and characterization of novel variants of the tryptophan 2,3-dioxygenase gene: differential regulation in the mouse nervous system during development. Neurosci Res. 2009;64:111-7 pubmed publisher
    ..Our findings indicate that tdo and its novel variants may play an important role in not only the liver but also in local areas in developing and adult brain. ..
  38. Mellor A, Munn D, Chandler P, Keskin D, Johnson T, Marshall B, et al. Tryptophan catabolism and T cell responses. Adv Exp Med Biol. 2003;527:27-35 pubmed
  39. Inayoshi Y, Kaneoka H, Machida Y, Terajima M, Dohda T, Miyake K, et al. Repression of GR-mediated expression of the tryptophan oxygenase gene by the SWI/SNF complex during liver development. J Biochem. 2005;138:457-65 pubmed, we studied the role of SWI/SNF containing BRM or BRG1 in the expression of the liver-specific tryptophan oxygenase (TO) and tyrosine aminotransferase genes...
  40. Efimov I, Basran J, Thackray S, Handa S, Mowat C, Raven E. Structure and reaction mechanism in the heme dioxygenases. Biochemistry. 2011;50:2717-24 pubmed publisher
  41. Bodaghi B, Goureau O, Zipeto D, Laurent L, Virelizier J, Michelson S. Role of IFN-gamma-induced indoleamine 2,3 dioxygenase and inducible nitric oxide synthase in the replication of human cytomegalovirus in retinal pigment epithelial cells. J Immunol. 1999;162:957-64 pubmed
    ..Thus, CMV infection blocks the inducible nitric oxide synthase pathway activated by IFN-gamma and IL-1beta, but cannot counteract the IFN-induced IDO pathway, which ultimately controls its replication in primary human RPE cells. ..
  42. Forouhar F, Anderson J, Mowat C, Vorobiev S, Hussain A, Abashidze M, et al. Molecular insights into substrate recognition and catalysis by tryptophan 2,3-dioxygenase. Proc Natl Acad Sci U S A. 2007;104:473-8 pubmed publisher
    ..The active site is completely devoid of water during catalysis, which is supported by our electrochemical studies showing significant stabilization of the enzyme upon substrate binding...
  43. Batabyal D, Yeh S. Substrate-protein interaction in human tryptophan dioxygenase: the critical role of H76. J Am Chem Soc. 2009;131:3260-70 pubmed publisher
    ..The important structural and functional roles of H76 in hTDO is underscored by the observation that the electronic configuration of the active ternary complex, l-Trp-O(2)-hTDO, is sensitive to the H76 mutations. ..
  44. Huengsberg M, Winer J, Gompels M, Round R, Ross J, Shahmanesh M. Serum kynurenine-to-tryptophan ratio increases with progressive disease in HIV-infected patients. Clin Chem. 1998;44:858-62 pubmed
    ..This may lead to changes in quinolinic acid and explain some of the pathogenesis of AIDS dementia. ..
  45. Littlejohn T, Takikawa O, Truscott R, Walker M. Asp274 and his346 are essential for heme binding and catalytic function of human indoleamine 2,3-dioxygenase. J Biol Chem. 2003;278:29525-31 pubmed
    ..This observation indicates that Asp274 may coordinate to heme directly as the distal ligand or is essential in maintaining the conformation of the heme pocket. ..
  46. Kamiya A, Kojima N, Kinoshita T, Sakai Y, Miyaijma A. Maturation of fetal hepatocytes in vitro by extracellular matrices and oncostatin M: induction of tryptophan oxygenase. Hepatology. 2002;35:1351-9 pubmed
    ..such conditions, fetal hepatic cells failed to express genes for adult liver-specific enzymes, such as tryptophan oxygenase (TO)...
  47. Roy E, Takikawa O, Kranz D, Brown A, Thomas D. Neuronal localization of indoleamine 2,3-dioxygenase in mice. Neurosci Lett. 2005;387:95-9 pubmed
    ..Thus, neuronal IDO could contribute to the vulnerability of neurons to inflammatory conditions. ..
  48. Davydov R, Chauhan N, Thackray S, Anderson J, Papadopoulou N, Mowat C, et al. Probing the ternary complexes of indoleamine and tryptophan 2,3-dioxygenases by cryoreduction EPR and ENDOR spectroscopy. J Am Chem Soc. 2010;132:5494-500 pubmed publisher
    ..This substrate interaction further helps control the reactivity of the heme-bound dioxygen by "shielding" it from water. ..
  49. Yamamoto S, Hayaishi O. Tryptophan pyrrolase of rabbit intestine. D- and L-tryptophan-cleaving enzyme or enzymes. J Biol Chem. 1967;242:5260-6 pubmed
  50. Chung L, Li X, Sugimoto H, Shiro Y, Morokuma K. ONIOM study on a missing piece in our understanding of heme chemistry: bacterial tryptophan 2,3-dioxygenase with dual oxidants. J Am Chem Soc. 2010;132:11993-2005 pubmed publisher
    ..The comparison between Xanthomonas campestris TDO and some heme as well non-heme oxygenases is also discussed. ..
  51. Miller C, Llenos I, Dulay J, Weis S. Upregulation of the initiating step of the kynurenine pathway in postmortem anterior cingulate cortex from individuals with schizophrenia and bipolar disorder. Brain Res. 2006;1073-1074:25-37 pubmed
    ..02). Unlike the results for schizophrenia and bipolar disorder, the increase in TDO2 protein in the major depression group was not associated with an increase in kynurenine concentration. ..
  52. Guillemin G, Smythe G, Takikawa O, Brew B. Expression of indoleamine 2,3-dioxygenase and production of quinolinic acid by human microglia, astrocytes, and neurons. Glia. 2005;49:15-23 pubmed
    ..However, astrocytes and neurons had the ability to catabolize QUIN. This study also provides the first evidence of IDO expression and lack of production of QUIN in culture of primary human neurons. ..
  53. Miller C, Llenos I, Dulay J, Barillo M, Yolken R, Weis S. Expression of the kynurenine pathway enzyme tryptophan 2,3-dioxygenase is increased in the frontal cortex of individuals with schizophrenia. Neurobiol Dis. 2004;15:618-29 pubmed
    ..These results add to the evidence that kynurenine pathway changes might be involved in the pathogenesis of schizophrenia and the schizophrenia-like psychoses of other disorders. ..