Advertisement

Amino Acids

, Volume 46, Issue 9, pp 2155–2163 | Cite as

Human indoleamine 2,3-dioxygenase-2 has substrate specificity and inhibition characteristics distinct from those of indoleamine 2,3-dioxygenase-1

  • Georgios Pantouris
  • Martynas Serys
  • Hajime J. Yuasa
  • Helen J. Ball
  • Christopher G. MowatEmail author
Original Article

Abstract

Indoleamine 2,3-dioxygenase-2 (IDO2) is one of three enzymes (alongside tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase (IDO1)) that catalyse dioxygenation of l-tryptophan as the first step in the kynurenine pathway. Despite the reported expression of IDO2 in tumours, some fundamental characteristics of the enzyme, such as substrate specificity and inhibition selectivity, are still to be clearly defined. In this study, we report the kinetic and inhibition characteristics of recombinant human IDO2. Choosing from a series of likely IDO2 substrates, we screened 54 tryptophan derivatives and tryptophan-like molecules, and characterised the 8 with which the enzyme was most active. Specificity of IDO2 for the two isomers of 1-methyltryptophan was also evaluated and the findings compared with those obtained in other studies on IDO2 and IDO1. Interestingly, IDO2 demonstrates behaviour distinct from that of IDO1 in terms of substrate specificity and affinity, such that we have identified tryptophan derivatives that are mutually exclusive as substrates for IDO1 and IDO2. Our results support the idea that the antitumour activity of 1-Me-d-Trp is unlikely to be related with competitive inhibition of IDO2, and also imply that there are subtle differences in active site structure in the two enzymes that may be exploited in the development of specific inhibitors of these enzymes, a route which may prove important in defining their role(s) in cancer.

Keywords

Indoleamine 2,3-dioxygenase-2 Kynurenine pathway Substrate Inhibitor Specificity 

Notes

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Austin CJD, Mailu BM, Maghzal GJ, Sanchez-Perez A, Rahlfs S, Zocher K, Yuasa HJ, Arthur JW, Becker K, Stocker R et al (2010) Biochemical characteristics and inhibitor selectivity of mouse indoleamine 2,3-dioxygenase-2. Amino Acids 39:565–578PubMedCrossRefGoogle Scholar
  2. Bakmiwewa SM, Fatokun AA, Tran A, Payne RJ, Hunt NH, Ball HJ (2012) Identification of selective inhibitors of indoleamine 2,3-dioxygenase. Bioorg Med Chem Lett 22:7641–7646PubMedCrossRefGoogle Scholar
  3. Ball HJ, Sanchez-Perez A, Weiser S, Austin CJD, Astelbauer F, Miu J, McQuillan JA, Stocker R, Jermiin LS, Hunt NH (2007) Characterization of an indoleamine 2,3-dioxygenase-like protein found in humans and mice. Gene 396:203–213PubMedCrossRefGoogle Scholar
  4. Basran J, Rafice SA, Chauhan N, Efimov I, Cheesman MR, Ghamsari L, Raven EL (2008) A kinetic, spectroscopic, and redox study of human tryptophan 2,3-dioxygenase. Biochemistry 47:4752–4760PubMedCrossRefGoogle Scholar
  5. Batabyal D, Yeh SR (2007) Human tryptophan dioxygenase: a comparison to indoleamine 2,3-dioxygenase. J Am Chem Soc 129:15690–15701PubMedCrossRefGoogle Scholar
  6. Chang MY, Metz R, Muller AJ, Prendergast GC (2009) IDO2 (indoleamine 2,3-dioxygenase 2) Atlas Genet Cytogenet Oncol Haematol. http://AtlasGeneticsOncology.org/Genes/IDO2ID44387ch8p11.html
  7. Chauhan N, Thackray SJ, Rafice SA, Eaton G, Lee M, Efimov I, Basran J, Jenkins PR, Mowat CG, Chapman SK, Raven EL (2009) Reassessment of the reaction mechanism in the heme dioxygenases. J Am Chem Soc 131:4186–4187PubMedCrossRefGoogle Scholar
  8. Efimov I, Basran J, Sun X, Chauhan N, Chapman SK, Mowat CG, Raven EL (2012) The mechanism of substrate inhibition in human indoleamine 2,3-dioxygenase. J Am Chem Soc 134:3034–3041PubMedCentralPubMedCrossRefGoogle Scholar
  9. Hou DY, Muller AJ, Sharma MD, DuHadaway J, Banerjee T, Johnson M, Mellor AL, Prendergast GC, Munn DH et al (2007) Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses. Cancer Res 67:792–801PubMedCrossRefGoogle Scholar
  10. Lo BK, Jalili RB, Zloty D, Ghahary A, Cowan B, Dutz JP, Carr N, Shapiro J, McElwee KJ (2011) CXCR3 ligands promote expression of functional indoleamine 2,3-dioxygenase in basal cell carcinoma keratinocytes. Br J Dermatol 165:1030–1036PubMedCrossRefGoogle Scholar
  11. Löb S, Königsrainer A, Zieker D, Brücher BLDM, Rammensee HG, Opelz G, Terness P (2009a) IDO1 and IDO2 are expressed in human tumors: Levo- but not dextro-1-methyl tryptophan inhibits tryptophan catabolism. Cancer Immunol Immunother 58:153–157PubMedCrossRefGoogle Scholar
  12. Löb S, Königsrainer A, Rammensee HG, Opelz G, Terness P (2009b) Inhibitors of indoleamine-2,3-dioxygenase for cancer therapy: can we see the wood for the trees? Nat Rev Cancer 9:445–452PubMedCrossRefGoogle Scholar
  13. Meininger D, Zalameda L, Liu Y, Stepan LP, Borges L, McCarter JD, Sutherland CL (2011) Purification and kinetic characterization of human indoleamine 2,3-dioxygenases 1 and 2 (IDO1 and IDO2) and discovery of selective IDO1 inhibitors. Biochim Biophys Acta 1814:1947–1954PubMedCrossRefGoogle Scholar
  14. Metz R, DuHadaway JB, Kamasani U, Laury-Kleintop L, Muller AJ, Prendergast GC et al (2007) Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor indoleamine 2,3-dioxygenase inhibitory compound d-1-methyl-tryptophan. Cancer Res 67:7082–7087PubMedCrossRefGoogle Scholar
  15. Metz R, Rust S, Duhadaway JB, Mautino MR, Munn DH, Vahanian NN, Link CJ, Prendergast GC (2012) IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: a novel IDO effector pathway targeted by d-1-methyltryptophan. Oncoimmunology 1:1460–1468PubMedCentralPubMedCrossRefGoogle Scholar
  16. Papadopoulou ND, Mewies M, McLean KJ, Seward HE, Svistunenko DA, Munro AW, Raven EL (2005) Redox and spectroscopic properties of human indoleamine 2,3-dioxygenase and a His303Ala variant: implications for catalysis. Biochemistry 44:14318–14328PubMedCrossRefGoogle Scholar
  17. Qian F, Liao J, Villella J, Edwards R, Kalinski P, Lele S, Shrikant P, Odunsi K (2012) Effects of 1-methyltryptophan stereoisomers on IDO2 enzyme activity and IDO2-mediated arrest of human T cell proliferation. Cancer Immunol Immunother 61:2013–2020PubMedCrossRefGoogle Scholar
  18. Sørensen RB, Køllgaard T, Andersen RS, van den Berg JH, Svane IM, Straten PT, Andersen MH et al (2011) Spontaneous cytotoxic T-cell reactivity against indoleamine 2,3-dioxygenase-2. Cancer Res 71:2038–2044PubMedCrossRefGoogle Scholar
  19. Takikawa O, Kuroiwa T, Yamazaki F, Kido R (1988) Characterization of indoleamine 2,3-dioxygenase in various human cells induced by IFN-γ and evaluation of the enzyme-mediated tryptophan degradation in its anticellular activity. J Biol Chem 263:2041–2048PubMedGoogle Scholar
  20. Yuasa HJ, Takubo M, Takahashi A, Hasegawa T, Noma H, Suzuki T (2007) Evolution of vertebrate indoleamine 2,3-dioxygenases. J Mol Evol 65:705–714PubMedCrossRefGoogle Scholar
  21. Yuasa HJ, Ball HJ, Austin CJD, Hunt NH (2010) 1-l-Methyltryptophan is a more effective inhibitor of vertebrate IDO2 enzymes than 1-d-methyltryptophan. Comp Biochem Physiol B 157:10–15PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2014

Authors and Affiliations

  • Georgios Pantouris
    • 1
  • Martynas Serys
    • 1
  • Hajime J. Yuasa
    • 2
  • Helen J. Ball
    • 3
  • Christopher G. Mowat
    • 1
    Email author
  1. 1.EaStCHEM, School of ChemistryUniversity of EdinburghEdinburghUK
  2. 2.Laboratory of Biochemistry, Department of Applied Science, Faculty of Science, National University of ScienceNational University Corporation Kochi UniversityKochiJapan
  3. 3.Molecular Immunopathology Unit, Discipline of Pathology, School of Medical Sciences, and Bosch InstituteUniversity of SydneySydneyAustralia

Personalised recommendations