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Amino Acids

, Volume 39, Issue 2, pp 565–578 | Cite as

Biochemical characteristics and inhibitor selectivity of mouse indoleamine 2,3-dioxygenase-2

  • Christopher Jonathan Daraius Austin
  • B. M. Mailu
  • G. J. Maghzal
  • A. Sanchez-Perez
  • S. Rahlfs
  • K. Zocher
  • H. J. Yuasa
  • J. W. Arthur
  • K. Becker
  • R. Stocker
  • N. H. Hunt
  • H. J. BallEmail author
Original Article

Abstract

The first step in the kynurenine pathway of tryptophan catabolism is the cleavage of the 2,3-double bond of the indole ring of tryptophan. In mammals, this reaction is performed independently by indoleamine 2,3-dioxygenase-1 (IDO1), tryptophan 2,3-dioxygenase (TDO) and the recently discovered indoleamine 2,3-dioxygenase-2 (IDO2). Here we describe characteristics of a purified recombinant mouse IDO2 enzyme, including its pH stability, thermal stability and structural features. An improved assay system for future studies of recombinant/isolated IDO2 has been developed using cytochrome b 5 as an electron donor. This, the first description of the interaction between IDO2 and cytochrome b 5, provides further evidence of the presence of a physiological electron carrier necessary for activity of enzymes in the “IDO family”. Using this assay, the kinetic activity and substrate range of IDO2 were shown to be different to those of IDO1. 1-Methyl-d-tryptophan, a current lead IDO inhibitor used in clinical trials, was a poor inhibitor of both IDO1 and IDO2 activity. This suggests that its immunosuppressive effect may be independent of pharmacological inhibition of IDO enzymes, in the mouse at least. The different biochemical characteristics of the mouse IDO proteins suggest that they have evolved to have distinct biological roles.

Keywords

Cytochrome b5 Oxidation/reduction Electron donation IDO2 

Notes

Acknowledgments

This work was supported by the Australian Research Council, the National Health and Medical Research Council and the German Research Council (SFB 535, TP A12 to KB). Boniface Mailu is a scholar of the German Academic Exchange Service which is gratefully acknowledged. RS was supported by a NHMRC Senior Principal Research Fellowship, a University of Sydney Professorial Fellowship, and the University of Sydney Medical Foundation. We thank Joanne Jamie and Robert Willows of Macquarie University for use of the MUCAB CD spectrometer.

Supplementary material

726_2010_475_MOESM1_ESM.doc (895 kb)
Supplementary material (DOC 895 kb)

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Christopher Jonathan Daraius Austin
    • 1
  • B. M. Mailu
    • 2
  • G. J. Maghzal
    • 3
  • A. Sanchez-Perez
    • 1
  • S. Rahlfs
    • 2
  • K. Zocher
    • 2
  • H. J. Yuasa
    • 4
  • J. W. Arthur
    • 5
  • K. Becker
    • 2
  • R. Stocker
    • 3
  • N. H. Hunt
    • 1
  • H. J. Ball
    • 1
    Email author
  1. 1.Molecular Immunopathology Unit, Discipline of Pathology and Bosch InstituteUniversity of SydneyCamperdownAustralia
  2. 2.Interdisciplinary Research CenterGiessen UniversityGiessenGermany
  3. 3.Centre for Vascular Research, School of Medical Sciences (Pathology) and Bosch Institute, Sydney Medical SchoolUniversity of SydneySydneyAustralia
  4. 4.Laboratory of Biochemistry, Department of Applied Science, Faculty of ScienceNational University Corporation Kochi UniversityKochiJapan
  5. 5.Discipline of Medicine, Central Clinical School, Sydney BioinformaticsUniversity of SydneySydneyAustralia

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