Inhibition of indoleamine 2,3 dioxygenase activity by H2O2

Journal article


Poljak, Anne, Grant, Ross, Austin, Chris J. D., Jamie, Joanne F., Willows, Robert D., Takikawa, Osamu, Littlejohn, Tamantha K., Truscott, Roger J. W., Walker, Mark J., Sachdev, Peminder and Smythe, George A.. (2006). Inhibition of indoleamine 2,3 dioxygenase activity by H2O2. Archives of Biochemistry and Biophysics. 450(1), pp. 9 - 19. https://doi.org/10.1016/j.abb.2006.03.003
AuthorsPoljak, Anne, Grant, Ross, Austin, Chris J. D., Jamie, Joanne F., Willows, Robert D., Takikawa, Osamu, Littlejohn, Tamantha K., Truscott, Roger J. W., Walker, Mark J., Sachdev, Peminder and Smythe, George A.
Abstract

Indoleamine 2,3-dioxygenase is the first and rate limiting enzyme of the kynurenine pathway of tryptophan metabolism, has potent effects on cell proliferation and mediates antimicrobial, antitumorogenic, and immunosuppressive effects. As a potent cytotoxic effector, the mechanisms of indoleamine 2,3-dioxygenase inhibition deserve greater attention. The work presented here represents the first systematic study exploring the mechanisms by which low levels of hydrogen peroxide (10–100 μM) inhibit indoleamine 2,3-dioxygenase in vitro. Following brief peroxide exposure both enzyme inhibition and structural changes were observed. Loss of catalysis was accompanied by oxidation of several cysteine residues to sulfinic and sulfonic acids, observed by electrospray and MALDI mass spectrometry. Enzyme activity could in part be preserved in the presence of sulfhydryl containing compounds, particularly DTT and methionine. However, these structural alterations did not prevent substrate (l-tryptophan) binding. Some enzyme activity could be recovered in the presence of thioredoxin, indicating that the inhibitory effect of H2O2 is at least partially reversible in vitro. We present evidence that cysteine oxidation represents one mechanism of indoleamine 2,3-dioxygenase inhibition.

Keywordsindoleamine 2; 3-dioxygenase; hydrogen peroxide; inhibition; kynurenine pathway; tryptophan metabolism; cysteine; oxidation
Year2006
JournalArchives of Biochemistry and Biophysics
Journal citation450 (1), pp. 9 - 19
PublisherAcademic Press
ISSN0003-9861
Digital Object Identifier (DOI)https://doi.org/10.1016/j.abb.2006.03.003
Scopus EID2-s2.0-33646858094
Page range9 - 19
Research GroupSchool of Behavioural and Health Sciences
Publisher's version
File Access Level
Controlled
Place of publicationUnited States of America
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