Loading...
Inhibition of indoleamine 2,3 dioxygenase activity by H2O2
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
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
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.
Keywords
indoleamine 2, 3-dioxygenase, hydrogen peroxide, inhibition, kynurenine pathway, tryptophan metabolism, cysteine, oxidation
Date
2006
Type
Journal article
Journal
Archives of Biochemistry and Biophysics
Book
Volume
450
Issue
1
Page Range
9-19
Article Number
ACU Department
Collections
Relation URI
Source URL
Event URL
Open Access Status
License
File Access
Controlled