Inhibition of indoleamine 2,3 dioxygenase activity by H2O2

Anne Poljak, Ross Grant, Chris J D Austin, Joanne F. Jamie, Robert D. Willows, Osamu Takikawa, Tamantha K. Littlejohn, Roger J W Truscott, Mark J. Walker, Perminder Sachdev, George A. Smythe

Research output: Contribution to journalArticleResearchpeer-review

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. Crown

LanguageEnglish
Pages9-19
Number of pages11
JournalArchives of Biochemistry and Biophysics
Volume450
Issue number1
DOIs
Publication statusPublished - 1 Jun 2006

Fingerprint

Indoleamine-Pyrrole 2,3,-Dioxygenase
Enzyme activity
Enzymes
Tryptophan
Cysteine
Sulfinic Acids
Kynurenine
Enzyme inhibition
Oxidation
Thioredoxins
Sulfonic Acids
Matrix-Assisted Laser Desorption-Ionization Mass Spectrometry
Peroxides
Cell proliferation
Immunosuppressive Agents
Crowns
Catalysis
Sulfhydryl Compounds
Metabolism
Methionine

Cite this

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, Perminder ; Smythe, George A. / Inhibition of indoleamine 2,3 dioxygenase activity by H2O2. In: Archives of Biochemistry and Biophysics. 2006 ; Vol. 450, No. 1. pp. 9-19.
@article{6971b9fdfb9447c888f8ddcc2ffe0365,
title = "Inhibition of indoleamine 2,3 dioxygenase activity by H2O2",
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. Crown",
author = "Anne Poljak and Ross Grant and Austin, {Chris J D} and Jamie, {Joanne F.} and Willows, {Robert D.} and Osamu Takikawa and Littlejohn, {Tamantha K.} and Truscott, {Roger J W} and Walker, {Mark J.} and Perminder Sachdev and Smythe, {George A.}",
year = "2006",
month = "6",
day = "1",
doi = "10.1016/j.abb.2006.03.003",
language = "English",
volume = "450",
pages = "9--19",
journal = "Archives of Biochemistry and Biophysics",
issn = "0003-9861",
publisher = "Academic Press Inc.",
number = "1",

}

Poljak, A, Grant, R, Austin, CJD, Jamie, JF, Willows, RD, Takikawa, O, Littlejohn, TK, Truscott, RJW, Walker, MJ, Sachdev, P & Smythe, GA 2006, 'Inhibition of indoleamine 2,3 dioxygenase activity by H2O2', Archives of Biochemistry and Biophysics, vol. 450, no. 1, pp. 9-19. https://doi.org/10.1016/j.abb.2006.03.003

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, Perminder; Smythe, George A.

In: Archives of Biochemistry and Biophysics, Vol. 450, No. 1, 01.06.2006, p. 9-19.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Inhibition of indoleamine 2,3 dioxygenase activity by H2O2

AU - Poljak, Anne

AU - Grant, Ross

AU - Austin, Chris J D

AU - Jamie, Joanne F.

AU - Willows, Robert D.

AU - Takikawa, Osamu

AU - Littlejohn, Tamantha K.

AU - Truscott, Roger J W

AU - Walker, Mark J.

AU - Sachdev, Perminder

AU - Smythe, George A.

PY - 2006/6/1

Y1 - 2006/6/1

N2 - 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. Crown

AB - 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. Crown

UR - http://www.scopus.com/inward/record.url?scp=33646858094&partnerID=8YFLogxK

U2 - 10.1016/j.abb.2006.03.003

DO - 10.1016/j.abb.2006.03.003

M3 - Article

VL - 450

SP - 9

EP - 19

JO - Archives of Biochemistry and Biophysics

T2 - Archives of Biochemistry and Biophysics

JF - Archives of Biochemistry and Biophysics

SN - 0003-9861

IS - 1

ER -