Hydrogen peroxide signaling via its transformation to a stereospecific alkyl hydroperoxide that escapes reductive inactivation

Raphael F. Queiroz; Christopher P. Stanley; Kathryn Wolhuter; Stephanie M.Y. Kong; Ragul Rajivan; Naomi McKinnon; Giang T.H. Nguyen; Antonella Roveri; Sebastian Guttzeit; Philip Eaton; William A. Donald; Fulvio Ursini; Christine C. Winterbourn; Anita Ayer; Roland Stocker

doi:10.1038/s41467-021-26991-5

Hydrogen peroxide signaling via its transformation to a stereospecific alkyl hydroperoxide that escapes reductive inactivation

Raphael F. Queiroz, Christopher P. Stanley, Kathryn Wolhuter, Stephanie M.Y. Kong, Ragul Rajivan, Naomi McKinnon, Giang T.H. Nguyen, Antonella Roveri, Sebastian Guttzeit, Philip Eaton, William A. Donald, Fulvio Ursini, Christine C. Winterbourn, Anita Ayer^*, Roland Stocker

^*Corresponding author for this work

Cardiovascular Research

Research output: Contribution to journal › Article › peer-review

10 Citations (Scopus)

Abstract

During systemic inflammation, indoleamine 2,3-dioxygenase 1 (IDO1) becomes expressed in endothelial cells where it uses hydrogen peroxide (H₂O₂) to oxidize L-tryptophan to the tricyclic hydroperoxide, cis-WOOH, that then relaxes arteries via oxidation of protein kinase G 1α. Here we show that arterial glutathione peroxidases and peroxiredoxins that rapidly eliminate H₂O₂, have little impact on relaxation of IDO1-expressing arteries, and that purified IDO1 forms cis-WOOH in the presence of peroxiredoxin 2. cis-WOOH oxidizes protein thiols in a selective and stereospecific manner. Compared with its epimer trans-WOOH and H₂O₂, cis-WOOH reacts slower with the major arterial forms of glutathione peroxidases and peroxiredoxins while it reacts more readily with its target, protein kinase G 1α. Our results indicate a paradigm of redox signaling by H₂O₂ via its enzymatic conversion to an amino acid-derived hydroperoxide that ‘escapes’ effective reductive inactivation to engage in selective oxidative activation of key target proteins.

Original language	English
Article number	6626
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-26991-5
Publication status	Published - Dec 2021

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Queiroz, R. F., Stanley, C. P., Wolhuter, K., Kong, S. M. Y., Rajivan, R., McKinnon, N., Nguyen, G. T. H., Roveri, A., Guttzeit, S., Eaton, P., Donald, W. A., Ursini, F., Winterbourn, C. C., Ayer, A., & Stocker, R. (2021). Hydrogen peroxide signaling via its transformation to a stereospecific alkyl hydroperoxide that escapes reductive inactivation. Nature Communications, 12(1), Article 6626. https://doi.org/10.1038/s41467-021-26991-5

@article{04241650c64d445088177f758afba66b,

title = "Hydrogen peroxide signaling via its transformation to a stereospecific alkyl hydroperoxide that escapes reductive inactivation",

abstract = "During systemic inflammation, indoleamine 2,3-dioxygenase 1 (IDO1) becomes expressed in endothelial cells where it uses hydrogen peroxide (H2O2) to oxidize L-tryptophan to the tricyclic hydroperoxide, cis-WOOH, that then relaxes arteries via oxidation of protein kinase G 1α. Here we show that arterial glutathione peroxidases and peroxiredoxins that rapidly eliminate H2O2, have little impact on relaxation of IDO1-expressing arteries, and that purified IDO1 forms cis-WOOH in the presence of peroxiredoxin 2. cis-WOOH oxidizes protein thiols in a selective and stereospecific manner. Compared with its epimer trans-WOOH and H2O2, cis-WOOH reacts slower with the major arterial forms of glutathione peroxidases and peroxiredoxins while it reacts more readily with its target, protein kinase G 1α. Our results indicate a paradigm of redox signaling by H2O2 via its enzymatic conversion to an amino acid-derived hydroperoxide that {\textquoteleft}escapes{\textquoteright} effective reductive inactivation to engage in selective oxidative activation of key target proteins.",

author = "Queiroz, {Raphael F.} and Stanley, {Christopher P.} and Kathryn Wolhuter and Kong, {Stephanie M.Y.} and Ragul Rajivan and Naomi McKinnon and Nguyen, {Giang T.H.} and Antonella Roveri and Sebastian Guttzeit and Philip Eaton and Donald, {William A.} and Fulvio Ursini and Winterbourn, {Christine C.} and Anita Ayer and Roland Stocker",

note = "Funding Information: This work was supported by National Health & Medical Research Council Program Grant and Senior Principal Research Fellowship to R.S.; and an Early to Mid-Career Research Grant from NSW Health to C.P.S. W.A.D. thanks the Australian Research Council for financial support. We thank A. Peskin (University of Otago) for help with initial experiments on Prx2 expression, A.J. Kettle (University of Otago) for providing isotopically labeled GSSG and GSH-NEM, N.J. Bulleid (University of Glasgow) for providing Prx4 plasmid, and J. Chiu and P. Hogg (both University of Sydney) for providing purified TrxR. We also thank F.C. Meotti and J.C. Toledo Jr. (both University of Sao Paulo) for their generous advice on the kinetic modeling and D. Newington for his help with animal experiments. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1038/s41467-021-26991-5",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

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number = "1",

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Queiroz, RF, Stanley, CP, Wolhuter, K, Kong, SMY, Rajivan, R, McKinnon, N, Nguyen, GTH, Roveri, A, Guttzeit, S, Eaton, P, Donald, WA, Ursini, F, Winterbourn, CC, Ayer, A & Stocker, R 2021, 'Hydrogen peroxide signaling via its transformation to a stereospecific alkyl hydroperoxide that escapes reductive inactivation', Nature Communications, vol. 12, no. 1, 6626. https://doi.org/10.1038/s41467-021-26991-5

TY - JOUR

T1 - Hydrogen peroxide signaling via its transformation to a stereospecific alkyl hydroperoxide that escapes reductive inactivation

AU - Queiroz, Raphael F.

AU - Stanley, Christopher P.

AU - Wolhuter, Kathryn

AU - Kong, Stephanie M.Y.

AU - Rajivan, Ragul

AU - McKinnon, Naomi

AU - Nguyen, Giang T.H.

AU - Roveri, Antonella

AU - Guttzeit, Sebastian

AU - Eaton, Philip

AU - Donald, William A.

AU - Ursini, Fulvio

AU - Winterbourn, Christine C.

AU - Ayer, Anita

AU - Stocker, Roland

N1 - Funding Information: This work was supported by National Health & Medical Research Council Program Grant and Senior Principal Research Fellowship to R.S.; and an Early to Mid-Career Research Grant from NSW Health to C.P.S. W.A.D. thanks the Australian Research Council for financial support. We thank A. Peskin (University of Otago) for help with initial experiments on Prx2 expression, A.J. Kettle (University of Otago) for providing isotopically labeled GSSG and GSH-NEM, N.J. Bulleid (University of Glasgow) for providing Prx4 plasmid, and J. Chiu and P. Hogg (both University of Sydney) for providing purified TrxR. We also thank F.C. Meotti and J.C. Toledo Jr. (both University of Sao Paulo) for their generous advice on the kinetic modeling and D. Newington for his help with animal experiments. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12

Y1 - 2021/12

N2 - During systemic inflammation, indoleamine 2,3-dioxygenase 1 (IDO1) becomes expressed in endothelial cells where it uses hydrogen peroxide (H2O2) to oxidize L-tryptophan to the tricyclic hydroperoxide, cis-WOOH, that then relaxes arteries via oxidation of protein kinase G 1α. Here we show that arterial glutathione peroxidases and peroxiredoxins that rapidly eliminate H2O2, have little impact on relaxation of IDO1-expressing arteries, and that purified IDO1 forms cis-WOOH in the presence of peroxiredoxin 2. cis-WOOH oxidizes protein thiols in a selective and stereospecific manner. Compared with its epimer trans-WOOH and H2O2, cis-WOOH reacts slower with the major arterial forms of glutathione peroxidases and peroxiredoxins while it reacts more readily with its target, protein kinase G 1α. Our results indicate a paradigm of redox signaling by H2O2 via its enzymatic conversion to an amino acid-derived hydroperoxide that ‘escapes’ effective reductive inactivation to engage in selective oxidative activation of key target proteins.

AB - During systemic inflammation, indoleamine 2,3-dioxygenase 1 (IDO1) becomes expressed in endothelial cells where it uses hydrogen peroxide (H2O2) to oxidize L-tryptophan to the tricyclic hydroperoxide, cis-WOOH, that then relaxes arteries via oxidation of protein kinase G 1α. Here we show that arterial glutathione peroxidases and peroxiredoxins that rapidly eliminate H2O2, have little impact on relaxation of IDO1-expressing arteries, and that purified IDO1 forms cis-WOOH in the presence of peroxiredoxin 2. cis-WOOH oxidizes protein thiols in a selective and stereospecific manner. Compared with its epimer trans-WOOH and H2O2, cis-WOOH reacts slower with the major arterial forms of glutathione peroxidases and peroxiredoxins while it reacts more readily with its target, protein kinase G 1α. Our results indicate a paradigm of redox signaling by H2O2 via its enzymatic conversion to an amino acid-derived hydroperoxide that ‘escapes’ effective reductive inactivation to engage in selective oxidative activation of key target proteins.

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U2 - 10.1038/s41467-021-26991-5

DO - 10.1038/s41467-021-26991-5

M3 - Article

AN - SCOPUS:85119120188

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 6626

ER -

Hydrogen peroxide signaling via its transformation to a stereospecific alkyl hydroperoxide that escapes reductive inactivation

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