King's College London

Research portal

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

Research output: Contribution to journalArticlepeer-review

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

Original languageEnglish
Article number6626
JournalNature Communications
Volume12
Issue number1
DOIs
PublishedDec 2021

Bibliographical 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: © 2021, The Author(s).

King's Authors

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.

View graph of relations

© 2020 King's College London | Strand | London WC2R 2LS | England | United Kingdom | Tel +44 (0)20 7836 5454