Myeloperoxidase-catalyzed oxidation of cyanide to cyanate: A potential carbamylation route involved in the formation of atherosclerotic plaques?

Cédric Delporte, Karim Zouaoui Boudjeltia, Paul G. Furtmüller, Richard A. Maki, Marc Dieu, Caroline Noyon, Monika Soudi, Damien Dufour, Catherine Coremans, Vincent Nuyens, Florence Reye, Alexandre Rousseau, Martine Raes, Nicole Moguilevsky, Michel Vanhaeverbeek, Jean Ducobu, Jean Nève, Bernard Robaye, Luc Vanhamme, Wanda F. ReynoldsChristian Obinger, Pierre Van Antwerpen

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Protein carbamylation by cyanate is a post-translational modification associated with several (patho)physiological conditions, including cardiovascular disorders. However, the biochemical pathways leading to protein carbamylation are incompletely characterized. This work demonstrates that the heme protein myeloperoxidase (MPO), which is secreted at high concentrations at inflammatory sites from stimulated neutrophils and monocytes, is able to catalyze the two-electron oxidation of cyanide to cyanate and promote the carbamylation of taurine, lysine, and low-density lipoproteins. We probed the role of cyanide as both electron donor and low-spin ligand by pre-steady-state and steady-state kinetic analyses and analyzed reaction products by MS. Moreover, we present two further pathways of carbamylation that involve reaction products of MPO, namely oxidation of cyanide by hypochlorous acid and reaction of thiocyanate with chloramines. Finally, using an in vivo approach with mice on a high-fat diet and carrying the human MPO gene, we found that during chronic exposure to cyanide, mimicking exposure to pollution and smoking, MPO promotes protein-bound accumulation of carbamyllysine (homocitrulline) in atheroma plaque, demonstrating a link between cyanide exposure and atheroma. In summary, our findings indicate that cyanide is a substrate for MPO and suggest an additional pathway for in vivo cyanate formation and protein carbamylation that involves MPO either directly or via its reaction products hypochlorous acid or chloramines. They also suggest that chronic cyanide exposure could promote the accumulation of carbamylated proteins in atherosclerotic plaques.

langue originaleAnglais
Pages (de - à)6374-6386
Nombre de pages13
journalJournal of Biological Chemistry
Numéro de publication17
Les DOIs
Etat de la publicationPublié - 27 avr. 2018

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