Abstract
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.
Original language | English |
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Pages (from-to) | 6374-6386 |
Number of pages | 13 |
Journal | The Journal of Biological Chemistry |
Volume | 293 |
Issue number | 17 |
DOIs | |
Publication status | Published - 27 Apr 2018 |
Funding
This study was supported by Austrian Science Funds Grant FWF P 20664 (to P. G. F.) and doctoral program BioToP Grant W1224 (to M. S.), Belgian National Fund for Scientific Research (FRS) Grants 3.4553.08 and T.0136.13 PDR, Université Libre de Bruxelles Grant FER-207, and Department of Inter-national Relationships of the Université Libre de Bruxelles Grant BRIC SJ/AL/BRIC/130. This study was also supported in part by National Insti-tutes of Health Grants RO1-NS074303 (to W. F. R.) and R43 AG040935 (to R. A. M.). This work was also supported by the Institute of Pathology and Genetics (IRSPG, Loverval, Belgium) and the “CHU of Charleroi.” Additional funds to support this work were provided by Sanford Burnham Prebys Medical Discovery Institute. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the respon-sibility of the authors and does not necessarily represent the official views of the National Institutes of Health. 2Postdoctoral researcher supported by the Belgian Fund for Scientific Research (FRS-FNRS).
Funders | Funder number |
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Austrian Science Funds | FWF P 20664 |
National Insti-tutes of Health | |
National Institutes of Health | RO1-NS074303 |
National Institute on Aging | R43AG040935 |
Children's Discovery Institute | |
Intelligence Community Postdoctoral Research Fellowship Program | W1224 |
Institute of Genetics | |
Austrian Science Fund | |
Fonds De La Recherche Scientifique - FNRS | 3.4553.08 |
Vrije Universiteit Brussel | |
Chung Hua University | |
Université Libre de Bruxelles | BRIC SJ/AL/BRIC/130, FER-207 |
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