Myeloperoxidase-catalyzed oxidation of cyanide to cyanate: A potential carbamylation route involved in the formation of atherosclerotic plaques?
Myeloperoxidase-catalyzed oxidation of cyanide to cyanate: A potential carbamylation route involved in the formation of atherosclerotic plaques?
复制标题
DOI：
10.1074/jbc.m117.801076
复制
发表时间：
2018-04-27
影响因子：
4.8
通讯作者：
Van Antwerpen, Pierre
中科院分区：
文献类型：
--
作者：
Delporte, Cedric;Boudjeltia, Karim Zouaoui;Van Antwerpen, Pierre
氰酸酯对蛋白质的氨甲基化是一种翻译后修饰，与几种(病理)生理条件有关，包括心血管疾病。然而，导致蛋白质氨甲基化的生化途径还不完全确定。这项工作表明，在炎症部位高浓度分泌的血红素蛋白髓过氧化物酶(MPO)能够催化氰化物的双电子氧化生成氰酸酯，并促进牛磺酸、赖氨酸和低密度脂蛋白的氨甲基化。通过稳态前动力学分析和稳态动力学分析，探讨了氰化物作为电子供体和低自旋配体的作用，并对反应产物进行了MS分析，提出了两条涉及MPO反应产物的氨甲酰化反应途径，即次氯酸氧化氰化物和硫氰酸盐与氯胺的反应。最后，通过对高脂饮食和携带人类MPO基因的小鼠进行体内实验，我们发现，在长期暴露于氰化物期间，MPO促进了动脉粥样硬化斑块中与蛋白质结合的氨基甲酰赖氨酸(高瓜氨酸)的积累，从而证明了氰化物暴露与动脉粥样硬化之间的联系。综上所述，我们的发现表明氰化物是MPO的底物，并提示了体内氰酸盐形成和蛋白质氨基甲酰化的另一种途径，该途径直接或通过其反应产物次氯酸或氯胺涉及MPO。他们还表明，慢性氰化物暴露可能会促进动脉粥样硬化斑块中氨基甲酰化蛋白的积累。
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.