The pattern of apolipoprotein A-I lysine carbamylation reflects its lipidation state and the chemical environment within human atherosclerotic aorta.
The pattern of apolipoprotein A-I lysine carbamylation reflects its lipidation state and the chemical environment within human atherosclerotic aorta.
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DOI：
10.1016/j.jbc.2022.101832
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发表时间：
2022-04
影响因子：
4.8
通讯作者：
Hazen, Stanley L.
中科院分区：
文献类型：
--
作者：
Battle, Shawna;Gogonea, Valentin;Willard, Belinda;Wang, Zeneng;Fu, Xiaoming;Huang, Ying;Graham, Linda M.;Cameron, Scott J.;DiDonato, Joseph A.;Crabb, John W.;Hazen, Stanley L.
蛋白质赖氨酸氨甲酰化是一种不可逆的翻译后修饰，导致产生高瓜氨酸（N-ε-氨甲酰赖氨酸），其不再具有带电荷的ε-氨基部分。两种不同的途径可以促进蛋白质氨甲酰化。一种是尿素分解，形成氰酸酯（CNO−）和反应性亲电试剂异氰酸酯的平衡混合物。第二种途径涉及髓过氧化物酶（MPO）催化的硫氰酸盐（SCN−）氧化，产生CNO−和异氰酸盐。载脂蛋白A-I（apoA-I）是高密度脂蛋白（HDL）的主要蛋白质成分，是MPO催化的体内修饰的靶点，可将心脏保护性脂蛋白转化为促动脉粥样硬化和促凋亡的脂蛋白。我们假设，监测位点特异性氨甲酰化模式的载脂蛋白A-I恢复从人类动脉粥样硬化主动脉可以提供洞察动脉壁内的化学环境。为了测试这一点，我们首先映射从apoA-I的体外氨甲酰化获得的氨甲酰赖氨酸通过尿素驱动的（非酶）和炎症驱动的（酶）途径在脂质贫乏和脂化apoA-I（重构HDL）。我们的研究结果表明，在HDL上的已知MPO结合位点附近的赖氨酸残基优先通过酶（MPO）氨甲酰化途径靶向，而非酶途径导致氨甲酰化赖氨酸残基沿着apoA-I多肽链几乎均匀分布。对人主动脉粥样硬化的apoA-I进行定量蛋白质组学分析，发现21个赖氨酸残基中有16个被氨甲酰化，并表明体内大多数apoA-I氨甲酰化通过非酶CNO−途径发生在“脂质贫乏”的apoA-I形式上。从动脉组织中回收的apoA-I氨甲酰化的监测模式可以提供对apoA-I结构和人类动脉粥样硬化内的化学环境的见解。
Protein lysine carbamylation is an irreversible post-translational modification resulting in generation of homocitrulline (N-ε-carbamyllysine), which no longer possesses a charged ε-amino moiety. Two distinct pathways can promote protein carbamylation. One results from urea decomposition, forming an equilibrium mixture of cyanate (CNO−) and the reactive electrophile isocyanate. The second pathway involves myeloperoxidase (MPO)-catalyzed oxidation of thiocyanate (SCN−), yielding CNO− and isocyanate. Apolipoprotein A-I (apoA-I), the major protein constituent of high-density lipoprotein (HDL), is a known target for MPO-catalyzed modification in vivo, converting the cardioprotective lipoprotein into a proatherogenic and proapoptotic one. We hypothesized that monitoring site-specific carbamylation patterns of apoA-I recovered from human atherosclerotic aorta could provide insights into the chemical environment within the artery wall. To test this, we first mapped carbamyllysine obtained from in vitro carbamylation of apoA-I by both the urea-driven (nonenzymatic) and inflammatory-driven (enzymatic) pathways in lipid-poor and lipidated apoA-I (reconstituted HDL). Our results suggest that lysine residues within proximity of the known MPO-binding sites on HDL are preferentially targeted by the enzymatic (MPO) carbamylation pathway, whereas the nonenzymatic pathway leads to nearly uniform distribution of carbamylated lysine residues along the apoA-I polypeptide chain. Quantitative proteomic analyses of apoA-I from human aortic atheroma identified 16 of the 21 lysine residues as carbamylated and suggested that the majority of apoA-I carbamylation in vivo occurs on “lipid-poor” apoA-I forms via the nonenzymatic CNO− pathway. Monitoring patterns of apoA-I carbamylation recovered from arterial tissues can provide insights into both apoA-I structure and the chemical environment within human atheroma.
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影响因子：
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作者：
Chen Z;Ding S;Wang YP;Chen L;Mao JY;Yang Y;Sun JT;Yang K
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Yang K
影响因子：
3.9
作者：
Chantepie, Sandrine;Malle, Ernst;Kontush, Anatol
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Kontush, Anatol
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9.8
作者：
GONEN, B;GOLDBERG, AP;SCHONFELD, G
通讯作者：
SCHONFELD, G
影响因子：
16.6
作者：
Hogrebe A;von Stechow L;Bekker-Jensen DB;Weinert BT;Kelstrup CD;Olsen JV
通讯作者：
Olsen JV
影响因子：
19.6
作者：
HORKKO, S;SAVOLAINEN, MJ;KESANIEMI, YA
通讯作者：
KESANIEMI, YA