An Inhibitor of Protein Arginine Methyltransferases, 7,7′-Carbonylbis(azanediyl)bis(4-hydroxynaphthalene-2-sulfonic acid (AMI-1), Is a Potent Scavenger of NADPH-Oxidase-Derived Superoxide
An Inhibitor of Protein Arginine Methyltransferases, 7,7′-Carbonylbis(azanediyl)bis(4-hydroxynaphthalene-2-sulfonic acid (AMI-1), Is a Potent Scavenger of NADPH-Oxidase-Derived Superoxide
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DOI：
10.1124/mol.109.061077
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发表时间：
2010-02-01
影响因子：
3.6
通讯作者：
Fulton, David J. R.
中科院分区：
文献类型：
--
作者：
Chen, Feng;Fulton, David J. R.
蛋白质甲基化是影响核蛋白和核酸结合蛋白活性的一种重要的翻译后机制。关于蛋白质甲基化在胞浆蛋白调控中的重要性，人们知之甚少。在心血管疾病中观察到蛋白质甲基化增加，并与活性氧产生增加同时发生。然而，活性氧物种和蛋白质甲基化之间的关系的本质还知之甚少。因此，本研究的目的是确定蛋白质甲基化是否影响NADPH氧化酶(NOx)的催化活性，NADPH氧化酶是一类负责产生超氧化物的酶。我们发现，蛋白精氨酸甲基转移酶选择性抑制剂7，7‘-carbonylbis(azanediyl)bis(4-hydroxynaphthalene-2-sulfonic酸(AMI1)是NOx产生的超氧化物的有效拮抗剂。然而，结构和机械上不同的蛋白质甲基化和共表达蛋白质精氨酸甲基转移酶1的抑制剂并不影响NOx的活性。相反，急性心肌梗死-1的作用是快速可逆的，并可以在使用化学合成的超氧化物的检测中得到证明。我们的结论是，蛋白质甲基化不调节NADPH-氧化酶的活性，AMI1是一种有效的抗氧化剂，其效力高于4，5-二羟基-1，3-苯二磺酸(TIRON)和4-hydroxy-2，2，6，6-tetramethylpiperydine-1-oxyl(TEMPOL)。
The methylation of proteins is an important post-translational mechanism that has been established to influence the activity of nuclear and nucleic acid binding proteins. Much less is known about the importance of protein methylation in the regulation of cytosolic proteins. Increased methylation of proteins is observed in cardiovascular disease and occurs in conjunction with elevated production of reactive oxygen species. However, the nature of the relationship between reactive oxygen species and protein methylation is poorly understood. Therefore, the goal of the current study was to determine whether protein methylation influences the catalytic activity of the NADPH oxidases (Nox), which are a family of enzymes responsible for the generation of superoxide. We found that the selective inhibitor of protein arginine methyltransferases 7,7'-carbonylbis(azanediyl)bis(4-hydroxynaphthalene-2-sulfonic acid (AMI-1) was a potent antagonist of Nox-derived superoxide production. However, structurally and mechanistically dissimilar inhibitors of protein methylation and coexpression of protein arginine methyltransferase 1 did not influence Nox activity. Rather, the effect of AMI-1 was rapidly reversible and could be demonstrated in an assay using chemically synthesized superoxide. We conclude that protein methylation does not regulate the activity of NADPH-oxidases and that AMI-1 is a potent antioxidant with a greater potency than 4,5-dihydroxy-1,3-benzenedisulfonic acid (Tiron) and 4-hydroxy-2,2,6,6-tetramethylpiperydine-1-oxyl (Tempol).