Redox Control of Protein Arginine Methyltransferase 1 (PRMT1) Activity
Redox Control of Protein Arginine Methyltransferase 1 (PRMT1) Activity
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DOI：
10.1074/jbc.m115.651380
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发表时间：
2015-06-12
影响因子：
4.8
通讯作者：
Hevel, Joan M.
中科院分区：
文献类型：
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作者：
Morales, Yalemi;Nitzel, Damon V.;Hevel, Joan M.
不对称二甲基精氨酸（ADMA）水平升高与心血管疾病的危险因素相关。ADMA由蛋白质精氨酸甲基转移酶（PRMT）催化精氨酸残基甲基化的蛋白质产生，并由二甲基精氨酸二甲氨基水解酶降解。报告显示，在氧化应激条件下，二甲基精氨酸二甲氨基水解酶活性下调，PRMT 1蛋白表达上调，导致许多人得出结论，ADMA积累是通过PRMT合成增加和降解减少而发生的。然而，我们现在报告称，人类主要PRMT亚型PRMT 1的甲基转移酶活性在氧化条件下会受损。氧化的PRMT 1显示活性降低，这可以通过还原来挽救。该氧化事件涉及一个或多个半胱氨酸残基被氧化成次磺酸（-SOH）。我们证明了过氧化氢浓度依赖性抑制PRMT 1活性，在生理H2 O2浓度下很容易逆转。我们的研究结果挑战了PRMT 1表达增加必然导致ADMA合成增加的单方面观点，并表明酶活性可以以氧化还原敏感的方式进行调节。
Elevated levels of asymmetric dimethylarginine (ADMA) correlate with risk factors for cardiovascular disease. ADMA is generated by the catabolism of proteins methylated on arginine residues by protein arginine methyltransferases (PRMTs) and is degraded by dimethylarginine dimethylaminohydrolase. Reports have shown that dimethylarginine dimethylaminohydrolase activity is down-regulated and PRMT1 protein expression is up-regulated under oxidative stress conditions, leading many to conclude that ADMA accumulation occurs via increased synthesis by PRMTs and decreased degradation. However, we now report that the methyltransferase activity of PRMT1, the major PRMT isoform in humans, is impaired under oxidative conditions. Oxidized PRMT1 displays decreased activity, which can be rescued by reduction. This oxidation event involves one or more cysteine residues that become oxidized to sulfenic acid (-SOH). We demonstrate a hydrogen peroxide concentration-dependent inhibition of PRMT1 activity that is readily reversed under physiological H2O2 concentrations. Our results challenge the unilateral view that increased PRMT1 expression necessarily results in increased ADMA synthesis and demonstrate that enzymatic activity can be regulated in a redox-sensitive manner.