Reactive oxygen species inhibit catalytic activity of peptidylarginine deiminase.

Reactive oxygen species inhibit catalytic activity of peptidylarginine deiminase.
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DOI:
10.1080/14756366.2017.1368505
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发表时间:
2017-12
影响因子:
5.6
通讯作者:
Nielsen CH
Nielsen CH
中科院分区:
医学2区
文献类型:
--
作者:
Damgaard D;Bjørn ME;Jensen PØ;Nielsen CH

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肽基精氨酸脱亚胺酶(PAD)催化的瓜氨酸酶在多种慢性炎症性疾病和恶性肿瘤中可能起重要的致病作用。PAD 2、PAD 4和瓜氨酸化蛋白存在于类风湿性关节炎患者的滑膜中。PAD活性依赖于钙和还原条件。然而,活性氧(ROS)已被证明可以诱导粒细胞中组蛋白的瓜氨酸化。在这里,我们检查过氧化氢和白细胞衍生的活性氧调节PAD活性的能力,使用瓜氨酸纤维蛋白原作为读出。浓度高于40 µM的H2O2以剂量依赖性方式抑制PAD 2和PAD 4的催化活性。PMA刺激的白细胞瓜氨酸化纤维蛋白原,当NADPH氧化酶抑制剂二苯碘鎓(DPI)抑制ROS形成时,这种瓜氨酸显著增强。相比之下,刺激白细胞释放的PAD不受外源性H2O2(浓度高达1000 µM)的影响。ROS在调节PAD活性中的作用可能在预防蛋白质高瓜氨酸血症中起重要作用。
Protein citrullination catalysed by peptidylarginine deiminase (PAD) may play an important pathogenic role in several chronic inflammatory diseases and malignancies. PAD2, PAD4, and citrullinated proteins are found in the synovium of rheumatoid arthritis patients. PAD activity is dependent on calcium and reducing conditions. However, reactive oxygen species (ROS) have been shown to induce citrullination of histones in granulocytes. Here we examine the ability of H2O2 and leukocyte-derived ROS to regulate PAD activity using citrullination of fibrinogen as read-out. H2O2 at concentrations above 40 µM inhibited the catalytic activity of PAD2 and PAD4 in a dose-dependent manner. PMA-stimulated leukocytes citrullinated fibrinogen and this citrullination was markedly enhanced when ROS formation was inhibited by the NADPH oxidase inhibitor diphenyleneiodonium (DPI). In contrast, PAD released from stimulated leukocytes was unaffected by exogenously added H2O2 at concentrations up to 1000 µM. The role of ROS in regulating PAD activity may play an important part in preventing hypercitrullination of proteins.
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