Substrate specificity and kinetic studies of PADs 1, 3, and 4 identify potent and selective inhibitors of protein arginine deiminase 3.
Substrate specificity and kinetic studies of PADs 1, 3, and 4 identify potent and selective inhibitors of protein arginine deiminase 3.
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DOI：
10.1021/bi100363t
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发表时间：
2010-06-15
期刊：
影响因子：
2.9
通讯作者：
Thompson, Paul R.
中科院分区：
文献类型：
--
作者：
Knuckley, Bryan;Causey, Corey P.;Jones, Justin E.;Bhatia, Monica;Dreyton, Christina J.;Osborne, Tanesha C.;Takahara, Hidenari;Thompson, Paul R.
瓜氨酸蛋白已显示出调节许多生理途径（例如，先天免疫应答和基因转录），并且当失调时，已知与许多人类疾病相关，包括癌症、类风湿性关节炎和多发性硬化症。这种修饰，也称为脱亚胺化，是由一组称为蛋白质精氨酸脱亚胺酶（PAD）的酶催化的。在哺乳动物中，有五个PAD家族成员（即，PAD 1、2、3、4和6），其表现出组织特异性表达模式，并且在其亚细胞定位中变化。最近报道了PAD 4的动力学表征，并且这些努力指导了两种最有效的PAD 4抑制剂（即，F-和Cl-脒）。除了是有效的PAD 4抑制剂之外，我们在这里显示Cl-脒还表现出对PAD 1和3的强抑制作用，从而表明其作为泛PAD抑制剂的效用。鉴于越来越多的疾病，其中失调的PAD活性已牵连，PAD选择性抑制剂的发展是至关重要的。为了帮助实现这一目标，我们表征了PAD 1和3的催化机制和底物特异性。在此，我们报告这些研究的结果，这表明，像PAD 4，PADs 1和3采用反向质子化机制。此外，底物特异性研究提供了有助于鉴别PAD 3选择性抑制剂的关键信息。这些化合物，表示为F4-和C14-脒，是迄今为止描述的最有效的PAD 3抑制剂。
Protein citrullination has been shown to regulate numerous physiological pathways (e.g., the innate immune response and gene transcription), and is, when dysregulated, known to be associated with numerous human diseases, including cancer, rheumatoid arthritis, and multiple sclerosis. This modification, also termed deimination, is catalyzed by a group of enzymes called the Protein Arginine Deiminases (PADs). In mammals, there are five PAD family members (i.e., PADs 1, 2, 3, 4, and 6) that exhibit tissue specific expression patterns, and vary in their subcellular localization. The kinetic characterization of PAD4 was recently reported, and these efforts guided the development of the two most potent PAD4 inhibitors (i.e., F- and Cl-amidine) known to date. In addition to being potent PAD4 inhibitors, we show here that Cl-amidine also exhibits a strong inhibitory effect against PADs 1 and 3, thus indicating its utility as a pan PAD inhibitor. Given the increasing number of diseases in which dysregulated PAD activity has been implicated, the development of PAD-selective inhibitors is of paramount importance. To aid that goal, we characterized the catalytic mechanism and substrate specificity of PADs 1 and 3. Herein, we report the results of these studies, which suggest that, like PAD4, PADs 1 and 3 employ a reverse protonation mechanism. Additionally, the substrate specificity studies provided critical information that aided the identification of PAD3-selective inhibitors. These compounds, denoted F4- and Cl4-amidine, are the most potent PAD3 inhibitors ever described.
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影响因子：
3.8
作者：
Chang X;Han J;Pang L;Zhao Y;Yang Y;Shen Z
通讯作者：
Shen Z
影响因子：
3.5
作者：
Chavanas, S;Méchin, MC;Simon, M
通讯作者：
Simon, M
DOI：
10.1073/pnas.0407159102
发表时间：
2005-03-08
影响因子：
11.1
作者：
Lee, YH;Coonrod, SA;Stallcup, MR
通讯作者：
Stallcup, MR
影响因子：
15
作者：
Li, Ling;Li, Zhimin;Zhang, Liwen
通讯作者：
Zhang, Liwen
影响因子：
2.9
作者：
Kearney, PL;Bhatia, M;Thompson, PR
通讯作者：
Thompson, PR