Insights into the mechanism of streptonigrin-induced protein arginine deiminase inactivation.
Insights into the mechanism of streptonigrin-induced protein arginine deiminase inactivation.
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DOI：
10.1016/j.bmc.2013.12.064
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发表时间：
2014-02-15
影响因子：
3.5
通讯作者：
Thompson PR
中科院分区：
文献类型：
--
作者：
Dreyton CJ;Anderson ED;Subramanian V;Boger DL;Thompson PR
瓜氨酸蛋白只是200多种已知的PTM之一。这种修饰由蛋白质精氨酸脱亚胺酶（人类中的PAD 1-4和PAD 6）催化，将精氨酸残基的带正电荷的胍基转化为中性脲基。鉴于PAD活性失调与人类疾病之间的密切联系，我们启动了一项计划，以开发PAD抑制剂作为这些疾病和其他疾病的潜在治疗药物，PAD被认为在这些疾病中发挥作用。具有抗肿瘤和抗细菌活性的链黑菌素后来被鉴定为高效的PAD 4抑制剂。为了理解为什么链黑菌素是一种如此有效和选择性的PAD 4抑制剂，我们通过检查模拟链黑菌素A、B、C和/或D环的几种类似物的抑制作用来探索其结构-活性关系。我们报告的7-氨基-喹啉-5，8-二酮核心链黑菌素作为一个非常有效的药效团，作为泛PAD抑制剂的鉴定。
Protein citrullination is just one of more than 200 known PTMs. This modification, catalyzed by the Protein Arginine Deiminases (PADs 1–4 and PAD6 in humans), converts the positively charged guanidinium group of an arginine residue into a neutral ureido-group. Given the strong links between dysregulated PAD activity and human disease, we initiated a program to develop PAD inhibitors as potential therapeutics for these and other diseases in which the PADs are thought to play a role. Streptonigrin which possesses both anti-tumor and anti-bacterial activity was later identified as a highly potent PAD4 inhibitor. In an effort to understand why streptonigrin is such a potent and selective PAD4 inhibitor, we explored its structure-activity relationships by examining the inhibitory effects of several analogues that mimic the A, B, C, and/or D rings of streptonigrin. We report the identification of the 7-amino-quinoline-5,8-dione core of streptonigrin as a highly potent pharmacophore that acts as a pan-PAD inhibitor.
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DOI：
10.1084/jem.20100239
发表时间：
2010-08-30
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Li P;Li M;Lindberg MR;Kennett MJ;Xiong N;Wang Y
通讯作者：
Wang Y
影响因子：
2.7
作者：
Lange, Sigrun;Goegel, Stefanie;Ferretti, Patrizia
通讯作者：
Ferretti, Patrizia
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：
5.3
作者：
Li, Pingxin;Yao, Hongjie;Wang, Yanming
通讯作者：
Wang, Yanming
DOI：
10.1039/c0cc02634d
发表时间：
2010-10-14
期刊：
Chemical communications (Cambridge, England)
影响因子：
--
作者：
Knuckley B;Jones JE;Bachovchin DA;Slack J;Causey CP;Brown SJ;Rosen H;Cravatt BF;Thompson PR
通讯作者：
Thompson PR