Luo Yuan, Arita Kyouhei, Bhatia Monica, Knuckley Bryan, Lee Young-Ho, Stallcup Michael R, Sato Mamoru, Thompson Paul R
Department of Chemistry and Biochemistry, University of South Carolina, 631 Sumter Street, Columbia, South Carolina 29208, USA.
Biochemistry. 2006 Oct 3;45(39):11727-36. doi: 10.1021/bi061180d.
Protein arginine deiminase 4 (PAD4) is a transcriptional coregulator that catalyzes the calcium-dependent conversion of specific arginine residues in proteins to citrulline. Recently, we reported the synthesis and characterization of F-amidine, a potent and bioavailable irreversible inactivator of PAD4. Herein, we report our efforts to identify the steric and leaving group requirements for F-amidine-induced PAD4 inactivation, the structure of the PAD4-F-amidine x calcium complex, and in vivo studies with N-alpha-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide (Cl-amidine), a PAD4 inactivator with enhanced potency. The PAD4 inactivators described herein will be useful pharmacological probes in characterizing the incompletely defined physiological role(s) of this enzyme. In addition, they represent potential lead compounds for the treatment of rheumatoid arthritis because a growing body of evidence supports a role for PAD4 in the onset and progression of this chronic autoimmune disorder.
蛋白精氨酸脱亚氨酶4（PAD4）是一种转录共调节因子，可催化蛋白质中特定精氨酸残基钙依赖性地转化为瓜氨酸。最近，我们报道了F-脒的合成与特性，F-脒是一种强效且具有生物利用度的PAD4不可逆失活剂。在此，我们报告了我们为确定F-脒诱导PAD4失活的空间和离去基团要求、PAD4-F-脒x钙复合物的结构以及使用N-α-苯甲酰基-N5-（2-氯-1-亚氨基乙基）-L-鸟氨酸酰胺（Cl-脒）进行体内研究的工作，Cl-脒是一种效力增强的PAD4失活剂。本文所述的PAD4失活剂将是用于表征该酶尚未完全明确的生理作用的有用药理学探针。此外，它们代表了治疗类风湿性关节炎的潜在先导化合物，因为越来越多的证据支持PAD4在这种慢性自身免疫性疾病的发病和进展中起作用。
