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蛋白质精氨酸甲基转移酶1的动力学机制

Kinetic mechanism of protein arginine methyltransferase 1.

作者信息

Obianyo Obiamaka, Osborne Tanesha C, Thompson Paul R

机构信息

Department of Chemistry & Biochemistry, University of South Carolina, 631 Sumter Street, Columbia, South Carolina 29208, USA.

出版信息

Biochemistry. 2008 Sep 30;47(39):10420-7. doi: 10.1021/bi800904m. Epub 2008 Sep 5.

Abstract

Protein arginine methyltransferases (PRMTs) are SAM-dependent enzymes that catalyze the mono- and dimethylation of peptidyl arginine residues. Although all PRMTs produce monomethyl arginine (MMA), type 1 PRMTs go on to form asymmetrically dimethylated arginine (ADMA), while type 2 enzymes form symmetrically dimethylated arginine (SDMA). PRMT1 is the major type 1 PRMT in vivo, thus it is the primary producer of the competitive NOS inhibitor, ADMA. Hence, potent inhibitors, which are highly selective for this particular isozyme, could serve as excellent therapeutics for heart disease. However, the design of such inhibitors is impeded by a lack of information regarding this enzyme's kinetic and catalytic mechanisms. Herein we report an analysis of the kinetic mechanism of human PRMT1 using both an unmethylated and a monomethylated substrate peptide based on the N-terminus of histone H4. The results of initial velocity and product and dead-end inhibition experiments indicate that PRMT1 utilizes a rapid equilibrium random mechanism with the formation of dead-end EAP and EBQ complexes. This mechanism is gratifyingly consistent with previous results demonstrating that PRMT1 catalyzes substrate dimethylation in a partially processive manner.

摘要

蛋白质精氨酸甲基转移酶(PRMTs)是一类依赖S-腺苷甲硫氨酸(SAM)的酶,可催化肽基精氨酸残基的单甲基化和二甲基化反应。尽管所有PRMTs都能产生单甲基精氨酸(MMA),但1型PRMTs会进一步形成不对称二甲基化精氨酸(ADMA),而2型酶则形成对称二甲基化精氨酸(SDMA)。PRMT1是体内主要的1型PRMT,因此它是竞争性一氧化氮合酶(NOS)抑制剂ADMA的主要产生者。因此,对这种特定同工酶具有高度选择性的强效抑制剂,可作为治疗心脏病的理想药物。然而,由于缺乏关于该酶动力学和催化机制的信息,此类抑制剂的设计受到了阻碍。在此,我们报告了一项基于组蛋白H4 N端的未甲基化和单甲基化底物肽对人PRMT1动力学机制的分析。初速度、产物及终产物抑制实验结果表明,PRMT1利用快速平衡随机机制,形成终产物EAP和EBQ复合物。这一机制与先前的结果令人满意地一致,即PRMT1以部分连续的方式催化底物二甲基化。

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