Protein S-guanylation by the biological signal 8-nitroguanosine 3′,5′-cyclic monophosphate
Protein S-guanylation by the biological signal 8-nitroguanosine 3′,5′-cyclic monophosphate
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DOI：
10.1038/nchembio.2007.33
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发表时间：
2007-11-01
影响因子：
14.8
通讯作者：
Akaike, Takaaki
中科院分区：
文献类型：
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作者：
Sawa, Tomohiro;Zaki, Mohammad Hasan;Akaike, Takaaki
一氧化氮 (NO) 的信号通路主要依赖于鸟苷 3',5'-环单磷酸 (cGMP, 1)。在此，我们报道了 cGMP 硝化衍生物 8-硝基鸟苷 3', 5'- 环单磷酸 (8-硝基-cGMP, 2) 在 NO 介导的信号转导中的形成和化学生物学。免疫细胞化学显示各种培养细胞中以 NO 依赖性方式产生显着的 8-硝基-cGMP。这一发现得到了 HPLC 加电化学检测和串联质谱法的证实。 8-硝基-cGMP 激活 cGMP 依赖性蛋白激酶，并显示出独立于 cGMP 活性的独特氧化还原活性特性。 8-硝基-cGMP 形成蛋白质 Cys-cGMP 加合物被认为是一种新的翻译后修饰，我们称之为蛋白质 S-鸟苷酸化。 8-Nitro-cGMP 似乎通过 Keap1 的高度亲核半胱氨酸硫氢基的 S-鸟苷酸化来调节氧化还原传感器信号蛋白 Keap1。这项研究揭示了 8-硝基-cGMP 是 NO 的第二信使，并揭示了 NO 信号转导的生理学和化学生物学的新领域。
The signaling pathway of nitric oxide (NO) depends mainly on guanosine 3',5'-cyclic monophosphate (cGMP, 1). Here we report the formation and chemical biology of a nitrated derivative of cGMP, 8-nitroguanosine 3', 5'- cyclic monophosphate (8-nitro-cGMP, 2), in NO-mediated signal transduction. Immunocytochemistry demonstrated marked 8-nitro-cGMP production in various cultured cells in an NO-dependent manner. This finding was confirmed by HPLC plus electrochemical detection and tandem mass spectrometry. 8-Nitro-cGMP activated cGMP-dependent protein kinase and showed unique redox-active properties independent of cGMP activity. Formation of protein Cys-cGMP adducts by 8-nitro-cGMP was identified as a new post-translational modification, which we call protein S-guanylation. 8-Nitro-cGMP seems to regulate the redox-sensor signaling protein Keap1, via S-guanylation of the highly nucleophilic cysteine sulfhydryls of Keap1. This study reveals 8-nitro-cGMP to be a second messenger of NO and sheds light on new areas of the physiology and chemical biology of signal transduction by NO.