Article abstract
Nature Chemical Biology 3, 727 - 735 (2007)
Published online: 30 September 2007 | doi:10.1038/nchembio.2007.33
Protein S-guanylation by the biological signal 8-nitroguanosine 3',5'-cyclic monophosphate
Tomohiro Sawa1,7, Mohammad Hasan Zaki1,7, Tatsuya Okamoto1, Teruo Akuta1, Yoshiko Tokutomi2, Shokei Kim-Mitsuyama2, Hideshi Ihara3, Akira Kobayashi4, Masayuki Yamamoto4,5, Shigemoto Fujii1, Hirokazu Arimoto6 & Takaaki Akaike1
Abstract
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.
- Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
- Department of Pharmacology and Molecular Therapeutics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
- Department of Biological Science, Graduate School of Science, Osaka Prefecture University, 1-1 Gakuen-cho, Sakai, Osaka 599-8531, Japan.
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Sendai 980-8575, Japan.
- JST-ERATO Environmental Response Project, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan.
- Department of Biomolecular Chemistry, Graduate School of Life Sciences, Tohoku University, 1-1 Amamiya-machi, Tsutsumidori, Sendai 981-8555, Japan.
- These authors contributed equally to this work.
Correspondence to: Takaaki Akaike1 e-mail: takakaik@gpo.kumamoto-u.ac.jp
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