title: Protein S-guanylation by the biological signal 8-nitroguanosine 3',5'-cyclic monophosphate.
abstract: The signaling pathway of nitric oxide (NO) depends mainly on guanosine 3',5'-cyclic monophosphate (cGMP). Here we report the formation and chemical biology of a nitrated derivative of cGMP, 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), 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.
authors: Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
authors: Tomohiro
authors: T
authors: Sawa
authors: Mohammad Hasan
authors: MH
authors: Zaki
authors: Tatsuya
authors: T
authors: Okamoto
authors: Teruo
authors: T
authors: Akuta
authors: Yoshiko
authors: Y
authors: Tokutomi
authors: Shokei
authors: S
authors: Kim-Mitsuyama
authors: Hideshi
authors: H
authors: Ihara
authors: Akira
authors: A
authors: Kobayashi
authors: Masayuki
authors: M
authors: Yamamoto
authors: Shigemoto
authors: S
authors: Fujii
authors: Hirokazu
authors: H
authors: Arimoto
authors: Takaaki
authors: T
authors: Akaike
mesh_terms: D000818:Animals; D002460:Cell Line; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D017293:Protein S / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013455:Sulfur / Q000737:chemistry / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
chemical_list: C525106:8-nitroguanosine 3',5'-cyclic monophosphate; D007527:Isoenzymes; D017293:Protein S; D013481:Superoxides; D013455:Sulfur; D052250:Nitric Oxide Synthase Type III; D005978:Glutathione; D006152:Cyclic GMP