Submit Manuscript  

Article Details


Antioxidant Effect of a Nitrated Cyclic Nucleotide Functioning as an Endogenous Electrophile

[ Vol. 11 , Issue. 14 ]

Author(s):

Tomohiro Sawa, Hideshi Ihara and Takaaki Akaike   Pages 1854 - 1860 ( 7 )

Abstract:


We describe here physiological formation of a unique nitrated cyclic nucleotide, 8-nitroguanosine 3,5-cyclic monophosphate (8-nitro-cGMP) and its potent antioxidant activity. Our earlier studies revealed the NO-dependent guanine nitration in several types of cells. In fact, we identified physiological formation and functions of 8-nitro-cGMP, which is the first demonstration of a new second messenger derived from cGMP in mammals since the discovery of cGMP more than 40 years ago. Using immunocytochemical methods, we confirmed 8-nitro-cGMP formation in cultured macrophages, hepatocyte-like cells, adipocytes, and endothelial cells, depending on NO production. We further verified 8- nitro-cGMP formation via HPLC plus electrochemical detection and tandem mass spectrometry. 8-Nitro-cGMP as an electrophile reacts efficiently with sulfhydryls of proteins to generate a novel post-translational modification, which we call protein S-guanylation. Particular intracellular proteins can readily undergo S-guanylation by 8-nitro-cGMP. 8-NitrocGMP regulates the redox-sensor signaling protein Keap1, via S-guanylation of the highly nucleophilic cysteine sulfhydryls of Keap1. More importantly, we clarified that S-guanylation of Keap1 is involved in potent antioxidant effects mediated by 8-nitro-cGMP, by inducing oxidative stress-response genes such as heme oxygenase-1. Our discovery of 8-nitrocGMP and its unique antioxidant effects thus shed light on new areas of oxidative stress research. Protein S-guanylation induced by 8-nitro-cGMP thus may have important implications in pharmaceutical chemistry and development of therapeutics for many diseases.

Keywords:

Oxidative stress, antioxidant, reactive oxygen species, nitric oxide, adaptive response, electrophile, nitrated cyclic nucleotide, signal transduction, tandem mass spectrometry, redox-sensor signaling protein Keap1, heme oxygenase-1, diabetes, cancer, inflammatory diseases, flavonoids

Affiliation:

Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo,Kumamoto 860-8556, Japan.



Read Full-Text article