Formation, signaling functions, and metabolisms of nitrated cyclic nucleotide

Nitric Oxide. 2013 Nov 1;34:10-8. doi: 10.1016/j.niox.2013.04.004. Epub 2013 Apr 28.


8-Nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP) is a unique derivative of guanosine 3',5'-cyclic monophosphate (cGMP) formed in mammalian and plant cells in response to production of nitric oxide and reactive oxygen species. 8-Nitro-cGMP possesses signaling activity inherited from parental cGMP, including induction of vasorelaxation through activation of cGMP-dependent protein kinase. On the other hand, 8-nitro-cGMP mediates cellular signaling that is not observed for native cGMP, e.g., it behaves as an electrophile and reacts with protein sulfhydryls, which results in cGMP adduction to protein sulfhydryls (protein S-guanylation). Several proteins have been identified as targets for endogenous protein S-guanylation, including Kelch-like ECH-associated protein 1 (Keap1), H-Ras, and mitochondrial heat shock proteins. 8-Nitro-cGMP signaling via protein S-guanylation of those proteins may have evolved to convey adaptive cellular stress responses. 8-Nitro-cGMP may not undergo conventional cGMP metabolism because of its resistance to phosphodiesterases. Hydrogen sulfide has recently been identified as a potent regulator for metabolisms of electrophiles including 8-nitro-cGMP, through sulfhydration of electrophiles, e.g., leading to the formation of 8-SH-cGMP. Better understanding of the molecular basis for the formation, signaling functions, and metabolisms of 8-nitro-cGMP would be useful for the development of new diagnostic approaches and treatment of diseases related to oxidative stress and redox metabolisms.

Keywords: 15-deoxy-Δ(12,14)-prostaglandin J(2); 15d-PGJ(2); 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; 4-hydroxy-2-nonenal; 4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one; 60-kDa heat-shock protein; 8-Nitro-cGMP; 8-bromo-cGMP; 8-bromoguanosine 3′,5′-cyclic monophosphate; 8-nitroguanosine 3′,5′-cyclic monophosphate; ATP; CBS; CSE; ELISA; ETC; Electrophile; GSH; GTP; HNE; HO-1; HPLC-ECD; HSP60; Hydrogen sulfide; IFN-γ; IL-1β; Keap1; Kelch-like ECH-associated protein 1; LC–MS/MS; LPS; MI; MPO; N(G)-nitro-l-arginine methyl ester; N(ω)-monomethyl-l-arginine; NADPH oxidase; NADPH oxidase 2; NOS; NS 2028; Nox; Nox2; Nrf2; ODQ; Oxidative stress; PDEs; PKG; PTM; Protein S-guanylation; RAR; RNOS; ROS; SOD; TNFα; adenosine 3′,5′-cyclic monophosphate; adenosine 5′-triphosphate; cAMP; cGMP; cGMP-dependent protein kinase; cPTIO; cystathionine β-synthase; cystathionine γ-lyase; eNOS; electron transport chain; endothelial NOS; enzyme-linked immunosorbent assay; glutathione; guanosine 3′,5′-cyclic monophosphate; guanosine 5′-triphosphate; heme oxygenase-1; high-performance liquid chromatography with electrochemical detector; iNOS; inducible NOS; interferon-γ; interleukin-1β; l-NAME; l-NMMA; lipopolysaccharide; liquid chromatography with tandem mass spectrometry; mPTP; mitochondrial permeability transition pore; myeloperoxidase; myocardial infarction; nNOS; neuronal NOS; nitric oxide synthases; nuclear factor erythroid 2-related factor 2; pGC; particulate-type guanylyl cyclase; phosphodiesterases; post-translational modification; reactive nitrogen oxide species; reactive oxygen species; retinoic acid receptor; sGC; soluble-type guanylyl cyclase; superoxide dismutase; tumor necrosis factor α.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cyclic GMP / analogs & derivatives*
  • Cyclic GMP / metabolism
  • Humans
  • Protein Processing, Post-Translational*
  • Signal Transduction


  • 8-nitroguanosine 3',5'-cyclic monophosphate
  • Cyclic GMP