Protein S-guanylation by the biological signal 8-nitroguanosine 3',5'-cyclic monophosphate

Nat Chem Biol. 2007 Nov;3(11):727-35. doi: 10.1038/nchembio.2007.33. Epub 2007 Sep 30.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cyclic GMP / analogs & derivatives*
  • Cyclic GMP / chemistry
  • Cyclic GMP / pharmacology
  • Glutathione / metabolism
  • Immunohistochemistry
  • Isoenzymes / metabolism
  • Mice
  • Mice, Knockout
  • Molecular Structure
  • Nitric Oxide Synthase Type III / deficiency
  • Nitric Oxide Synthase Type III / genetics
  • Nitric Oxide Synthase Type III / metabolism
  • Oxidation-Reduction
  • Protein S / chemistry
  • Protein S / metabolism*
  • Signal Transduction / drug effects*
  • Sulfur / chemistry
  • Sulfur / metabolism
  • Superoxides / metabolism

Substances

  • 8-nitroguanosine 3',5'-cyclic monophosphate
  • Isoenzymes
  • Protein S
  • Superoxides
  • Sulfur
  • Nitric Oxide Synthase Type III
  • Glutathione
  • Cyclic GMP

Associated data

  • PubChem-Substance/26683837
  • PubChem-Substance/26683838
  • PubChem-Substance/26683839
  • PubChem-Substance/26683840
  • PubChem-Substance/26683841
  • PubChem-Substance/26683842
  • PubChem-Substance/26683843
  • PubChem-Substance/26683844
  • PubChem-Substance/26683845
  • PubChem-Substance/26683846
  • PubChem-Substance/26683847
  • PubChem-Substance/26683848
  • PubChem-Substance/26683849
  • PubChem-Substance/26683850
  • PubChem-Substance/26683851
  • PubChem-Substance/26683852
  • PubChem-Substance/26683853
  • PubChem-Substance/26683854
  • PubChem-Substance/26683855
  • PubChem-Substance/26683856
  • PubChem-Substance/26683857
  • PubChem-Substance/26683858
  • PubChem-Substance/26683859
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  • PubChem-Substance/26683867
  • PubChem-Substance/26683868
  • PubChem-Substance/26683869
  • PubChem-Substance/26683870
  • PubChem-Substance/26683871
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  • PubChem-Substance/26683879