Amino Acids

, Volume 41, Issue 1, pp 123–130 | Cite as

Protein cysteine S-guanylation and electrophilic signal transduction by endogenous nitro-nucleotides

  • Khandaker Ahtesham Ahmed
  • Tomohiro Sawa
  • Takaaki Akaike
Review Article

Abstract

Nitric oxide (NO), a gaseous free radical that is synthesized in organisms by nitric oxide synthases, participates in a critical fashion in the regulation of diverse physiological functions such as vascular and neuronal signal transduction, host defense, and cell death regulation. Two major pathways of NO signaling involve production of the second messenger guanosine 3′,5′-cyclic monophosphate (cGMP) and posttranslational modification (PTM) of redox-sensitive cysteine thiols of proteins. We recently clarified the physiological formation of 8-nitroguanosine 3′,5′-cyclic monophosphate (8-nitro-cGMP) as the first demonstration, since the discovery of cGMP more than 40 years ago, of a new second messenger derived from cGMP in mammals. 8-Nitro-cGMP is electrophilic and reacts efficiently with sulfhydryls of proteins to produce a novel PTM via cGMP adduction, a process that we named protein S-guanylation. 8-Nitro-cGMP may regulate electrophilic signaling on the basis of its electrophilicity through induction of S-guanylation of redox sensor proteins. Examples include S-guanylation of the redox sensor protein Kelch-like ECH-associated protein 1 (Keap1), which leads to activation of NF-E2-related factor 2 (Nrf2)-dependent expression of antioxidant and cytoprotective genes. This S-guanylation-mediated activation of an antioxidant adaptive response may play an important role in cytoprotection during bacterial infections and oxidative stress. Identification of new redox-sensitive proteins as targets for S-guanylation may help development of novel therapeutics for oxidative stress- and inflammation-related disorders and vascular diseases as well as understanding of cellular protection against oxidative stress.

Keywords

Nitric oxide Reactive oxygen species Oxidative stress Posttranslational modification Redox signal ROS signal Electrophilic signal Adaptive response 

Notes

Acknowledgments

We thank Judith B. Gandy for her excellent editing of the manuscript. This work was supported in part by Grants-in-Aid for Scientific Research (B, C: Nos. 21390097, 21590312) and on Innovative Areas (Research in a Proposed Area: Nos. 20117001, 20117005) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, by Advanced Education Program for Young Scientists in Integrated Clinical, Basic and Social Medicine, Kumamoto University, and by Grants-in-Aid from the Ministry of Health, Labor and Welfare of Japan.

References

  1. Akaike T (2000) Mechanisms of biological S-nitrosation and its measurement. Free Radic Res 33:461–469PubMedCrossRefGoogle Scholar
  2. Akaike T, Okamoto S, Sawa T, Yoshitake J, Tamura F, Ichimori K, Miyazaki K, Sasamoto K, Maeda H (2003) 8-Nitroguanosine formation in viral pneumonia and its implication for pathogenesis. Proc Natl Acad Sci USA 100:685–690PubMedCrossRefGoogle Scholar
  3. Alvarez B, Radi R (2003) Peroxynitrite reactivity with amino acids and proteins. Amino Acids 25:295–311PubMedCrossRefGoogle Scholar
  4. Baker PR, Lin Y, Schopfer FJ, Woodcock SR, Groeger AL, Batthyany C, Sweeney S, Long MH, Iles KE, Baker LM, Branchaud BP, Chen YE, Freeman BA (2005) Fatty acid transduction of nitric oxide signaling: multiple nitrated unsaturated fatty acid derivatives exist in human blood and urine and serve as endogenous peroxisome proliferator-activated receptor ligands. J Biol Chem 280:42464–42475PubMedCrossRefGoogle Scholar
  5. Balazy M, Iesaki T, Park JL, Jiang H, Kaminski PM, Wolin MS (2001) Vicinal nitrohydroxyeicosatrienoic acids: vasodilator lipids formed by reaction of nitrogen dioxide with arachidonic acid. J Pharmacol Exp Ther 299:611–619PubMedGoogle Scholar
  6. Bartesaghi S, Ferrer-Sueta G, Peluffo G, Valez V, Zhang H, Kalyanaraman B, Radi R (2007) Protein tyrosine nitration in hydrophilic and hydrophobic environments. Amino Acids 32:501–515PubMedCrossRefGoogle Scholar
  7. Batthyany C, Schopfer FJ, Baker PR, Duran R, Baker LM, Huang Y, Cervenansky C, Branchaud BP, Freeman BA (2006) Reversible post-translational modification of proteins by nitrated fatty acids in vivo. J Biol Chem 281:20450–20463PubMedCrossRefGoogle Scholar
  8. Beckman JS, Carson M, Smith CD, Koppenol WH (1993) ALS, SOD and peroxynitrite. Nature 364:584PubMedCrossRefGoogle Scholar
  9. Bredt DS, Hwang PM, Snyder H (1990) Localization of nitric oxide synthase indicating a neural role for nitric oxide. Nature 347:768–770PubMedCrossRefGoogle Scholar
  10. Dinkova-Kostova AT, Holtzclaw WD, Cole RN, Itoh K, Wakabayashi N, Katoh Y, Yamamoto M, Talalay P (2002) Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci USA 99:11908–11913PubMedCrossRefGoogle Scholar
  11. Dinkova-Kostova AT, Holtzclaw WD, Kensler TW (2005) The role of Keap1 in cellular protective responses. Chem Res Toxicol 18:1779–1791PubMedCrossRefGoogle Scholar
  12. Doi K, Akaike T, Fujii S, Tanaka S, Ikebe N, Beppu T, Shibahara S, Ogawa M, Maeda H (1999) Induction of haem oxygenase-1 by nitric oxide and ischaemia in experimental solid tumours and implications for tumour growth. Br J Cancer 80:1945–1954PubMedCrossRefGoogle Scholar
  13. Eaton P (2006) Protein thiol oxidation in health and disease: techniques for measuring disulfides and related modifications in complex protein mixtures. Free Radic Biol Med 40:1889–1899PubMedCrossRefGoogle Scholar
  14. Eiserich JP, Hristova M, Cross CE, Jones AD, Freeman BA, Halliwell B, van der Vliet A (1998) Formation of nitric oxide-derived inflammatory oxidants by myeloperoxidase in neutrophils. Nature 391:393–397PubMedCrossRefGoogle Scholar
  15. Feelisch M (2007) Nitrated cyclic GMP as a new cellular signal. Nat Chem Biol 3:687–688PubMedCrossRefGoogle Scholar
  16. Forrester MT, Thompson JW, Foster MW, Nogueira L, Moseley MA, Stamler JS (2009) Proteomic analysis of S-nitrosylation and denitrosylation by resin-assisted capture. Nat Biotechnol 27:557–559PubMedCrossRefGoogle Scholar
  17. Freeman BA, Baker PR, Schopfer FJ, Woodcock SR, Napolitano A, d’Ischia M (2008) Nitro-fatty acid formation and signaling. J Biol Chem 283:15515–15519PubMedCrossRefGoogle Scholar
  18. Griffith OW, Stuehr DJ (1995) Nitric oxide synthases: properties and catalytic mechanism. Annu Rev Physiol 57:707–736PubMedCrossRefGoogle Scholar
  19. Hess DT, Matsumoto A, Kim SO, Marshall HE, Stamler JS (2005) Protein S-nitrosylation: purview and parameters. Nat Rev Mol Cell Biol 6:150–166PubMedCrossRefGoogle Scholar
  20. Hoki Y, Murata M, Hiraku Y, Ma N, Matsumine A, Uchida A, Kawanishi S (2007) 8-Nitroguanine as a potential biomarker for progression of malignant fibrous histiocytoma, a model of inflammation-related cancer. Oncol Rep 18:1165–1169PubMedGoogle Scholar
  21. Hong SJ, Gokulrangan G, Schoneich C (2007) Proteomic analysis of age dependent nitration of rat cardiac proteins by solution isoelectric focusing coupled to nanoHPLC tandem mass spectrometry. Exp Gerontol 42:639–651PubMedCrossRefGoogle Scholar
  22. Ishima Y, Akaike T, Kragh-Hansen U, Hiroyama S, Sawa T, Suenaga A, Maruyama T, Kai T, Otagiri M (2008) S-Nitrosylated human serum albumin-mediated cytoprotective activity is enhanced by fatty acid binding. J Biol Chem 283:34966–34975PubMedCrossRefGoogle Scholar
  23. Itoh K, Tong KI, Yamamoto M (2004) Molecular mechanism activating Nrf2-Keap1 pathway in regulation of adaptive response to electrophiles. Free Radic Biol Med 36:1208–1213PubMedCrossRefGoogle Scholar
  24. Jones DP (2008) Radical-free biology of oxidative stress. Am J Physiol 295:C849–C868CrossRefGoogle Scholar
  25. Madhusoodanan KS, Murad F (2007) NO-cGMP signaling and regenerative medicine involving stem cells. Neurochem Res 32:681–694PubMedCrossRefGoogle Scholar
  26. Mannick JB (2007) Regulation of apoptosis by protein S-nitrosylation. Amino Acids 32:523–526PubMedCrossRefGoogle Scholar
  27. Martinez-Ruiz A, Lamas S (2007) Signalling by NO-induced protein S-nitrosylation and S-glutathionylation: convergences and divergences. Cardiovasc Res 75:220–228PubMedCrossRefGoogle Scholar
  28. Martinez-Ruiz A, Lamas S (2009) Two decades of new concepts in nitric oxide signaling: from the discovery of a gas messenger to the mediation of nonenzymatic posttranslational modifications. IUBMB Life 61:91–98PubMedCrossRefGoogle Scholar
  29. Masuda M, Nishino H, Ohshima H (2002) Formation of 8-nitroguanosine in cellular RNA as a biomarker of exposure to reactive nitrogen oxide species. Chem Biol Interact 139:187–197PubMedCrossRefGoogle Scholar
  30. Miyamoto Y, Akaike T, Maeda H (2000) S-Nitrosylated human α1-protease inhibitor. Biochim Biophys Acta 1477:90–97PubMedCrossRefGoogle Scholar
  31. Motohashi H, Yamamoto M (2004) Nrf2-Keap1 defines a physiologically important stress response mechanism. Trends Mol Med 10:549–557PubMedCrossRefGoogle Scholar
  32. Motterlini R, Gonzales A, Foresti R, Clark JE, Green CJ, Winslow RM (1998) Heme oxygenase-1-derived carbon monoxide contributes to the suppression of acute hypertensive responses in vivo. Circ Res 83:568–577PubMedGoogle Scholar
  33. Murad F (1986) Cyclic guanosine monophosphate as a mediator of vasodilation. J Clin Invest 78:1–5PubMedCrossRefGoogle Scholar
  34. Ohshima H, Sawa T, Akaike T (2006) 8-Nitroguanine, a product of nitrative DNA damage caused by reactive nitrogen species: formation, occurrence, and implications in inflammation and carcinogenesis. Antioxid Redox Signal 8:1033–1045PubMedCrossRefGoogle Scholar
  35. Otterbein LE, Bach FH, Alam J, Soares M, Lu HT, Wysk M, Davis RJ, Flavell RA, Choi AMK (2000) Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med 6:422–428PubMedCrossRefGoogle Scholar
  36. Patel RP, Moellering D, Murphy-Ullrich J, Jo H, Beckman JS, Darley-Usmar VM (2000) Cell signaling by reactive nitrogen and oxygen species in atherosclerosis. Free Radic Biol Med 28:1780–1794PubMedCrossRefGoogle Scholar
  37. Poole LB, Karplus PA, Claiborne A (2004) Protein sulfenic acids in redox signaling. Annu Rev Pharmacol Toxicol 44:325–347PubMedCrossRefGoogle Scholar
  38. Radi R (2004) Nitric oxide, oxidants, and protein tyrosine nitration. Proc Natl Acad Sci USA 101:4003–4008PubMedCrossRefGoogle Scholar
  39. Radi R, Beckman JS, Bush KM, Freeman BA (1991) Peroxynitrite oxidation of sulfhydryls. The cytotoxic potential of superoxide and nitric oxide. J Biol Chem 266:4244–4250PubMedGoogle Scholar
  40. Saito Y, Taguchi H, Fujii S, Sawa T, Kida E, Kabuto C, Akaike T, Arimoto H (2008) 8-Nitroguanosines as chemical probes of the protein S-guanylation. Chem Commun 5984–5986Google Scholar
  41. Sawa T, Ohshima H (2006) Nitrative DNA damage in inflammation and its possible role in carcinogenesis. Nitric Oxide 14:91–100PubMedCrossRefGoogle Scholar
  42. Sawa T, Akaike T, Ichimori K, Akuta T, Kaneko K, Nakayama H, Stuehr DJ, Maeda H (2003) Superoxide generation mediated by 8-nitroguanosine, a highly redox-active nucleic acid derivative. Biochem Biophys Res Commun 311:300–306PubMedCrossRefGoogle Scholar
  43. Sawa T, Tatemichi M, Akaike T, Barbin A, Ohshima H (2006) Analysis of urinary 8-nitroguanine, a marker of nitrative nucleic acid damage, by high-performance liquid chromatography-electrochemical detection coupled with immunoaffinity purification: association with cigarette smoking. Free Radic Biol Med 40:711–720PubMedCrossRefGoogle Scholar
  44. Sawa T, Zaki MH, Okamoto T, Akuta T, Tokutomi Y, Kim-Mitsuyama S, Ihara H, Kobayashi A, Yamamoto M, Fujii S, Arimoto H, Akaike T (2007) Protein S-guanylation by the biological signal 8-nitroguanosine 3′,5′-cyclic monophosphate. Nat Chem Biol 3:727–735PubMedCrossRefGoogle Scholar
  45. Sawa T, Arimoto H, Akaike T (2010) Chemical conjugation of protein thiols by nitric oxide and electrophiles in regulation of redox signaling. Bioconj Chem (in press)Google Scholar
  46. Schopfer FJ, Baker PR, Freeman BA (2003) NO-dependent protein nitration: a cell signaling event or an oxidative inflammatory response? Trends Biochem Sci 28:646–654PubMedCrossRefGoogle Scholar
  47. Squadrito GL, Pryor WA (1998) Oxidative chemistry of nitric oxide: the roles of superoxide, peroxynitrite, and carbon dioxide. Free Radic Biol Med 25:392–403PubMedCrossRefGoogle Scholar
  48. Stamler JS, Lamas S, Fang FC (2001) Nitrosylation. The prototypic redox-based signaling mechanism. Cell 106:675–683PubMedCrossRefGoogle Scholar
  49. Sugiura H, Ichinose M, Tomaki M, Ogawa H, Koarai A, Kitamuro T, Komaki Y, Akita T, Nishino H, Okamoto S, Akaike T, Hattori T (2004) Quantitative assessment of protein-bound tyrosine nitration in airway secretions from patients with inflammatory airway disease. Free Radic Res 38:49–57PubMedCrossRefGoogle Scholar
  50. Szabo C, Ischiropoulos H, Radi R (2007) Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat Rev Drug Discov 6:662–680PubMedCrossRefGoogle Scholar
  51. Tanaka S, Akaike T, Fang J, Beppu T, Ogawa M, Tamura F, Miyamoto Y, Maeda H (2003) Antiapoptotic effect of haem oxygenase-1 induced by nitric oxide in experimental solid tumour. Br J Cancer 88:902–909PubMedCrossRefGoogle Scholar
  52. Tazawa H, Tatemichi M, Sawa T, Gilibert I, Ma N, Hiraku Y, Donehower LA, Ohgaki H, Kawanishi S, Ohshima H (2007) Oxidative and nitrative stress caused by subcutaneous implantation of a foreign body accelerates sarcoma development in Trp53 +/− mice. Carcinogenesis 28:191–198PubMedCrossRefGoogle Scholar
  53. Terasaki Y, Akuta T, Terasaki M, Sawa T, Mori T, Okamoto T, Ozaki M, Takeya M, Akaike T (2006) Guanine nitration in idiopathic pulmonary fibrosis and its implication for carcinogenesis. Am J Respir Crit Care Med 174:665–673PubMedCrossRefGoogle Scholar
  54. Trostchansky A, Rubbo H (2006) Lipid nitration and formation of lipid-protein adducts: biological insights. Amino Acids 32:517–522PubMedCrossRefGoogle Scholar
  55. Wakabayashi N, Dinkova-Kostova AT, Holtzclaw WD, Kang MI, Kobayashi A, Yamamoto M, Kensler TW, Talalay P (2004) Protection against electrophile and oxidant stress by induction of the phase 2 response: fate of cysteines of the Keap1 sensor modified by inducers. Proc Natl Acad Sci USA 101:2040–2045PubMedCrossRefGoogle Scholar
  56. Winterbourn CC, Hampton MB (2008) Thiol chemistry and specificity in redox signaling. Free Radic Biol Med 45:549–561PubMedCrossRefGoogle Scholar
  57. Yamakura F, Matsumoto T, Ikeda K, Taka H, Fujimura T, Murayama K, Watanabe E, Tamaki M, Imai T, Takamori K (2005) Nitrated and oxidized products of a single tryptophan residue in human Cu, Zn-superoxide dismutase treated with either peroxynitrite-carbon dioxide or myeloperoxidase-hydrogen peroxide-nitrite. J Biochem 138:57–69PubMedCrossRefGoogle Scholar
  58. Yasuhara R, Miyamoto Y, Akaike T, Akuta T, Nakamura M, Takami M, Morimura N, Yasu K, Kamijo R (2005) Interleukin-1β induces death in chondrocyte-like ATDC5 cells through mitochondrial dysfunction and energy depletion in a reactive nitrogen and oxygen species-dependent manner. Biochem J 389:315–323PubMedCrossRefGoogle Scholar
  59. Yermilov V, Rubio J, Ohshima H (1995) Formation of 8-nitroguanine in DNA treated with peoxynitrite in vitro and its rapid removal from DNA by depurination. FEBS Lett 376:207–210PubMedCrossRefGoogle Scholar
  60. Yoshitake J, Akaike T, Akuta T, Tamura F, Ogura T, Esumi H, Maeda H (2004) Nitric oxide as an endogenous mutagen for Sendai virus without antiviral activity. J Virol 78:8709–8719PubMedCrossRefGoogle Scholar
  61. Yoshitake J, Kato K, Yoshioka D, Sueishi Y, Sawa T, Akaike T, Yoshimura T (2008) Suppression of NO production and 8-nitroguanosine formation by phenol-containing endocrine-disrupting chemicals in LPS-stimulated macrophages: involvement of estrogen receptor-dependent or -independent pathways. Nitric Oxide 18:223–228PubMedCrossRefGoogle Scholar
  62. Yuasa I, Ma N, Matsubara H, Fukui Y, Uji Y (2008) Inducible nitric oxide synthase mediates retinal DNA damage in Goto-Kakizaki rat retina. Jpn J Ophthalmol 52:314–322PubMedCrossRefGoogle Scholar
  63. Zaki MH, Fuji S, Okamoto T, Islam S, Khan S, Ahmed KA, Sawa T, Akaike T (2009) Cytoprotective function of heme oxygenase 1 induced by a nitrated cyclic nucleotide formed during murine salmonellosis. J Immunol 182:3746–3756PubMedCrossRefGoogle Scholar
  64. Zuckerbraun BS, Billiar TR, Otterbein SL, Kim PK, Liu F, Choi AM, Bach FH, Otterbein LE (2004) Carbon monoxide protects against liver failure through nitric oxide-induced heme oxygenase 1. J Exp Med 198:1707–1716CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Khandaker Ahtesham Ahmed
    • 1
  • Tomohiro Sawa
    • 1
  • Takaaki Akaike
    • 1
  1. 1.Department of Microbiology, Graduate School of Medical SciencesKumamoto UniversityKumamotoJapan

Personalised recommendations