Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Sies, Helmut / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred

12 Issues per year

IMPACT FACTOR 2017: 3.022

CiteScore 2017: 2.81

SCImago Journal Rank (SJR) 2017: 1.562
Source Normalized Impact per Paper (SNIP) 2017: 0.705

See all formats and pricing
More options …
Volume 398, Issue 11


Reactive nitrogen species (RNS)-resistant microbes: adaptation and medical implications

Sujeenthar Tharmalingam / Azhar Alhasawi / Varun P. Appanna / Joe Lemire
  • The Biofilm Research Group, Department of Biological Sciences, The University of Calgary, 2500 University Dr. NW, Calgary T2N 1N4, Alberta, Canada
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Vasu D. Appanna
Published Online: 2017-06-15 | DOI: https://doi.org/10.1515/hsz-2017-0152


Nitrosative stress results from an increase in reactive nitrogen species (RNS) within the cell. Though the RNS – nitric oxide (·NO) and peroxynitrite (ONOO) – play pivotal physiological roles, at elevated concentrations, these moieties can be poisonous to both prokaryotic and eukaryotic cells alike due to their capacity to disrupt a variety of essential biological processes. Numerous microbes are known to adapt to nitrosative stress by elaborating intricate strategies aimed at neutralizing RNS. In this review, we will discuss both the enzymatic systems dedicated to the elimination of RNS as well as the metabolic networks that are tailored to generate RNS-detoxifying metabolites – α-keto-acids. The latter has been demonstrated to nullify RNS via non-enzymatic decarboxylation resulting in the production of a carboxylic acid, many of which are potent signaling molecules. Furthermore, as aerobic energy production is severely impeded during nitrosative stress, alternative ATP-generating modules will be explored. To that end, a holistic understanding of the molecular adaptation to nitrosative stress, reinforces the notion that neutralization of toxicants necessitates significant metabolic reconfiguration to facilitate cell survival. As the alarming rise in antimicrobial resistant pathogens continues unabated, this review will also discuss the potential for developing therapies that target the alternative ATP-generating machinery of bacteria.

Keywords: ATP; α-keto-acids; metabolism; phosphotransfer; reactive nitrogen species; RNS-resistant microbes


  • Afanas’ev, I.B. (2007). Signaling functions of free radicals superoxide & nitric oxide under physiological & pathological conditions. Mol. Biotechnol. 37, 2–4.PubMedCrossrefGoogle Scholar

  • Alhasawi, A., Auger, C., Appanna, V.P., Chahma, M., and Appanna, V.D. (2014). Zinc toxicity and ATP production in Pseudomonas fluorescens. J. Appl. Microbiol. 117, 65–73.CrossrefPubMedGoogle Scholar

  • Alhasawi, A., Leblanc, M., Appanna, N.D., Auger, C., and Appanna, V.D. (2015). Aspartate metabolism and pyruvate homeostasis triggered by oxidative stress in Pseudomonas fluorescens: a functional metabolomic study. Metabolomics 11, 1792–1801.CrossrefGoogle Scholar

  • Alderton, W.K., Cooper, C.E., and Knowles, R.G. (2001). Nitric oxide synthases: structure, function and inhibition. Biochem. J. 357, 593–615.PubMedCrossrefGoogle Scholar

  • Andersson, E., Schain, F., Svedling, M., Claesson, H.E., and Forsell, P.K. (2006). Interaction of human 15-lipoxygenase-1 with phosphatidylinositol bisphosphates results in increased enzyme activity. Biochim. Biophys. Acta. 1761, 1498–1505.PubMedCrossrefGoogle Scholar

  • Andrae, U., Singh, J., and Ziegler-Skylakakis, K. (1985). Pyruvate and related alpha-ketoacids protect mammalian cells in culture against hydrogen peroxide-induced cytotoxicity. Toxicol. Lett. 28, 93–98.PubMedCrossrefGoogle Scholar

  • Anjum, M.F., Stevanin, T.M., Read, R.C., and Moir, J.W. (2002). Nitric oxide metabolism in Neisseria meningitidis. J. Bacteriol. 184, 2987–2993.PubMedCrossrefGoogle Scholar

  • Appanna, V.P., Auger, C., Thomas, S.C., and Omri, A. (2014). Fumarate metabolism and ATP production in Pseudomonas fluorescens exposed to nitrosative stress. Antonie Van Leeuwenhoek 106, 431–438.CrossrefPubMedGoogle Scholar

  • Appanna, V.P., Alhasawi, A.A., Auger, C., Thomas, S.C., and Appanna, V.D. (2016). Phospho-transfer networks and ATP homeostasis in response to an ineffective electron transport chain in Pseudomonas fluorescens. Arch. Biochem. Biophys. 606, 26–33.CrossrefGoogle Scholar

  • Aratani, Y., Kura, F., Watanabe, H., Akagawa, H., Takano, Y., Suzuki, K., Dinauer, M.C., Maeda, N., and Koyama, H. (2002). Relative contributions of myeloperoxidase and NADPH-oxidase to the early host defense against pulmonary infections with Candida albicans and Aspergillus fumigatus. Med. Mycol. 40, 557–563.CrossrefGoogle Scholar

  • Auger, C. and Appanna, V.D. (2015). A novel ATP-generating machinery to counter nitrosative stress is mediated by substrate-level phosphorylation. Biochim. Biophys. Acta. 1850, 43–50.CrossrefPubMedGoogle Scholar

  • Auger, C., Lemire, J., Cecchini, D., Bignucolo, A., and Appanna, V.D. (2011). The metabolic reprogramming evoked by nitrosative stress triggers the anaerobic utilization of citrate in Pseudomonas fluorescens. PLoS One 6, e28469.CrossrefPubMedGoogle Scholar

  • Auger, C., Han, S., Appanna, V.P., Thomas, S.C., Ulibarri, G., and Appanna, V.D. (2013). Metabolic reengineering invoked by microbial systems to decontaminate aluminum: implications for bioremediation technologies. Biotechnol. Adv. 31, 266–273.PubMedCrossrefGoogle Scholar

  • Baker, P.R., Schopfer, F.J., O’Donnell, V.B., and Freeman, B.A. (2009). Convergence of nitric oxide and lipid signaling: anti-inflammatory nitro-fatty acids. Free Radic. Biol. Med. 46, 989–1003.CrossrefPubMedGoogle Scholar

  • Barth, K.R., Isabella, V.M., Wright, L.F., and Clark, V.L. (2009). Resistance to peroxynitrite in Neisseria gonorrhoeae. Microbiology 155, 2532–2545.CrossrefPubMedGoogle Scholar

  • Batthyany, C., Schopfer, F.J., Baker, P.R., Duran, R., Baker, L.M., Huang, Y., Cervenansky, C., Branchaud, B.P., and Freeman, B.A. (2006). Reversible post-translational modification of proteins by nitrated fatty acids in vivo. J. Biol. Chem. 281, 20450–20463.CrossrefGoogle Scholar

  • Bayliak, M.M., Shmihel, H.V., Lylyk, M.P., Vytvytska, O.M., Storey, J.M., Storey, K.B., and Lushchak, V.I. (2015). Alpha-ketoglutarate attenuates toxic effects of sodium nitroprusside and hydrogen peroxide in Drosophila melanogaster. Environ. Toxicol. Pharmacol. 40, 650–659.PubMedCrossrefGoogle Scholar

  • Benthin, G., Bjorkhem, I., Breuer, O., Sakinis, A., and Wennmalm, A. (1997). Transformation of subcutaneous nitric oxide into nitrate in the rat. Biochem. J. 323, 853–858.CrossrefPubMedGoogle Scholar

  • Bignucolo, A., Appanna, V.P., Thomas, S.C., Auger, C., Han, S., Omri, A., and Appanna, V.D. (2013). Hydrogen peroxide stress provokes a metabolic reprogramming in Pseudomonas fluorescens: enhanced production of pyruvate. J. Biotechnol. 167, 309–315.PubMedCrossrefGoogle Scholar

  • Bjorklund, G. and Chirumbolo, S. (2017). Role of oxidative stress and antioxidants in daily nutrition and human health. Nutrition 33, 311–321.PubMedCrossrefGoogle Scholar

  • Bourret, T.J., Boylan, J.A., Lawrence, K.A., and Gherardini, F.C. (2011). Nitrosative damage to free and zinc-bound cysteine thiols underlies nitric oxide toxicity in wild-type Borrelia burgdorferi. Mol. Microbiol. 81, 259–273.CrossrefPubMedGoogle Scholar

  • Bowman, L.A., McLean, S., Poole, R.K., and Fukuto, J.M. (2011). The diversity of microbial responses to nitric oxide and agents of nitrosative stress close cousins but not identical twins. Adv. Microb. Physiol. 59, 135–219.PubMedCrossrefGoogle Scholar

  • Brune, B., Dimmeler, S., Molina y Vedia, L., and Lapetina, E.G. (1994). Nitric oxide: a signal for ADP-ribosylation of proteins. Life Sci. 54, 61–70.CrossrefPubMedGoogle Scholar

  • Bryan, N.S., Rassaf, T., Maloney, R.E., Rodriguez, C.M., Saijo, F., Rodriguez, J.R., and Feelisch, M. (2004). Cellular targets and mechanisms of nitros(yl)ation: an insight into their nature and kinetics in vivo. Proc. Natl. Acad. Sci. USA 101, 4308–4313.CrossrefGoogle Scholar

  • Bryk, R., Griffin, P., and Nathan, C. (2000). Peroxynitrite reductase activity of bacterial peroxiredoxins. Nature 407, 211–215.PubMedCrossrefGoogle Scholar

  • Cadet, J. and Wagner, J.R. (2014). Oxidatively generated base damage to cellular DNA by hydroxyl radical and one-electron oxidants: similarities and differences. Arch. Biochem. Biophys. 557, 47–54.PubMedCrossrefGoogle Scholar

  • Cairo, G. and Recalcati, S. (2007). Iron-regulatory proteins: molecular biology and pathophysiological implications. Expert Rev. Mol. Med. 9, 1–13.PubMedGoogle Scholar

  • Camargo, J.A. and Alonso, A. (2006). Ecological and toxicological effects of inorganic nitrogen pollution in aquatic ecosystems: A global assessment. Environ. Int. 32, 831–849.CrossrefPubMedGoogle Scholar

  • Cleeter, M.W., Cooper, J.M., Darley-Usmar, V.M., Moncada, S., and Schapira, A.H. (1994). Reversible inhibition of cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, by nitric oxide. Implications for neurodegenerative diseases. FEBS Lett. 345, 50–54.Google Scholar

  • Crane, B.R., Sudhamsu, J., and Patel, B.A. (2010). Bacterial nitric oxide synthases. Annu. Rev. Biochem. 79, 445–470.PubMedCrossrefGoogle Scholar

  • Crawford, M.A., Henard, C.A., Tapscott, T., Porwollik, S., McClelland, M., and Vazquez-Torres, A. (2016). DksA-Dependent transcriptional regulation in Salmonella experiencing nitrosative stress. Front Microbiol. 7, 444.PubMedGoogle Scholar

  • Di Meo, S., Reed, T.T., Venditti, P., and Victor, V.M. (2016). Role of ROS and RNS sources in physiological and pathological conditions. Oxid. Med. Cell Longev. 2016, 1245049.PubMedGoogle Scholar

  • Doi, Y., Shimizu, M., Fujita, T., Nakamura, A., Takizawa, N., and Takaya, N. (2014). Achromobacter denitrificans strain YD35 pyruvate dehydrogenase controls NADH production to allow tolerance to extremely high nitrite levels. Appl. Environ. Microbiol. 80, 1910–1918. doi: 10.1128/AEM.03316-13.PubMedCrossrefGoogle Scholar

  • Doi, Y. and Takaya, N. (2015). A novel A3 group aconitase tolerates oxidation and nitric oxide. J. Biol. Chem. 290, 1412–1421.PubMedCrossrefGoogle Scholar

  • Everts, B., Amiel, E., van der Windt, G.J., Freitas, T.C., Chott, R., Yarasheski, K.E., Pearce, E.L., and Pearce, E.J. (2012). Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells. Blood 120, 1422–1431.CrossrefPubMedGoogle Scholar

  • Flannagan, R.S., Heit, B., and Heinrichs, D.E. (2015). Antimicrobial mechanisms of macrophages and the immune evasion strategies of Staphylococcus aureus. Pathogens 4, 826–868.PubMedCrossrefGoogle Scholar

  • Forstermann, U. and Sessa, W.C. (2012). Nitric oxide synthases: regulation and function. Eur. Heart J. 33, 829–837, 837a–837d.PubMedCrossrefGoogle Scholar

  • Friedman, A. and Friedman, J. (2009). New biomaterials for the sustained release of nitric oxide: past, present and future. Expert Opin. Drug Deliv. 6, 1113–1122.PubMedCrossrefGoogle Scholar

  • Gardner, A.M., Helmick, R.A., and Gardner, P.R. (2002). Flavorubredoxin, an inducible catalyst for nitric oxide reduction and detoxification in Escherichia coli. J. Biol. Chem. 277, 8172–8177.CrossrefPubMedGoogle Scholar

  • Gladwin, M.T., Crawford, J.H., and Patel, R.P. (2004). The biochemistry of nitric oxide, nitrite, and hemoglobin: role in blood flow regulation. Free Radic. Biol. Med. 36, 707–717.CrossrefPubMedGoogle Scholar

  • Gomes, C.M., Giuffre, A., Forte, E., Vicente, J.B., Saraiva, L.M., Brunori, M., and Teixeira, M. (2002). A novel type of nitric-oxide reductase. Escherichia coli flavorubredoxin. J. Biol. Chem. 277, 25273–25276.CrossrefGoogle Scholar

  • Green, J., Rolfe, M.D., and Smith, L.J. (2014). Transcriptional regulation of bacterial virulence gene expression by molecular oxygen and nitric oxide. Virulence 5, 794–809.CrossrefPubMedGoogle Scholar

  • Greenacre, S.A. and Ischiropoulos, H. (2001). Tyrosine nitration: localisation, quantification, consequences for protein function and signal transduction. Free Radic. Res. 34, 541–581.PubMedCrossrefGoogle Scholar

  • Hamel, R., Appanna, V.D., Viswanatha, T., and Puiseux-Dao, S. (2004). Overexpression of isocitrate lyase is an important strategy in the survival of Pseudomonas fluorescens exposed to aluminum. Biochem. Biophys. Res. Commun. 317, 1189–1194. doi: 10.1016/j.bbrc.2004.03.157.CrossrefPubMedGoogle Scholar

  • Han, S., Lemire, J., Appanna, V.P., Auger, C., Castonguay, Z., Appanna, V.D. (2013). How aluminum, an intracellular ROS generator promotes hepatic and neurological diseases: the metabolic tale. Cell Biol. Toxicol. 29, 75–84.CrossrefPubMedGoogle Scholar

  • Hess, D.T., Matsumoto, A., Kim, S.O., Marshall, H.E., and Stamler, J.S. (2005). Protein S-nitrosylation: purview and parameters. Nat. Rev. Mol. Cell Biol. 6, 150–166.CrossrefPubMedGoogle Scholar

  • Hill, B.G., Dranka, B.P., Bailey, S.M., Lancaster, J.R., Jr., and Darley-Usmar, V.M. (2010). What part of NO don’t you understand? Some answers to the cardinal questions in nitric oxide biology. J. Biol. Chem. 285, 19699–19704.CrossrefPubMedGoogle Scholar

  • Hopper, R.A. and Garthwaite, J. (2006). Tonic and phasic nitric oxide signals in hippocampal long-term potentiation. J. Neurosci. 26, 11513–11521.PubMedCrossrefGoogle Scholar

  • Horan, S., Bourges, I., and Meunier, B. (2006). Transcriptional response to nitrosative stress in Saccharomyces cerevisiae. Yeast 23, 519–535.CrossrefPubMedGoogle Scholar

  • Hromatka, B.S., Noble, S.M., and Johnson, A.D. (2005). Transcriptional response of Candida albicans to nitric oxide and the role of the YHB1 gene in nitrosative stress and virulence. Mol. Biol. Cell 16, 4814–4826.CrossrefPubMedGoogle Scholar

  • Hutchings, M.I., Mandhana, N., and Spiro, S. (2002). The NorR protein of Escherichia coli activates expression of the flavorubredoxin gene norV in response to reactive nitrogen species. J. Bacteriol. 184, 4640–4643.PubMedCrossrefGoogle Scholar

  • Jain, K., Siddam, A., Marathi, A., Roy, U., Falck, J.R., and Balazy, M. (2008). The mechanism of oleic acid nitration by *NO(2). Free Radic. Biol. Med. 45, 269–283.CrossrefPubMedGoogle Scholar

  • Johansson, A., Moller, C., Fogh, J., and Harper, P. (2003). Biochemical characterization of porphobilinogen deaminase-deficient mice during phenobarbital induction of heme synthesis and the effect of enzyme replacement. Mol. Med. 9, 193–199.PubMedGoogle Scholar

  • Khan, B.V., Harrison, D.G., Olbrych, M.T., Alexander, R.W., and Medford, R.M. (1996). Nitric oxide regulates vascular cell adhesion molecule 1 gene expression and redox-sensitive transcriptional events in human vascular endothelial cells. Proc. Natl. Acad. Sci. USA 93, 9114–9119.CrossrefGoogle Scholar

  • Kinkel, T.L., Ramos-Montanez, S., Pando, J.M., Tadeo, D.V., Strom, E.N., Libby, S.J., and Fang, F.C. (2016). An essential role for bacterial nitric oxide synthase in Staphylococcus aureus electron transfer and colonization. Nat. Microbiol. 2, 16224.CrossrefPubMedGoogle Scholar

  • Klatt, P. and Lamas, S. (2000). Regulation of protein function by S-glutathiolation in response to oxidative and nitrosative stress. Eur. J. Biochem. 267, 4928–4944.PubMedCrossrefGoogle Scholar

  • Korkmaz, A., Yaren, H., Topal, T., and Oter, S. (2006). Molecular targets against mustard toxicity: implication of cell surface receptors, peroxynitrite production, and PARP activation. Arch. Toxicol. 80, 662–670.PubMedCrossrefGoogle Scholar

  • Laver, J.R., Stevanin, T.M., Messenger, S.L., Lunn, A.D., Lee, M.E., Moir, J.W., Poole, R.K., and Read, R.C. (2010). Bacterial nitric oxide detoxification prevents host cell S-nitrosothiol formation: a novel mechanism of bacterial pathogenesis. FASEB. J. 24, 286–295.PubMedCrossrefGoogle Scholar

  • Lee, J.H., Yang, E.S., and Park, J.W. (2003). Inactivation of NADP+-dependent isocitrate dehydrogenase by peroxynitrite. Implications for cytotoxicity and alcohol-induced liver injury. J. Biol. Chem. 278, 51360–51371.CrossrefPubMedGoogle Scholar

  • Lemire, J., Mailloux, R., Puiseux‐Dao, S., Appanna, V.D. (2009). Aluminum-induced defective mitochondrial metabolism perturbs cytoskeletal dynamics in human astrocytoma cells. J. Neurosci. Res. 87, 1474–1483.PubMedCrossrefGoogle Scholar

  • Li, H., Samouilov, A., Liu, X., and Zweier, J.L. (2003). Characterization of the magnitude and kinetics of xanthine oxidase-catalyzed nitrate reduction: evaluation of its role in nitrite and nitric oxide generation in anoxic tissues. Biochemistry 42, 1150–1159.CrossrefPubMedGoogle Scholar

  • Liu, V.W. and Huang, P.L. (2008). Cardiovascular roles of nitric oxide: a review of insights from nitric oxide synthase gene disrupted mice. Cardiovasc. Res. 77, 19–29.PubMedGoogle Scholar

  • Liu, L., Hausladen, A., Zeng, M., Que, L., Heitman, J., and Stamler, J.S. (2001). A metabolic enzyme for S-nitrosothiol conserved from bacteria to humans. Nature 410, 490–494.PubMedCrossrefGoogle Scholar

  • Liu, X.B., Hill, P., and Haile, D.J. (2002). Role of the ferroportin iron-responsive element in iron and nitric oxide dependent gene regulation. Blood Cells Mol. Dis. 29, 315–326.CrossrefPubMedGoogle Scholar

  • Mahnke, A., Meier, R.J., Schatz, V., Hofmann, J., Castiglione, K., Schleicher, U., Wolfbeis, O.S., Bogdan, C., and Jantsch, J. (2014). Hypoxia in Leishmania major skin lesions impairs the NO-dependent leishmanicidal activity of macrophages. J. Invest. Dermatol. 134, 2339–2346.PubMedCrossrefGoogle Scholar

  • Mailloux, R.J., Bériault, R., Lemire, J., Singh, R., Chénier, D.R., Hamel, R.D., Appanna, V.D. (2007). The tricarboxylic acid cycle, an ancient metabolic network with a novel twist. PLoS One 2, e690.CrossrefPubMedGoogle Scholar

  • Mailloux, R.J., Puiseux-Dao, S., Appanna, V.D. (2009). α-ketoglutarate abrogates the nuclear localization of HIF-1α in aluminum-exposed hepatocytes. Biochimie 91, 408–415.PubMedCrossrefGoogle Scholar

  • Martinez, M.C., and Andriantsitohaina, R. (2009). Reactive nitrogen species: molecular mechanisms and potential significance in health and disease. Antioxid. Redox Signal 11, 669–702.CrossrefPubMedGoogle Scholar

  • McBride, A.G., Borutaite, V., and Brown, G.C. (1999). Superoxide dismutase and hydrogen peroxide cause rapid nitric oxide breakdown, peroxynitrite production and subsequent cell death. Biochim. Biophys. Acta. 1454, 275–288.CrossrefPubMedGoogle Scholar

  • Middaugh, J., Hamel, R., Jean-Baptiste, G., Beriault, R., Chenier, D., and Appanna, V.D. (2005). Aluminum triggers decreased aconitase activity via Fe-S cluster disruption and the overexpression of isocitrate dehydrogenase and isocitrate lyase: a metabolic network mediating cellular survival. J. Biol. Chem. 280, 3159–3165.PubMedCrossrefGoogle Scholar

  • Missall, T.A., Lodge, J.K., and McEwen, J.E. (2004). Mechanisms of resistance to oxidative and nitrosative stress: implications for fungal survival in mammalian hosts. Eukaryot. Cell 3, 835–846.PubMedCrossrefGoogle Scholar

  • Mukhopadhyay, P., Zheng, M., Bedzyk, L.A., LaRossa, R.A., and Storz, G. (2004). Prominent roles of the NorR and Fur regulators in the Escherichia coli transcriptional response to reactive nitrogen species. Proc. Natl. Acad. Sci. USA 101, 745–750.CrossrefGoogle Scholar

  • Muller, B., Kleschyov, A.L., Alencar, J.L., Vanin, A., and Stoclet, J.C. (2002). Nitric oxide transport and storage in the cardiovascular system. Ann. N Y Acad. Sci. 962, 131–139.PubMedCrossrefGoogle Scholar

  • Murad, F. (2006). Shattuck Lecture. Nitric oxide and cyclic GMP in cell signaling and drug development. N. Engl. J. Med. 355, 2003–2011.PubMedCrossrefGoogle Scholar

  • Nath, K.A., Ngo, E.O., Hebbel, R.P., Croatt, A.J., Zhou, B., and Nutter, L.M. (1995). Alpha-Ketoacids scavenge H2O2 in vitro and in vivo and reduce menadione-induced DNA injury and cytotoxicity. Am. J. Physiol. 268, C227–236.Google Scholar

  • Nathan, C. (2003). Specificity of a third kind: reactive oxygen and nitrogen intermediates in cell signaling. J. Clin. Invest. 111, 769–778.PubMedCrossrefGoogle Scholar

  • Nittler, M.P., Hocking-Murray, D., Foo, C.K., and Sil, A. (2005). Identification of Histoplasma capsulatum transcripts induced in response to reactive nitrogen species. Mol. Biol. Cell 16, 4792–4813.CrossrefPubMedGoogle Scholar

  • Ohshima, H., Sawa, T., and 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, 1033–1045.CrossrefPubMedGoogle Scholar

  • Parente, A.F., Naves, P.E., Pigosso, L.L., Casaletti, L., McEwen, J.G., Parente-Rocha, J.A., and Soares, C.M. (2015). The response of Paracoccidioides spp. to nitrosative stress. Microbes. Infect. 17, 575–585.CrossrefPubMedGoogle Scholar

  • Parker, H., Albrett, A.M., Kettle, A.J., and Winterbourn, C.C. (2012). Myeloperoxidase associated with neutrophil extracellular traps is active and mediates bacterial killing in the presence of hydrogen peroxide. J. Leukoc. Biol. 91, 369–376.CrossrefPubMedGoogle Scholar

  • Peluffo, G., and Radi, R. (2007). Biochemistry of protein tyrosine nitration in cardiovascular pathology. Cardiovasc. Res. 75, 291–302.PubMedCrossrefGoogle Scholar

  • Pham-Huy, L.A., He, H., and Pham-Huy, C. (2008). Free radicals, antioxidants in disease and health. Int. J. Biomed. Sci. 4, 89–96.PubMedGoogle Scholar

  • Phaniendra, A., Jestadi, D.B., and Periyasamy, L. (2015). Free radicals: properties, sources, targets, and their implication in various diseases. Indian J. Clin. Biochem. 30, 11–26.PubMedCrossrefGoogle Scholar

  • Poole, R.K. (2005). Nitric oxide and nitrosative stress tolerance in bacteria. Biochem. Soc. Trans. 33, 176–180.CrossrefPubMedGoogle Scholar

  • Poole, R.K., and Hughes, M.N. (2000). New functions for the ancient globin family: bacterial responses to nitric oxide and nitrosative stress. Mol. Microbiol. 36, 775–783.PubMedCrossrefGoogle Scholar

  • Qu, W., Zhou, Y., Shao, C., Sun, Y., Zhang, Q., Chen, C., and Jia, J. (2009). Helicobacter pylori proteins response to nitric oxide stress. J. Microbiol. 47, 486–493.CrossrefPubMedGoogle Scholar

  • Radi, R. (2013). Protein tyrosine nitration: biochemical mechanisms and structural basis of functional effects. Acc. Chem. Res. 46, 550–559.CrossrefPubMedGoogle Scholar

  • Richardson, A.R., Dunman, P.M., and Fang, F.C. (2006). The nitrosative stress response of Staphylococcus aureus is required for resistance to innate immunity. Mol. Microbiol. 61, 927–939.PubMedCrossrefGoogle Scholar

  • Richardson, A.R., Libby, S.J., and Fang, F.C. (2008). A nitric oxide-inducible lactate dehydrogenase enables Staphylococcus aureus to resist innate immunity. Science 319, 1672–1676.CrossrefPubMedGoogle Scholar

  • Rogstam, A., Larsson, J.T., Kjelgaard, P., and von Wachenfeldt, C. (2007). Mechanisms of adaptation to nitrosative stress in Bacillus subtilis. J. Bacteriol. 189, 3063–3071.CrossrefPubMedGoogle Scholar

  • Sandoo, A., van Zanten, J.J., Metsios, G.S., Carroll, D., and Kitas, G.D. (2010). The endothelium and its role in regulating vascular tone. Open Cardiovasc. Med. J. 4, 302–312.PubMedCrossrefGoogle Scholar

  • Santos, R.M., Lourenco, C.F., Ledo, A., Barbosa, R.M., and Laranjinha, J. (2012). Nitric oxide inactivation mechanisms in the brain: role in bioenergetics and neurodegeneration. Int. J. Cell Biol. 2012, 391914.PubMedGoogle Scholar

  • Sawa, T., Zaki, M.H., Okamoto, T., Akuta, T., Tokutomi, Y., Kim-Mitsuyama, S., Ihara, H., Kobayashi, A., Yamamoto, M., Fujii, S., et al. (2007). Protein S-guanylation by the biological signal 8-nitroguanosine 3′,5′-cyclic monophosphate. Nat. Chem. Biol. 3, 727–735.PubMedCrossrefGoogle Scholar

  • Schleicher, U., Paduch, K., Debus, A., Obermeyer, S., Konig, T., Kling, J.C., Ribechini, E., Dudziak, D., Mougiakakos, D., Murray, P.J., et al. (2016). TNF-mediated restriction of arginase 1 expression in myeloid cells triggers type 2 NO synthase activity at the site of infection. Cell Rep. 15, 1062–1075.PubMedCrossrefGoogle Scholar

  • Stern, A.M., Liu, B., Bakken, L.R., Shapleigh, J.P., and Zhu, J. (2013). A novel protein protects bacterial iron-dependent metabolism from nitric oxide. J. Bacteriol. 195, 4702–4708.PubMedCrossrefGoogle Scholar

  • Storm, J., Sethia, S., Blackburn, G.J., Chokkathukalam, A., Watson, D.G., Breitling, R., Coombs, G.H., and Muller, S. (2014). Phosphoenolpyruvate carboxylase identified as a key enzyme in erythrocytic Plasmodium falciparum carbon metabolism. PLoS Pathog. 10, e1003876.CrossrefPubMedGoogle Scholar

  • Szabo, C., Ischiropoulos, H., and Radi, R. (2007). Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat. Rev. Drug Discov. 6, 662–680.PubMedCrossrefGoogle Scholar

  • Thomson, L. (2015). 3-nitrotyrosine modified proteins in atherosclerosis. Dis. Markers 2015, 708282.PubMedGoogle Scholar

  • Thomas, C., Mackey, M.M., Diaz, A.A., and Cox, D.P. (2009). Hydroxyl radical is produced via the Fenton reaction in submitochondrial particles under oxidative stress: implications for diseases associated with iron accumulation. Redox Rep. 14, 102–108.PubMedCrossrefGoogle Scholar

  • Tillmann, A., Gow, N.A., and Brown, A.J. (2011). Nitric oxide and nitrosative stress tolerance in yeast. Biochem. Soc. Trans. 39, 219–223.PubMedCrossrefGoogle Scholar

  • Ullmann, B.D., Myers, H., Chiranand, W., Lazzell, A.L., Zhao, Q., Vega, L.A., Lopez-Ribot, J.L., Gardner, P.R., and Gustin, M.C. (2004). Inducible defense mechanism against nitric oxide in Candida albicans. Eukaryot. Cell 3, 715–723.PubMedCrossrefGoogle Scholar

  • Uppu, R.M. and Pryor, W.A. (1996). Carbon dioxide catalysis of the reaction of peroxynitrite with ethyl acetoacetate: an example of aliphatic nitration by peroxynitrite. Biochem. Biophys Res. Commun. 229, 764–769.PubMedCrossrefGoogle Scholar

  • Villacorta, L., Zhang, J., Garcia-Barrio, M.T., Chen, X.L., Freeman, B.A., Chen, Y.E., and Cui, T. (2007). Nitro-linoleic acid inhibits vascular smooth muscle cell proliferation via the Keap1/Nrf2 signaling pathway. Am. J. Physiol. Heart Circ. Physiol. 293, H770–776.CrossrefPubMedGoogle Scholar

  • Virag, L. and Szabo, C. (2002). The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. Pharmacol. Rev. 54, 375–429.CrossrefPubMedGoogle Scholar

  • Wanstall, J.C., Homer, K.L., and Doggrell, S.A. (2005). Evidence for, and importance of, cGMP-independent mechanisms with NO and NO donors on blood vessels and platelets. Curr. Vasc. Pharmacol. 3, 41–53.PubMedCrossrefGoogle Scholar

  • Weidinger, A. and Kozlov, A.V. (2015). Biological activities of reactive oxygen and nitrogen species: oxidative stress versus signal transduction. Biomolecules 5, 472–484.PubMedCrossrefGoogle Scholar

  • White, P.J., Charbonneau, A., Cooney, G.J., and Marette, A. (2010). Nitrosative modifications of protein and lipid signaling molecules by reactive nitrogen species. Am. J. Physiol. Endocrinol. Metab. 299, E868–878.CrossrefPubMedGoogle Scholar

  • Wright, M.M., Kim, J., Hock, T.D., Leitinger, N., Freeman, B.A., and Agarwal, A. (2009). Human haem oxygenase-1 induction by nitro-linoleic acid is mediated by cAMP, AP-1 and E-box response element interactions. Biochem. J. 422, 353–361.PubMedCrossrefGoogle Scholar

  • Yermilov, V., Rubio, J., and Ohshima, H. (1995). Formation of 8-nitroguanine in DNA treated with peroxynitrite in vitro and its rapid removal from DNA by depurination. FEBS Lett. 376, 207–210.CrossrefPubMedGoogle Scholar

  • Zhao, J. (2007). Interplay among nitric oxide and reactive oxygen species: a complex network determining cell survival or death. Plant Signal. Behav. 2, 544–547.CrossrefPubMedGoogle Scholar

  • Zhou, S., Narukami, T., Nameki, M., Ozawa, T., Kamimura, Y., Hoshino, T., and Takaya, N. (2012). Heme-biosynthetic porphobilinogen deaminase protects Aspergillus nidulans from nitrosative stress. Appl. Environ. Microbiol. 78, 103–109.CrossrefPubMedGoogle Scholar

  • Zmijewski, J.W., Landar, A., Watanabe, N., Dickinson, D.A., Noguchi, N., and Darley-Usmar, V.M. (2005). Cell signalling by oxidized lipids and the role of reactive oxygen species in the endothelium. Biochem. Soc. Trans. 33, 1385–1389.PubMedCrossrefGoogle Scholar

About the article

Received: 2017-04-27

Accepted: 2017-06-07

Published Online: 2017-06-15

Published in Print: 2017-10-26

Conflict of interest statement: All authors declare that they have no conflict of interest.

Citation Information: Biological Chemistry, Volume 398, Issue 11, Pages 1193–1208, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/hsz-2017-0152.

Export Citation

©2017 Walter de Gruyter GmbH, Berlin/Boston.Get Permission

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

Ying Wang, Robyn Branicky, Alycia Noë, and Siegfried Hekimi
The Journal of Cell Biology, 2018, Page jcb.201708007

Comments (0)

Please log in or register to comment.
Log in