The Diversity of Microbial Responses to Nitric Oxide and Agents of Nitrosative Stress: Close Cousins but Not Identical Twins

https://doi.org/10.1016/B978-0-12-387661-4.00006-9Get rights and content

Abstract

Nitric oxide and related nitrogen species (reactive nitrogen species) now occupy a central position in contemporary medicine, physiology, biochemistry, and microbiology. In particular, NO plays important antimicrobial defenses in innate immunity but microbes have evolved intricate NO-sensing and defense mechanisms that are the subjects of a vast literature. Unfortunately, the burgeoning NO literature has not always been accompanied by an understanding of the intricacies and complexities of this radical and other reactive nitrogen species so that there exists confusion and vagueness about which one or more species exert the reported biological effects. The biological chemistry of NO and derived/related molecules is complex, due to multiple species that can be generated from NO in biological milieu and numerous possible reaction targets. Moreover, the fate and disposition of NO is always a function of its biological environment, which can vary significantly even within a single cell. In this review, we consider newer aspects of the literature but, most importantly, consider the underlying chemistry and draw attention to the distinctiveness of NO and its chemical cousins, nitrosonium (NO+), nitroxyl (NO, HNO), peroxynitrite (ONOO), nitrite (NO2), and nitrogen dioxide (NO2). All these species are reported to be generated in biological systems from initial formation of NO (from nitrite, NO synthases, or other sources) or its provision in biological experiments (typically from NO gas, S-nitrosothiols, or NO donor compounds). The major targets of NO and nitrosative damage (metal centers, thiols, and others) are reviewed and emphasis is given to newer “-omic” methods of unraveling the complex repercussions of NO and nitrogen oxide assaults. Microbial defense mechanisms, many of which are critical for pathogenicity, include the activities of hemoglobins that enzymically detoxify NO (to nitrate) and NO reductases and repair mechanisms (e.g., those that reverse S-nitrosothiol formation). Microbial resistance to these stresses is generally inducible and many diverse transcriptional regulators are involved—some that are secondary sensors (such as Fnr) and those that are “dedicated” (such as NorR, NsrR, NssR) in that their physiological function appears to be detecting primarily NO and then regulating expression of genes that encode enzymes with NO as a substrate. Although generally harmful, evidence is accumulating that NO may have beneficial effects, as in the case of the squid-Vibrio light-organ symbiosis, where NO serves as a signal, antioxidant, and specificity determinant. Progress in this area will require a thorough understanding not only of the biology but also of the underlying chemical principles.

Section snippets

Overview

Nitric oxide (NO) is a small and freely diffusible species once known primarily as a toxic component of air pollution. In physiology and biochemistry, it was well known as a poison and ligand for heme proteins. The discovery of the enzymic generation of NO in mammalian systems and its cell signaling functions represents a watershed moment in the evolution of our understanding of biological signal transduction. The importance of NO as a molecule of real biological significance cannot, however,

Historical Perspective

The modern era of NO research may be considered to begin in the 1980s when NO was identified as the endothelium-derived relaxing factor (EDRF). This remarkable story and its culmination in a Nobel Prize and the designation of NO as “molecule of the year” by Science in 1992 are covered well elsewhere, especially in accounts by the laureates (Furchgott, 1999, Ignarro, 1999, Ignarro, 2005, Murad, 1999). NO was also shown to participate in the regulation of the nervous and immune systems, and it

Nitrite Reduction and Denitrification

The major source of NO in man is via the action of NOS (see Section 3.3), but other sources should be briefly considered. Nitrite is protonated under acidic conditions (as in the stomach) and the resulting nitrous acid will yield NO and other nitrogen oxides; the beneficial effects of acidified nitrite in killing ingested pathogens, gastric mucosal integrity and other effects are discussed elsewhere (Lundberg et al., 2004). Acidified nitrite is sometimes, but perhaps not ideally, used as a

NO, Its Redox Chemistry, and NO2

The biological chemistry of NO and derived/related molecules is potentially complex due to a multitude of species that can be generated from NO in a biological milieu and the multiple possible reaction targets associated with these derived species (for an overview, see Lehnert and Scheidt, 2010). Moreover, the fate and disposition of NO is always a function of its biochemical environment, which can vary significantly even within a single cell. The redox relationship between NO and

Laboratory Methods

Working with many of the nitrogen oxides described above can be accomplished using either authentic compounds, or in many cases, it is more convenient to use donor species. Herein, we discuss briefly aspects of working with the nitrogen oxides that appear to be of the most current interest—NO, NO2, N2O3, NO2, HNO, and ONOO. For several nitrogen oxide species discussed below, the use of donor compounds is prevalent and even necessary. There are several important factors that need to be

Targets of RNS in Microorganisms

It is frequently stated that NO is a highly reactive gas and must interact with numerous and diverse biological targets. In fact, as we outline in Section 4.1, NO is not especially reactive but it is true that its targets are not as restricted as those of another “gasotransmitter,” carbon monoxide (CO) (Davidge et al., 2009a). The direct cellular effects of NO are incompletely understood because of the complexity of NO chemistry introduced in Section 4. Nevertheless, various biomolecules are

Global and Systems Approaches to Understanding Responses to NO and RNS

Due to the complex nature of the interactions between microorganisms and various RNS, many studies now utilize a variety of “omic” techniques available to more fully understand the targets of and responses to these stresses. Global/systems approaches have the advantage of being able to highlight predicted as well as unexpected and novel responses of the microbe. These approaches are able to show us the interactions, robustness, and modularity of the complex microbial systems in place for the

Conclusions

The past 15 years have seen a remarkable transformation of our appreciation of the assaults on microbes by NO and RNS and also the elaborate and effective defense measures mounted. Certain recurrent themes are evident. Microbes (in most cases, the information relates to bacteria) are able to resist NO in their environments by a relatively small number of detoxification mechanisms, the best understood being globins that catalyze NO conversion to nitrate and reductases that produce nitroxyl

References (332)

  • V.B. Borisov et al.

    Reaction of nitric oxide with the oxidized di-heme and heme-copper oxygen-reducing centers of terminal oxidases: different reaction pathways and end-products

    J. Inorg. Biochem.

    (2009)
  • L. Brunelli et al.

    The comparative toxicity of nitric oxide and peroxynitrite to Escherichia coli

    Arch. Biochem. Biophys.

    (1995)
  • M. Brunori

    Nitric oxide moves myoglobin centre stage

    Trends Biochem. Sci.

    (2001)
  • M.R. Buddha et al.

    Regioselective nitration of tryptophan by a complex between bacterial nitric-oxide synthase and tryptophanyl-tRNA synthetase

    J. Biol. Chem.

    (2004)
  • C.S. Butler et al.

    Cytochrome bo(3) from Escherichia coli: the binding and turnover of nitric oxide

    Biochem. Biophys. Res. Commun.

    (2002)
  • P. Cabello et al.

    Hydroxylamine assimilation by Rhodobacter capsulatus E1F1—requirement of the hcp gene (hybrid cluster protein) located in the nitrate assimilation nas gene region for hydroxylamine reduction

    J. Biol. Chem.

    (2004)
  • G. Cappelli et al.

    Profiling of Mycobacterium tuberculosis gene expression during human macrophage infection: upregulation of the alternative sigma factor G, a group of transcriptional regulators, and proteins with unknown function

    Res. Microbiol.

    (2006)
  • Y.J. Chen et al.

    A bacterial, nitric oxide synthase from a Nocardia species

    Biochem. Biophys. Res. Commun.

    (1994)
  • A. Claiborne et al.

    Purification of the o-dianisidine peroxidase from Escherichia coli B. Physicochemical characterization and analysis of its dual catalatic and peroxidatic activities.

    J. Biol. Chem.

    (1979)
  • N.M. Cook et al.

    Nitroxyl-mediated disruption of thiol proteins: inhibition of the yeast transcription factor Ace1

    Arch. Biochem. Biophys.

    (2003)
  • H. Corker et al.

    Nitric oxide formation by Escherichia coli—dependence on nitrite reductase, the NO-sensing regulator FNR, and flavohemoglobin Hmp

    J. Biol. Chem.

    (2003)
  • S. Daff

    NO synthase: structures and mechanisms

    Nitric Oxide-Biol. Ch.

    (2010)
  • N. Dasgupta et al.

    Characterization of a two-component system, devR-devS, of Mycobacterium tuberculosis

    Tuber. Lung Dis.

    (2000)
  • K.S. Davidge et al.

    Carbon monoxide in biology and microbiology: surprising roles for the "Detroit perfume"

    Adv. Microb. Physiol.

    (2009)
  • K.S. Davidge et al.

    Carbon monoxide-releasing antibacterial molecules target respiration and global transcriptional regulators

    J. Biol. Chem.

    (2009)
  • A.M. Dukelow et al.

    Effects of nebulized diethylenetetraamine-NONOate in a mouse model of acute Pseudomonas aeruginosa pneumonia

    Chest

    (2002)
  • O. Einsle

    Structure and function of formate-dependent cytochrome c nitrite reductase, NrfA

    Methods Enzymol.

    (2011)
  • P.J. Farmer et al.

    Coordination chemistry of the HNO ligand with hemes and synthetic coordination complexes

    J. Inorg. Biochem.

    (2005)
  • J. Flatley et al.

    Transcriptional responses of Escherichia coli to S-nitrosoglutathione under defined chemostat conditions reveal major changes in methionine biosynthesis

    J. Biol. Chem.

    (2005)
  • P.C. Ford et al.

    Autoxidation kinetics of aqueous nitric oxide

    FEBS Lett.

    (1993)
  • M.W. Foster et al.

    Protein S-nitrosylation in health and disease: a current perspective

    Trends Mol. Med.

    (2009)
  • A.D. Frey et al.

    Bacterial hemoglobins and flavohemoglobins: versatile proteins and their impact on microbiology and biotechnology

    FEMS Microbiol. Rev.

    (2003)
  • A.D. Frey et al.

    The single-domain globin of Vitreoscilla augmentation of aerobic metabolism for biotechnological applications

    Adv. Microb. Physiol.

    (2011)
  • J.M. Fukuto et al.

    Examining nitroxyl in biological systems

    Methods Enzymol.

    (2008)
  • P.R. Gardner

    Nitric oxide dioxygenase function and mechanism of flavohemoglobin, hemoglobin, myoglobin and their associated reductases

    J. Inorg. Biochem.

    (2005)
  • A.M. Gardner et al.

    Flavohemoglobin detoxifies nitric oxide in aerobic, but not anaerobic, Escherichia coli—evidence for a novel inducible anaerobic nitric oxide-scavenging activity

    J. Biol. Chem.

    (2002)
  • P.R. Gardner et al.

    Nitric oxide sensitivity of the aconitases

    J. Biol. Chem.

    (1997)
  • P.R. Gardner et al.

    Nitric-oxide dioxygenase activity and function of flavohemoglobins—sensitivity to nitric oxide and carbon monoxide inhibition

    J. Biol. Chem.

    (2000)
  • A.M. Gardner et al.

    Flavorubredoxin, an inducible catalyst for nitric oxide reduction and detoxification in Escherichia coli

    J. Biol. Chem.

    (2002)
  • A.M. Gardner et al.

    Regulation of the nitric oxide reduction operon (norRVW) in Escherichia coli. Role of NorR and σ54 in the nitric oxide stress response

    J. Biol. Chem.

    (2003)
  • P.R. Gardner et al.

    Hemoglobins dioxygenate nitric oxide with high fidelity

    J. Inorg. Biochem.

    (2006)
  • S. Adak et al.

    Cloning, expression, and characterization of a nitric oxide synthase protein from Deinococcus radiodurans

    Proc. Natl. Acad. Sci. USA

    (2002)
  • T. Agapie et al.

    NO formation by a catalytically self-sufficient bacterial nitric oxide synthase from Sorangium cellulosum

    Proc. Natl. Acad. Sci. USA

    (2009)
  • T. Akaike et al.

    Antagonistic action of imidazolineoxyl N-oxides against endothelium-derived relaxing factor/.NO through a radical reaction

    Biochemistry.

    (1993)
  • W.K. Alderton et al.

    Nitric oxide synthases: structure, function and inhibition

    Biochem. J.

    (2001)
  • H. Arai et al.

    Transcriptional regulation of the flavohemoglobin gene for aerobic nitric oxide detoxification by the second nitric oxide-responsive regulator of Pseudomonas aeruginosa

    J. Bacteriol.

    (2005)
  • J. Assreuy et al.

    Production of nitric oxide and superoxide by activated macrophages and killing of Leishmania major

    Eur. J. Immunol.

    (1994)
  • Y. Barak et al.

    Role of nitric oxide in Salmonella typhimurium-mediated cancer cell killing

    BMC Cancer

    (2010)
  • M.D. Bartberger et al.

    On the acidity and reactivity of HNO in aqueous solution and biological systems

    Proc. Natl. Acad. Sci. USA

    (2001)
  • M.D. Bartberger et al.

    The reduction potential of nitric oxide (NO) and its importance to NO biochemistry

    Proc. Natl. Acad. Sci. USA

    (2002)
  • Cited by (0)

    View full text