Biology Reference
In-Depth Information
biological chemistry of NO and relatedmolecules is complex; NO in biolog-
ical environments reacts with several targets and generates a large amount of
species that in turn interact with other molecules (for an overview, see
Lehnert & Scheidt, 2009
). For instance, the intracellular NO toxicity mech-
anisms are related to the oxidation of NO and the production of various poi-
sonous substances such as the nitrosating nitrosonium ion (NO
รพ
), nitrite
(NO
2
) and peroxynitrite (ONOO
)(
Poole &Hughes, 2000
). Peroxynitrite
arises from the reaction of NOwith superoxide (O
2
)(
Hughes, 1999
), and in
living cells reacts with carbon dioxide to produce the adduct (ONOOCO
2
).
This product is broken down via twomechanisms, the first one producing car-
bon dioxide (CO
2
) and nitrate (NO
3
) and the other evolving nitrogen
dioxide (NO
2
) and the carbonate radical ion (reviewed in
Bowman,
McLean, Poole, & Fukuto, 2011; Poole & Hughes, 2000
).
Although NO is a toxic molecule, it has important functions in biolog-
ical systems, mainly in signalling and defence mechanisms. Generation of
NO by endothelial cells produces relaxation of vascular smooth muscle,
in part via the activation of the guanylate cyclase (
Murad, 1986
). NO is pro-
duced by NO synthases (NOSs) in various cell types by the oxidation of
L
-arginine to
L
-citrulline and NO in an NADPH- and O
2
-dependent man-
ner (
Stuehr, 1999
). NOSs were firstly reported in mammals where three
isoforms were identified, two constitutively expressed, endothelial and neu-
ronal, and an inducible NO synthase able to produce high levels of NO in
response to infection (reviewed in
Alderton, Cooper, & Knowles, 2001;
Lowenstein & Padalko, 2004
).
Elevated concentrations of NO generated by the immune system cause
inhibition of key bacterial enzymes such as terminal oxidases (
Stevanin et al.,
2000
) and enzymes with iron-sulphur (Fe-S) centres (
Gardner, Costantino,
Szabo, & Salzman, 1997
). NO produced by the host can diffuse easily across
the bacterial membrane where it reacts with haems (
Hausladen, Gow, &
Stamler, 2001
), Fe-S clusters (
Cruz-Ramos et al., 2002
) and thiols (
Hess,
Matsumoto, Kim, Marshall, & Stamler, 2005
). Besides these toxic effects,
NO is also a modulator of protein function in bacteria through the
S
-nitrosylation of specific cysteine thiols: the presence of NO and other
RNS produces nitrosative stress, eliciting adaptative responses such as the
expression of genes related to NO and RNS tolerance and detoxification
(
Avila-Ramirez et al., 2013; Flatley et al., 2005; Monk et al., 2008;
Moore, Nakano, Wang, Ye, & Helmann, 2004; Mukhopadhyay, Zheng,
Bedzyk, LaRossa, & Storz, 2004; Pullan et al., 2007; Richardson,
Dunman, & Fang, 2006
and many others).