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CHAPTER 19 Nitric Oxide 341

NO may involve metal-independent interactions with other are susceptible to peroxynitrite-catalyzed tyrosine nitration, and
cellular proteins. NO reacts with thiols (compounds contain- this irreversible modification can be associated with either
ing the –SH group) to form nitrosothiols. In proteins, the thiol activation or inhibition of protein function. Detection of tyrosine
moiety is found in the amino acid cysteine. This posttranslational nitration in tissue is often used as a marker of excessive NO pro-
modification, termed S-nitrosylation or S-nitrosation, requires duction, although a direct causal role of tyrosine nitration in the
either metals or O to catalyze the formation of the nitrosothiol pathogenesis of any disease has not been definitively established.
2
adduct. S-nitrosylation is highly specific, with only certain cyste- Peroxynitrite-mediated protein modification is mitigated by
ine residues in proteins becoming S-nitrosylated. S-nitrosylation intracellular levels of glutathione, which can protect against tissue
can alter the function, stability, or localization of target proteins. damage by scavenging peroxynitrite. Factors that regulate the
Major targets of S-nitrosylation include H-ras, a regulator of cell biosynthesis and decomposition of glutathione may be important
proliferation that is activated by S-nitrosylation, and the metabolic modulators of the toxicity of NO.
enzyme glyceraldehyde-3-phosphate dehydrogenase, which is
inhibited when it is S-nitrosylated. Denitrosylation of proteins is Inactivation
poorly understood but may involve enzymes, such as thioredoxin,
or chemical reduction by intracellular reducing agents such as NO is highly labile due to its rapid reaction with metals, O , and
2
glutathione, an abundant intracellular sulfhydryl-containing com- reactive oxygen species. NO can react with heme and hemopro-
pound. Glutathione can also be S-nitrosylated under physiologic teins, including oxyhemoglobin, which oxidizes NO to nitrate.
conditions to generate S-nitrosoglutathione. S-nitrosoglutathione The reaction of NO with hemoglobin may also lead to S-nitrosyl-
may serve as an endogenous stabilized form of NO or as a carrier ation of hemoglobin, resulting in transport of NO throughout the
of NO. Vascular glutathione is decreased in diabetes mellitus and vasculature. NO is also inactivated by reaction with O to form
2
atherosclerosis, and the resulting deficiency of S-nitrosoglutathi- nitrogen dioxide. As noted, NO reacts with superoxide, which
one may account for the increased incidence of cardiovascular results in the formation of the highly reactive oxidizing species,
complications in these conditions. peroxynitrite. Scavengers of superoxide anion such as superoxide
dismutase may protect NO, enhancing its potency and prolonging
3. Tyrosine Nitration—Additional reactions of NO are seen, its duration of action.
especially in immune system cells producing large amounts of
NO. NO undergoes both oxidative and reductive reactions, which
allow it to nitrosylate thiols and add nitrate to tyrosines (described ■ PHARMACOLOGIC
below) or lead to stable oxidation products (Table 19–2). NO MANIPULATION OF NITRIC OXIDE
reacts very efficiently with superoxide to form peroxynitrite
–
(ONOO ), a highly reactive oxidant that leads to DNA damage, Inhibitors of Nitric Oxide Synthesis
nitration of tyrosine, and oxidation of cysteine to disulfides or to
various sulfur oxides (SO ). Several cellular enzymes synthesize NOS enzyme inhibitors are currently being evaluated for efficacy in
x
superoxide, and these enzymes are elevated in concert with NO diseases associated with elevated NO production, such as inflamma-
synthase in numerous inflammatory and degenerative diseases, tory conditions, sepsis, and neurodegenerative diseases. The major-
resulting in an increase in peroxynitrite levels. Numerous proteins ity of these inhibitors are arginine analogs that bind to the NOS

TABLE 19–2 Oxides of nitrogen.

Name Structure Known Function
Nitric oxide (NO) N=O • Vasodilator, platelet inhibitor, immune regulator, neurotransmitter
−
Peroxynitrite (NO ) O=N−O−O − Oxidant and nitrating agent
3
−
−
Nitroxyl anion (NO ) N =O Can form from nonspecific donation of an electron from metals to NO
Exhibits NO-like effects, possibly by first being oxidized to NO
−
+
Nitrous oxide (N O) N =N =O Anesthetic
2
+
Dinitrogen trioxide (N O ) O=N−N =O Auto-oxidation product of NO that can nitrosylate protein thiols
3
2
O −
−
Nitrite (NO ) O=N=O − Stable oxidation product of NO
2
Slowly metabolized to nitrosothiols, and decomposes to NO at acidic pH
+
−
Nitrate (NO ) O=N −O − Stable oxidation product of NO
3
O −