Biomedical Engineering Reference
In-Depth Information
9.10.7.4
Reactive Nitrogen Species
Peroxynitrite anion (ONOO
−
) is a short-lived (
10 ms; hence low-steady-state
concentration) oxidant produced by the reaction of short-range diffusible nitric
oxide (NO) with superoxide radical (O
•
2
) formed by plasmalemmal NAD(P)H
oxidases and the mitochondrial respiratory chain at diffusion-controlled rates (
∼
∼
1
×
10
10
/(mol
mol/mn [
1147
]).
181
Its toxic
effects can drop upon fast reduction to nitrite (NO
2
) or isomerization (same molec-
ular content, but different structure) to nitrate (NO
3
) by metalloporphyrins (e.g.,
manganese and iron metalloporphyrins) [
1147
]. Certain enzymes detoxify peroxyni-
trite. Various scavengers and neutralizers of peroxynitrite and peroxynitrite-derived
radicals include peroxiredoxin-5 that reduces peroxynitrite to nitrite, thiol-based
anti-oxidants, and selenocompounds (selenoprotein-P and glutathione peroxidase).
Peroxynitrite reacts in a pH-dependent manner mainly with carbon dioxide
(CO
2
) in aqueous phase (rapidly) as well as numerous types of molecules, among
which many possess thiols and transition metal centers such as hemin.
182
Reaction
of peroxynitrite and/or its derived radicals (e.g., carbonate [CO
•
3
] and nitrogen
dioxide [NO
2
] radicals) with targets causes 1- and 2-electron oxidations and
nitration [
1147
].
183
·
s; estimated production rate of 50-100
m) from its
formation site across membranes can provoke oxidative damage (oxidation and
nitration of proteins [cytosolic and membrane protein Tyr nitration], membrane
lipids, and DNA).
184
Peroxynitrous acid (ONOOH) in equilibrium with peroxynitrite (ONOO
−
) can
undergo isomerization to generate nitrate (NO
3
) or homolytic fission
185
to generate
1-electron oxidants hydroxyl (
•
OH) and (
•
NO
2
radicals [
1147
]. This reaction is slow
in aqueous compartments, but peroxynitrous acid crosses lipid bilayers and gives
rise in hydrophobic phases to
•
OH) and (NO
2
radicals to initiate lipid peroxidation
Diffusion of peroxynitrite (over length 5-20
181
Mitochondrial electron-transport chain represents a set of redox carriers in the inner mitochon-
drial membrane that enable the flow of electrons from substrates to oxygen. The potential energy in
the electron gradient is used to drive ATP synthesis, when protons move back across the membrane
via ATP synthase.
182
Transition metals include copper, iron, and manganese.
183
Both CO
•
3
and NO
2
are 1-electron oxidants that can oxidize amino acids, such as cysteine and
tyrosine to form cysteinyl and tyrosyl radicals.
184
Tyrosine nitration, dimerization, and hydroxylation by peroxynitrite form 3-nitrotyrosine, (3,3
)-
dityrosine, and (3,4
)-dihydrophenylalanine, respectively. The reaction of peroxynitrite-derived
radicals with lipids leads to peroxidation and formation of nitrito-, nitro-, nitrosoperoxo-, and
nitrated lipid oxidation adducts.
185
Rupture of a covalent bond in a molecule, in which the 2 resulting products keep one of the
bond electrons.
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