Reactive nitrogen species
Encyclopedia
Reactive nitrogen species (RNS) are a family of antimicrobial molecules derived from nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...

 (·NO) and superoxide
Superoxide
A superoxide, also known by the obsolete name hyperoxide, is a compound that possesses the superoxide anion with the chemical formula O2−. The systematic name of the anion is dioxide. It is important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature...

 (O2·) produced via the enzymatic activity of inducible nitric oxide synthase 2 (NOS2
Nitric oxide synthase 2A
Nitric oxide synthase, inducible is an enzyme that in humans is encoded by the NOS2 gene.Nitric oxide is a reactive free radical which acts as a biologic mediator in several processes, including neurotransmission and antimicrobial and antitumoral activities...

) and NADPH oxidase
NADPH oxidase
The NADPH oxidase is a membrane-bound enzyme complex. It can be found in the plasma membrane as well as in the membrane of phagosome.-Subunits:It is made up of six subunits...

 respectively. NOS2 is expressed primarily in macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...

s after induction by cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...

s and microbial products, notably interferon-gamma
Interferon-gamma
Interferon-gamma is a dimerized soluble cytokine that is the only member of the type II class of interferons. This interferon was originally called macrophage-activating factor, a term now used to describe a larger family of proteins to which IFN-γ belongs...

 (IFN-γ) and lipopolysaccharide
Lipopolysaccharide
Lipopolysaccharides , also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals.-Functions:LPS is the major...

 (LPS).

Reactive nitrogen species act together with reactive oxygen species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....

 (ROS) to damage cells, causing nitrosative stress. Therefore, these two species are often collectively referred to as ROS/RNS.

Reactive nitrogen species are also continuously produced in plants as by-products of aerobic metabolism or in response to stress.

Types

RNS are produced in animals starting with the reaction of nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...

 (·NO) with superoxide
Superoxide
A superoxide, also known by the obsolete name hyperoxide, is a compound that possesses the superoxide anion with the chemical formula O2−. The systematic name of the anion is dioxide. It is important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature...

 (O2·) to form peroxynitrite
Peroxynitrite
Peroxynitrite is the anion with the formula ONOO−. It is an unstable structural isomer of nitrate, NO3−, which has the same formula but a different structure. Although peroxynitrous acid is highly reactive, its conjugate base peroxynitrite is stable in basic solution...

 (ONOO):
  • ·NO (nitric oxide) + O2· (super oxide) → ONOO (peroxynitrite)


Superoxide anion (O2-) is a reactive oxygen species that reacts quickly with nitric oxide (NO) in the vasculature. The reaction produces peroxynitrite and depletes the bioactivity of NO. This is important because NO is a key mediator in many important vascular functions including regulation of smooth muscle tone and blood pressure, platelet activation, and vascular cell signaling.

Peroxynitrite itself is a highly reactive species which can directly react with various biological targets and components of the cell including lipids, thiols, amino acid residues, DNA bases, and low-molecular weight antioxidants. However, these reactions happen at a relatively slow rate. This slow reaction rate allows it to react more selectively throughout the cell. Peroxynitrite is able to get across cell membranes to some extent through anion channels. Additionally peroxynitrite can react with other molecules to form additional types of RNS including nitrogen dioxide
Nitrogen dioxide
Nitrogen dioxide is the chemical compound with the formula it is one of several nitrogen oxides. is an intermediate in the industrial synthesis of nitric acid, millions of tons of which are produced each year. This reddish-brown toxic gas has a characteristic sharp, biting odor and is a prominent...

 (·NO2) and dinitrogen trioxide
Dinitrogen trioxide
Dinitrogen trioxide is the chemical compound with the formula N2O3. This deep blue liquid is one of binary nitrogen oxides. It forms upon mixing equal parts of nitric oxide and nitrogen dioxide and cooling the mixture below −21 °C :Dinitrogen trioxide is only isolable at low...

 (N2O3) as well as other types of chemically reactive free radicals
Radical (chemistry)
Radicals are atoms, molecules, or ions with unpaired electrons on an open shell configuration. Free radicals may have positive, negative, or zero charge...

. Important reactions involving RNS include:
  • ONOO + H+ → ONOOH (peroxynitrous acid
    Peroxynitrous acid
    Peroxynitrous acid is a Reactive nitrogen species, commonly known as a free radical. It is the conjugate acid of peroxynitrite . It has a pKa of ~6.8. Peroxynitrous acid can homolyze to form nitrogen dioxide and hydroxyl radical as a pair of caged radicals...

    ) → ·NO2 (nitrogen dioxide) + ·OH (hydroxyl radical
    Hydroxyl radical
    The hydroxyl radical, •OH, is the neutral form of the hydroxide ion . Hydroxyl radicals are highly reactive and consequently short-lived; however, they form an important part of radical chemistry. Most notably hydroxyl radicals are produced from the decomposition of hydroperoxides or, in...

    )
  • ONOO + CO2 (carbon dioxide
    Carbon dioxide
    Carbon dioxide is a naturally occurring chemical compound composed of two oxygen atoms covalently bonded to a single carbon atom...

    ) → ONOOCO2 (nitrosoperoxycarbonate)
  • ONOOCO2·NO2 (nitrogen dioxide) + O=C(O·)O (carbonate radical)
  • ·NO + ·NO2 N2O3 (dinitrogen trioxide)

Biological targets

Peroxynitrite can react directly with proteins that contain transition metal centers. Therefore, it can modify proteins such as hemoglobin, myoglobin, and cytochrone c by oxidizing ferrous heme into its corresponding ferric forms. Peroxynitrite may also be able to change protein structure through the reaction with various amino acids in the peptide chain. The most common reaction with amino acids is cysteine oxidation. Another reaction is tyrosine nitration; however peroxynitrite does not react directly with tyrosine. Tyrosine reacts with other RNS that are produced by peroxynitrite. All of these reactions affect protein structure and function and thus have the potential to cause changes in the catalytic activity of enzymes, altered cytoskeletal organization, and impaired cell signal transduction.

External links

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