Peroxynitrite

Structure of the peroxynitrite anion

Formation of peroxynitrite and its potential reaction possibilities in the human metabolism . Peroxynitrite (ONOO ^- ) or peroxo nitric acid (NO ₂ OOH) can react directly with various biomolecules ( (a) and (b) ). The reaction of peroxynitrite with carbon dioxide (CO ₂ ) is particularly rapid and leads to the formation of radical nitrogen dioxide ( ^· NO ₂ ) and carbonate radical anions (CO ₃ ^{• -} ) (c) , which in turnCan damage proteins and DNA (d) . Peroxis nitric acid, which easily passes through cell membranes (e) , can break down in a hydrophobic environment into hydroxyl ( ^• OH) and nitrogen dioxide radicals (f) and thereby damage lipids and proteins (g) .

The peroxynitrite anion (ONOO ^- ) belongs to the reactive nitrogen and oxygen compounds (RNOS; reactive nitrogen oxide species or ROS; reactive oxygen species ). In an organism, these compounds can react with other compounds (proteins, DNA) and cause damage.

Peroxynitrite anions resulting from the recombination of nitrogen monoxide - and superoxide - radicals .

Superoxides and nitrogen monoxide ( ^• NO) are formed continuously in the metabolism in many different processes, for example the formation of NO from nitrite, by NO synthase (NOS), in the context of the immune system, in the auto-oxidation of biological molecules or in reactions of xanthine oxidase ( XO).

Neither superoxide nor NO are toxic in vivo as long as both do not occur in unphysiologically high concentrations or together. Superoxide radicals are very quickly defused using superoxide dismutases (SOD) or peroxidases (O ₂ ^{• -}  → H ₂ O ₂  → O ₂ , H ₂ O). On the other hand, NO mainly reacts with oxygenated hemoglobin to form nitrates.

Due to these and other protective mechanisms (for example glutathione , ascorbic acid , tocopherol ), the formation of even more toxic substances should be prevented. If this does not happen, peroxynitrite ions and hydroxyl radicals ( ^• OH) can arise.

Due to their high reactivity, hydroxyl radicals react very quickly with the closest compound. Peroxinitrites, on the other hand, have a longer half-life and can thus react more selectively with compounds. They are used, for example, by macrophages to ward off germs. They are highly potent cell toxins and arise from diffusion-controlled reactions between NO and superoxide radicals (O ₂ ^{• -}  +  ^• NO → ONOO ^- ). Peroxynitrites therefore arise quickly when NO and superoxides are produced simultaneously in large quantities or cannot be sufficiently broken down. For example, the formation of peroxynitrite ions can increase a million times under strongly pro-inflammatory conditions. Since superoxide radicals diffuse much more poorly than NO radicals and have a short half-life, the formation of peroxynitrite is primarily associated with the formation of superoxide radicals. Peroxynitrite ions themselves can develop their damaging effect within one to two cell diameters with a (physiological) half-life of around 10 ms.

Peroxinitrites or the resulting radicals can damage enzymes , the genetic material ( DNA ), the mitochondria and membranes ; Signal cascades can be changed or disturbed; the formation of Lewy bodies is favored and ultimately apoptosis can be initiated or necrosis can be caused. Vascular and cardiovascular diseases, circulatory shock , diseases of the immune system , pain, neurodegeneration, aging and others are associated with the development of peroxynitrite.

Peroxynitrite ions react with the always present carbon dioxide to form the short-lived nitrosoperoxycarbonate ion, which breaks down into two highly reactive radicals that are responsible for the DNA damage of peroxynitrites:

ONOO ^- + CO ₂ → ONOOCOO ^- → NO ₂ ^• + CO ₃ ^{• -}

Most of the numerous endogenous and exogenous peroxynitrite “scavengers” or “neutralizers” only interact with the secondary radicals (for example with ^• OH, ^• NO ₂ , CO ₃ ^{• -} ) and are therefore only of limited or low effectiveness . Metalloporphyrins (e.g. oxygenated hemoglobin ), on the other hand, react quickly and directly with peroxynitrite. Fe (III) porphyrins inactivate peroxynitrite ions by isomerizing them to nitrate ions . Corresponding compounds are being developed for clinical use and seem to offer promising therapeutic options for the diseases mentioned.

Individual evidence

1. ↑ Szabó C, Ischiropoulos H, Radi R: Peroxynitrite: biochemistry, pathophysiology and development of therapeutics Archived from the original on July 21, 2011. Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. (PDF) In: Nat Rev Drug Discov . 6, No. 8, August 2007, pp. 662-680. doi : 10.1038 / nrd2222 . PMID 17667957 . Retrieved October 18, 2010.