Nitrogen tyrosine nitration

The formation of peroxynitrite in cells and tissue is frequently characterized by the formation of nitrotyrosine. The formation of nitrotyrosine is not a very specific assay of peroxynitrite detection because the other nitrogen oxide may also take part in this process, but peroxynitrite is undoubtedly the most efficient nitrating agent. (Mechanism of tyrosine nitration by peroxynitrite and other reactive nitrogen compounds has been considered in Chapters 21 and 22.)... 

E3. Eiserich, J. P., Vossen, V., O Neill, C. A., Halliwell, B., Cross, C. E., and van der Vliet, A., Molecular mechanisms of damage by excess nitrogen oxides Nitration of tyrosine by gas-phase cigarette smoke. FEBS Lett. 353,53—56 (1994). 

The in vivo nitration of tyrosine by peroxynitrite and other reactive nitrogen species is implicated in many disease states and is an area of active research (40). It has recently been proposed that tyrosine nitration, mediated by nitric oxide and superoxide, is a regulated cell signaling pathway that provides quick response to the microenvironment of the cell (41 3). 

It was recently reported that the tryptophan residues of proteins could be nitrated by the action of peroxynitrite (67). This reactive nitrogen species (RNS) is generated from the reaction of nitric oxide with superoxide at a rate that is ten times greater than the destruction of superoxide by dismutases. The authors propose that the nitration of tryptophan, although less common than tyrosine nitration, could serve to modulate the function of some proteins. However, at this time the in vivo evidence for tryptophan nitration by RNS has yet to be reported. 

Conditions which favor peroxynitrite formation could result in dramatic shifts in the nitrite/nitrate ratio as well as significant loss of total nitrogen oxides through tyrosine nitration. 

Recently, Gunther et al. [41] proposed that nitric oxide may directly react with enzymes without intermediate formation of peroxynitrite. It is known that the oxidation of arachido-nic acid by prostaglandin H oxidase is mediated by the formation of enzyme tyrosyl radical (see Chapter 26). Correspondingly, it has been suggested that NO is able to react with this radical to form the tyrosine iminoxyl radical and then nitrotyrosine. Therefore, the NO-dependent nitration of protein tyrosine residue may occur without the formation of peroxynitrite or other nitrogen oxides. 

Deleterious protein cross-linking can also be induced by reactive nitrogen species (RNS) such as peroxynitrite ONOO formed by the reaction of superoxide with nitric oxide (NO). The cross-links are formed between tyrosine residues following nitration by peroxynitrite (Sitte, 2003). Carnosine appears to play roles not only in NO generation but also in protection against excess NO production by inducible nitric oxide synthetase (NOS), thereby preventing ONOO-mediated protein modification (Fontana et ah, 2002). Evidence for a carnosine-NO adduct has also been published (Nicoletti et al., 2007). 

The quinoline-based tyrosine kinase inhibitor pelitinib (31-11) incorporates a Michael acceptor function in the side chain that can form a covalent bond with a nucleophile on the target enzyme. Such an interaction would result in the irreversible inhibition of the target kinase. Reaction of aniline (31-1) with DMF acetal leads to the addition of a carbon atom to aniline nitrogen in the form of an amidine (31-2). This intermediate is next reacted with nitric in acetic acid to form the nitrated... 

For example, tyrosine residues on proteins are readily nitrated by a free radical mechanism (Prutz et al., 1985), where one nitrogen dioxide oxidizes the tyrosine to a phenyl radical that reacts with a second nitrogen dioxide to give nitroty-... 

NO can interact with other free radicals most notably, NO reacts with the superoxide anion (O 2) to produce the potent oxidant peroxynitrite (ONOO") (Radi et al., 1991). Although it is a simple molecule, ONOO is chemically complex. It can display hydroxyl radical-like and nitrogen dioxide (NO2) radical-like activity, can oxidize lipids, and can directly nitrate proteins. ONOO" has been shown to nitrate a tyrosine residue on superoxide dismutase (SOD) (Beckman et al., 1992). 

In addition to its direct inhibitory effects, NO can react with other oxidants such as super oxide, and form other reactive nitrogen species such as peroxynitrite. Peroxynitrite is immunosuppressive and was shown to inhibit proliferation of T lymphocytes in a dose-dependent manner via nitration of tyrosine residues thereby... 

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