Review Article

S-Nitrosation and Ubiquitin-Proteasome System Interplay in Neuromuscular Disorders

Figure 1

Tyrosine nitration versus S-nitrosation. Nitric oxide (NO), produced by NO synthase (NOS), can affect protein structure and function in different ways. Here only posttranslational modifications directly modifying protein residues are shown, tyrosine nitration (right) and cysteine S-nitrosation (left). The former adduct is irreversible (so far, no denitrating enzyme has ever been found) and responsible for protein damage occurring mostly upon the overproduction of NO. Indeed, under this condition (called nitrosative stress) NO can rapidly react with superoxide anion ( ) to form peroxinitrite (ONOOāˆ’) which is the main harmful radical species inducing tyrosine nitration. Conversely, upon physiological production of NO, reactive cysteines of both redox-sensitive proteins and glutathione (GSH) can undergo S-nitrosation, thereby generating their S-nitrosothiol derivatives, Prot-SNOs and S-nitrosoglutathione (GSNO), respectively. Prot-SNOs and GSNO are in equilibrium by transnitrosation reactions; therefore, the GSNO catabolizing enzyme, GSNOR reductase (GSNOR), by regulating GSNO levels also impacts on protein nitrosation extent. Thioredoxin 1 (Trx1) also participates in protein denitrosation by means of its vicinal thiols that reduce Prot-SNO and oxidize to an internal disulfide bridge, whose further reduction is catalyzed by Trx reductase (TrxR) and ensured by reducing equivalents provided by NADPH. Although both GSNOR and Trx1 concur to modulated protein S-nitrosation, it should be reminded that the former enzyme completely reduces GSNO to glutathione disulfide (GSSG) and ammonia (NH3), whereas the latter releases the NO moiety of Prot-SNOs as NO itself or nitroxyl anion (HNO), which are species still capable to target protein substrates.
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