S-Nitrosylation

In biochemistry, S-nitrosylation is the covalent attachment of a nitric oxide group (\sNO) to a cysteine thiol within a protein to form an S-nitrosothiol (SNO). S-Nitrosylation has diverse regulatory roles in bacteria, yeast and plants and in all mammalian cells. It thus operates as a fundamental mechanism for cellular signaling across phylogeny and accounts for the large part of NO bioactivity.

S-Nitrosylation is precisely targeted, reversible, spatiotemporally restricted and necessary for a wide range of cellular responses, including the prototypic example of red blood cell mediated autoregulation of blood flow that is essential for vertebrate life. Although originally thought to involve multiple chemical routes in vivo, accumulating evidence suggests that S-nitrosylation depends on enzymatic activity, entailing three classes of enzymes (S-nitrosylases) that operate in concert to conjugate NO to proteins, drawing analogy to ubiquitinylation. Beside enzymatic activity, hydrophobicity and low pka values also play a key role in regulating the process. S-Nitrosylation was first described by Stamler et al. and proposed as a general mechanism for control of protein function, including examples of both active and allosteric regulation of proteins by endogenous and exogenous sources of NO. The redox-based chemical mechanisms for S-nitrosylation in biological systems were also described concomitantly. Important examples of proteins whose activities were subsequently shown to be regulated by S-nitrosylation include the NMDA-type glutamate receptor in the brain. Aberrant S-nitrosylation following stimulation of the NMDA receptor would come to serve as a prototypic example of the involvement of S-nitrosylation in disease. S-Nitrosylation similarly contributes to physiology and dysfunction of cardiac, airway and skeletal muscle and the immune system, reflecting wide-ranging functions in cells and tissues. It is estimated that ~70% of the proteome is subject to S-nitrosylation and the majority of those sites are conserved. S-Nitrosylation is also known to show up in mediating pathogenicity in Parkinson's disease systems. S-Nitrosylation is thus established as ubiquitous in biology, having been demonstrated to occur in all phylogenetic kingdoms and has been described as the prototypic redox-based signalling mechanism,

Denitrosylation
The reverse of S-nitrosylation is denitrosylation, principally an enzymically controlled process. Multiple enzymes have been described to date, which fall into two main classes mediating denitrosylation of protein and low molecular weight SNOs, respectively. S-Nitrosoglutathione reductase (GSNOR) is exemplary of the low molecular weight class; it accelerates the decomposition of S-nitrosoglutathione (GSNO) and of SNO-proteins in equilibrium with GSNO. The enzyme is highly conserved from bacteria to humans. Thioredoxin (Trx)-related proteins, including Trx1 and 2 in mammals, catalyze the direct denitrosylation of S-nitrosoproteins  (in addition to their role in transnitrosylation ). Aberrant S-nitrosylation (and denitrosylation) has been implicated in multiple diseases, including heart disease, cancer and asthma as well as  neurological disorders, including stroke, chronic degenerative diseases (e.g., Parkinson's and Alzheimer's disease)   and amyotrophic lateral sclerosis (ALS).

Transnitrosylation
Another interesting aspect of S-nitrosylation includes the protein protein transnitrosylation, which is the transfer of an NO moiety from a SNO to the free thiols in another protein. Thioredoxin (Txn), a protein disulfide oxidoreductase for the cytosol and caspase 3 are a good example where transnitrosylation is significant in regulating cell death. Another example include, the structural changes in mammalian Hb to SNO-Hb under oxygen depleted conditions helps it to bind to AE1 (Anion Exchange, a membrane protein) and in turn gets transnitrosylated the later. Cdk5 (a neuronal-specific kinase) is known get nitrosylated at cysteine 83 and 157 in different neurodegenerative diseases like AD. This SNO-Cdk5 in turn is nitrosylated Drp1, the nitrosylated form of which can be considered as a therapeutic target.