S-Nitrosylation

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In biochemistry, S-nitrosylation is the covalent attachment of a nitric oxide group (−NO) 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. [1] It thus operates as a fundamental mechanism for cellular signaling across phylogeny and accounts for the large part of NO bioactivity.

Contents

S-Nitrosylation is precisely targeted, [2] reversible, [3] spatiotemporally restricted [4] [5] and necessary for a wide range of cellular responses, [6] including the prototypic example of red blood cell mediated autoregulation of blood flow that is essential for vertebrate life. [7] 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. [8] Beside enzymatic activity, hydrophobicity and low pka values also play a key role in regulating the process. [6] 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. [9] [10] [11] The redox-based chemical mechanisms for S-nitrosylation in biological systems were also described concomitantly. [12] Important examples of proteins whose activities were subsequently shown to be regulated by S-nitrosylation include the NMDA-type glutamate receptor in the brain. [13] [14] 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. [15] 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. [16] [17] [18] It is estimated that ~70% of the proteome is subject to S-nitrosylation and the majority of those sites are conserved. [19] S-Nitrosylation is also known to show up in mediating pathogenicity in Parkinson's disease systems. [20] S-Nitrosylation is thus established as ubiquitous in biology, having been demonstrated to occur in all phylogenetic kingdoms [21] and has been described as the prototypic redox-based signalling mechanism, [22]

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. [23] Thioredoxin (Trx)-related proteins, including Trx1 and 2 in mammals, catalyze the direct denitrosylation of S-nitrosoproteins [24] [25] [26] (in addition to their role in transnitrosylation [27] ). Aberrant S-nitrosylation (and denitrosylation) has been implicated in multiple diseases, including heart disease, [18] cancer and asthma [28] [29] [17] as well as neurological disorders, including stroke, [30] chronic degenerative diseases (e.g., Parkinson's and Alzheimer's disease) [31] [32] [33] and amyotrophic lateral sclerosis (ALS). [34]

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. [6] 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. [35] 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. [36]

Related Research Articles

<span class="mw-page-title-main">Protein disulfide-isomerase</span> Class of enzymes

Protein disulfide isomerase, or PDI, is an enzyme in the endoplasmic reticulum (ER) in eukaryotes and the periplasm of bacteria that catalyzes the formation and breakage of disulfide bonds between cysteine residues within proteins as they fold. This allows proteins to quickly find the correct arrangement of disulfide bonds in their fully folded state, and therefore the enzyme acts to catalyze protein folding.

<span class="mw-page-title-main">Nitric oxide synthase</span> Enzyme catalysing the formation of the gasotransmitter NO(nitric oxide)

Nitric oxide synthases (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule. It helps modulate vascular tone, insulin secretion, airway tone, and peristalsis, and is involved in angiogenesis and neural development. It may function as a retrograde neurotransmitter. Nitric oxide is mediated in mammals by the calcium-calmodulin controlled isoenzymes eNOS and nNOS. The inducible isoform, iNOS, involved in immune response, binds calmodulin at physiologically relevant concentrations, and produces NO as an immune defense mechanism, as NO is a free radical with an unpaired electron. It is the proximate cause of septic shock and may function in autoimmune disease.

Thioredoxin reductases are enzymes that reduce thioredoxin (Trx). Two classes of thioredoxin reductase have been identified: one class in bacteria and some eukaryotes and one in animals. In bacteria TrxR also catalyzes the reduction of glutaredoxin like proteins known as NrdH. Both classes are flavoproteins which function as homodimers. Each monomer contains a FAD prosthetic group, a NADPH binding domain, and an active site containing a redox-active disulfide bond.

<span class="mw-page-title-main">Thioredoxin</span> Class of reduction–oxidation proteins

Thioredoxin is a class of small redox proteins known to be present in all organisms. It plays a role in many important biological processes, including redox signaling. In humans, thioredoxins are encoded by TXN and TXN2 genes. Loss-of-function mutation of either of the two human thioredoxin genes is lethal at the four-cell stage of the developing embryo. Although not entirely understood, thioredoxin is linked to medicine through their response to reactive oxygen species (ROS). In plants, thioredoxins regulate a spectrum of critical functions, ranging from photosynthesis to growth, flowering and the development and germination of seeds. Thioredoxins play a role in cell-to-cell communication.

Respiratory burst is the rapid release of the reactive oxygen species (ROS), superoxide anion and hydrogen peroxide, from different cell types.

<span class="mw-page-title-main">Oxidative stress</span> Free radical toxicity

Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal redox state of cells can cause toxic effects through the production of peroxides and free radicals that damage all components of the cell, including proteins, lipids, and DNA. Oxidative stress from oxidative metabolism causes base damage, as well as strand breaks in DNA. Base damage is mostly indirect and caused by the reactive oxygen species generated, e.g., O2− (superoxide radical), OH (hydroxyl radical) and H2O2 (hydrogen peroxide). Further, some reactive oxidative species act as cellular messengers in redox signaling. Thus, oxidative stress can cause disruptions in normal mechanisms of cellular signaling.

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<span class="mw-page-title-main">Nitric oxide dioxygenase</span>

Nitric oxide dioxygenase (EC 1.14.12.17) is an enzyme that catalyzes the conversion of nitric oxide (NO) to nitrate (NO−
3) . The net reaction for the reaction catalyzed by nitric oxide dioxygenase is shown below:

<span class="mw-page-title-main">Formaldehyde dehydrogenase</span>

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<span class="mw-page-title-main">P4HB</span> Protein-coding gene in the species Homo sapiens

Protein disulfide-isomerase, also known as the beta-subunit of prolyl 4-hydroxylase (P4HB), is an enzyme that in humans encoded by the P4HB gene. The human P4HB gene is localized in chromosome 17q25. Unlike other prolyl 4-hydroxylase family proteins, this protein is multifunctional and acts as an oxidoreductase for disulfide formation, breakage, and isomerization. The activity of P4HB is tightly regulated. Both dimer dissociation and substrate binding are likely to enhance its enzymatic activity during the catalysis process.

<span class="mw-page-title-main">EIF2AK1</span> Protein-coding gene in the species Homo sapiens

Eukaryotic translation initiation factor 2-alpha kinase 1 is an enzyme that in humans is encoded by the EIF2AK1 gene.

<span class="mw-page-title-main">GLRX2</span> Protein-coding gene in the species Homo sapiens

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<i>S</i>-Nitrosothiol Organic compounds or groups of the form –S–N=O

In organic chemistry, S-nitrosothiols, also known as thionitrites, are organic compounds or functional groups containing a nitroso group attached to the sulfur atom of a thiol. S-Nitrosothiols have the general formula R−S−N=O, where R denotes an organic group. Originally suggested by Ignarro to serve as intermediates in the action of organic nitrates, endogenous S-nitrosothiols were discovered by Stamler and colleagues and shown to represent a main source of NO bioactivity in vivo. More recently, S-nitrosothiols have been implicated as primary mediators of protein S-nitrosylation, the oxidative modification of cysteine thiol that provides ubiquitous regulation of protein function.

Biological functions of nitric oxide are roles that nitric oxide plays within biology.

<i>S</i>-Nitrosoglutathione Chemical compound

S-Nitrosoglutathione (GSNO) is an endogenous S-nitrosothiol (SNO) that plays a critical role in nitric oxide (NO) signaling and is a source of bioavailable NO. NO coexists in cells with SNOs that serve as endogenous NO carriers and donors. SNOs spontaneously release NO at different rates and can be powerful terminators of free radical chain propagation reactions, by reacting directly with ROO• radicals, yielding nitro derivatives as end products. NO is generated intracellularly by the nitric oxide synthase (NOS) family of enzymes: nNOS, eNOS and iNOS while the in vivo source of many of the SNOs is unknown. In oxygenated buffers, however, formation of SNOs is due to oxidation of NO to dinitrogen trioxide (N2O3). Some evidence suggests that both exogenous NO and endogenously derived NO from nitric oxide synthases can react with glutathione to form GSNO.

<span class="mw-page-title-main">Methionine sulfoxide</span> Chemical compound

Methionine sulfoxide is the organic compound with the formula CH3S(O)CH2CH2CH(NH2)CO2H. It is an amino acid that occurs naturally although it is formed post-translationally.

Hydrogen sulfide is produced in small amounts by some cells of the mammalian body and has a number of biological signaling functions. Only two other such gases are currently known: nitric oxide (NO) and carbon monoxide (CO).

Ted M. Dawson is an American neurologist and neuroscientist. He is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases and Director of the Institute for Cell Engineering at Johns Hopkins University School of Medicine. He has joint appointments in the Department of Neurology, Neuroscience and Department of Pharmacology and Molecular Sciences.

Valina L. Dawson is an American neuroscientist who is the director of the Programs in Neuroregeneration and Stem Cells at the Institute for Cell Engineering at the Johns Hopkins University School of Medicine. She has joint appointments in the Department of Neurology, Neuroscience and Physiology. She is a member of the Graduate Program in Cellular and Molecular Medicine and Biochemistry, Cellular and Molecular Biology.

<span class="mw-page-title-main">Jonathan Stamler</span> English-American physician and biochemist

Jonathan Solomon Stamler is an English-born American physician and scientist. He is known for his discovery of protein S-nitrosylation, the addition of a nitric oxide (NO) group to cysteine residues in proteins, as a ubiquitous cellular signal to regulate enzymatic activity and other key protein functions in bacteria, plants and animals, and particularly in transporting NO on cysteines in hemoglobin as the third gas in the respiratory cycle.

References

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