S<\/em>-Nitrosylation is a post-translational modification in which a nictric oxide (NO) group is coupled to a thiol group of a cysteine residue resulting in a S<\/em>-nitrosothiol group^{\u200b1\u20135\u200b<\/sup><\/span>. NO is an important short-lived physiological messenger that is highly reactive^{\u200b1,2\u200b<\/sup><\/span>. It is generated through the conversion of L-arginine to L-citrulline and catalysed by the enzyme NO synthase^{\u200b2,3\u200b<\/sup><\/span>. The signaling of NO can be categorised in classical and non-classical ways. In the classical way, NO binds to the heme group of guanylyl cyclase, which stimulates the transformation from GTP to cGMP. cGMP is a second messenger, which in turn activates cGMP-dependent protein kinase. cGMP-dependent protein kinase reduces the concentration of potassium and calcium ions in the cytosol. This causes a hyperpolarization of the membrane potential which triggers neurotransmission and vasodilation. The non-classical way describes the process of NO signaling via covalent post-translational modifications which includes among others S<\/em>-nitrosylation^{\u200b3\u200b<\/sup><\/span>. The frequency of S-nitrosylation depends on the local concentration of NO and affects intracellular traffic processes, protein phosphorylation and protein-protein interactions^{\u200b3\u20135\u200b<\/sup><\/span>. Enzymes do not catalyse the reaction from the thiol to the S-nitrosothiol. However, the denitrosylation is regulated by two enzymes called S<\/em>-nitrosoglutathione reductase and thioredoxin. If these two enzymes are lacking or inhibited, high concentrations of S<\/em>-nitrosylated proteins occur^{\u200b2\u20134\u200b<\/sup><\/span>. NO concentrations above 100 nM induce S-nitrosylation^{\u200b4\u200b<\/sup><\/span>. The mechanism of S<\/em>-nitrosylation is shown in figure 1.<\/p>\n\n\n\n}}}}}}}

\"\" — Figure 1: Mechanism of S<\/em>-nitrosylation. First, a thiol of a cysteine residue is deprotoned. The formed thiolate then reacts with a NO molecule resulting in a S<\/em>-nitrosothiol.<\/figcaption><\/figure><\/div>\n\n\n\n
Although S<\/em>-nitrosylation is a non-enzymatic reaction (except prokaryotes), it is a highly selective modification and is dependent on different factors^{\u200b3,5\u200b<\/sup><\/span>. Target cysteine residues must be in close proximity of the NO source, within a I\/L-X-C-X2-D\/E motif as well as within a highly hydrophobic region formed by tertiary protein structure or membranes. In addition, the environment is decisive whether a protein is S<\/em>-nitrosylated or not. Since a thiolate is required for S<\/em>-nitrosylation, the reaction is strongly dependent on the neighbouring amino acids, as these strongly influence the pKa of cysteine. Furthermore, S<\/em>-nitrosylation is hindered by bulky amino acid residues such as phenylalanine, tyrosine, arginine and leucine. Over 3000 proteins with potential S<\/em>-nitrosylation sites have been identified^{\u200b2,3\u200b<\/sup><\/span>. S<\/em>-Nitrosylation results in a molecular mass increase of 29 Da^{\u200b2\u200b<\/sup><\/span>. Furthermore, the nitroso group causes an additional absorption in the range between 274 – 442 nm^{\u200b6\u200b<\/sup><\/span>, the maximum being at 336 nm^{\u200b7\u200b<\/sup><\/span>. The influence of the nitroso group on the absorbance was determined by the difference of the UV spectra of glutathione and S-nitrosoglutathione.<\/p>\n\n\n\n}}}}}
References<\/h3>

\n
1. <\/div>
Iwakiri Y, Satoh A, Chatterjee S, et al. Nitric oxide synthase generates nitric oxide locally to regulate compartmentalized protein S-nitrosylation and protein trafficking. *Proceedings of the National Academy of Sciences<\/i>. 2006;103:19777 LP \u2013 19782. doi:10.1073\/pnas.0605907103<\/a><\/div>\n <\/div>\n<\/li>*

\n
2. <\/div>
Lamotte O, Bertoldo JB, Besson-Bard A, et al. Protein S-nitrosylation: specificity and identification strategies in plants. *Frontiers in chemistry<\/i>. 2014;2:114. doi:10.3389\/fchem.2014.00114<\/a><\/div>\n <\/div>\n<\/li>*

\n
3. <\/div>
Fernando V, Zheng X, Walia Y, Sharma V, Letson J, Furuta S. S-Nitrosylation: An Emerging Paradigm of Redox Signaling. *Antioxidants (Basel, Switzerland)<\/i>. 2019;8. doi:10.3390\/antiox8090404<\/a><\/div>\n <\/div>\n<\/li>*

\n
4. <\/div>
Ehrenfeld P, Cordova F, Duran WN, Sanchez FA. S-nitrosylation and its role in breast cancer angiogenesis and metastasis. *Nitric Oxide<\/i>. 2019;87:52\u201359. doi:https:\/\/doi.org\/10.1016\/j.niox.2019.03.002<\/a><\/div>\n <\/div>\n<\/li>*

\n
5. <\/div>
Nakamura T, Prikhodko OA, Pirie E, et al. Aberrant protein S-nitrosylation contributes to the pathophysiology of neurodegenerative diseases. *Neurobiology of disease<\/i>. 2015;84:99\u2013108. doi:10.1016\/j.nbd.2015.03.017<\/a><\/div>\n <\/div>\n<\/li>*

\n
6. <\/div>
Hwang S, Meyerhoff ME. Organoditelluride-mediated catalytic S-nitrosothiol decomposition. *Journal of Materials Chemistry<\/i>. 2007;17:1462\u20131465. doi:10.1039\/B700375G<\/a><\/div>\n <\/div>\n<\/li>*

\n
7. <\/div>
Gordon JL, Reynolds MM, Brown MA. Nitric Oxide as a Potential Adjuvant Therapeutic for Neuroblastoma: Effects of NO on Murine N2a Cells. *Veterinary Sciences<\/i>. Published online April 23, 2020:51. doi:*10.3390\/vetsci7020051<\/a><\/div>\n <\/div>\n<\/li><\/ol><\/section>\n","protected":false},"excerpt":{"rendered":"
Overview S-Nitrosylation is a post-translational modification in which a nitric oxide molecule is bound via a reactive thiol group of a cysteine residue. S-nitrosylation has various regulatory roles in bacteria, yeasts, plants and mammalian cells. pKa NC Loss Gain Deltamass H AA UV-Spec Pattern – No H NO Av: 28.9982M: 28.9902 – C Yes – […]<\/p>\n","protected":false},"author":11,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[26],"tags":[53,57],"class_list":["post-390","post","type-post","status-publish","format-standard","hentry","category-bioinformatics","tag-no-signaling","tag-post-translational-modification"],"jetpack_featured_media_url":"","_links":{"self":[{"href":"https:\/\/www.protpi.ch\/blog\/wp-json\/wp\/v2\/posts\/390","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.protpi.ch\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.protpi.ch\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.protpi.ch\/blog\/wp-json\/wp\/v2\/users\/11"}],"replies":[{"embeddable":true,"href":"https:\/\/www.protpi.ch\/blog\/wp-json\/wp\/v2\/comments?post=390"}],"version-history":[{"count":16,"href":"https:\/\/www.protpi.ch\/blog\/wp-json\/wp\/v2\/posts\/390\/revisions"}],"predecessor-version":[{"id":534,"href":"https:\/\/www.protpi.ch\/blog\/wp-json\/wp\/v2\/posts\/390\/revisions\/534"}],"wp:attachment":[{"href":"https:\/\/www.protpi.ch\/blog\/wp-json\/wp\/v2\/media?parent=390"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.protpi.ch\/blog\/wp-json\/wp\/v2\/categories?post=390"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.protpi.ch\/blog\/wp-json\/wp\/v2\/tags?post=390"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}

pKa<\/td>	NC<\/td>	Loss<\/td>	Gain<\/td>	Deltamass<\/td>	H<\/td>	AA<\/td>	UV-Spec<\/td>	Pattern<\/td><\/tr>
–<\/td>	No<\/td>	H<\/td>	NO<\/td>	Av: 28.9982 M: 28.9902<\/td>	–<\/td>	C<\/td>	Yes<\/td>	– <\/td><\/tr><\/tbody><\/table> Physicochemical properties of S<\/em>-nitrosylation that are stored in the modification database of Prot pi (NC: Native charge; H: Relative hydrophobicity; AA: Modified amino acid; Pattern: Regex for sequence-motif recognition).<\/figcaption><\/figure>\n\n\n\n In-depth mechanism<\/h2>\n\n\n\n S<\/em>-Nitrosylation is a post-translational modification in which a nictric oxide (NO) group is coupled to a thiol group of a cysteine residue resulting in a S<\/em>-nitrosothiol group^{\u200b1\u20135\u200b<\/sup><\/span>. NO is an important short-lived physiological messenger that is highly reactive^{\u200b1,2\u200b<\/sup><\/span>. It is generated through the conversion of L-arginine to L-citrulline and catalysed by the enzyme NO synthase^{\u200b2,3\u200b<\/sup><\/span>. The signaling of NO can be categorised in classical and non-classical ways. In the classical way, NO binds to the heme group of guanylyl cyclase, which stimulates the transformation from GTP to cGMP. cGMP is a second messenger, which in turn activates cGMP-dependent protein kinase. cGMP-dependent protein kinase reduces the concentration of potassium and calcium ions in the cytosol. This causes a hyperpolarization of the membrane potential which triggers neurotransmission and vasodilation. The non-classical way describes the process of NO signaling via covalent post-translational modifications which includes among others S<\/em>-nitrosylation^{\u200b3\u200b<\/sup><\/span>. The frequency of S-nitrosylation depends on the local concentration of NO and affects intracellular traffic processes, protein phosphorylation and protein-protein interactions^{\u200b3\u20135\u200b<\/sup><\/span>. Enzymes do not catalyse the reaction from the thiol to the S-nitrosothiol. However, the denitrosylation is regulated by two enzymes called S<\/em>-nitrosoglutathione reductase and thioredoxin. If these two enzymes are lacking or inhibited, high concentrations of S<\/em>-nitrosylated proteins occur^{\u200b2\u20134\u200b<\/sup><\/span>. NO concentrations above 100 nM induce S-nitrosylation^{\u200b4\u200b<\/sup><\/span>. The mechanism of S<\/em>-nitrosylation is shown in figure 1.<\/p>\n\n\n\n}}}}}}} $\"\"$ Figure 1: Mechanism of S<\/em>-nitrosylation. First, a thiol of a cysteine residue is deprotoned. The formed thiolate then reacts with a NO molecule resulting in a S<\/em>-nitrosothiol.<\/figcaption><\/figure><\/div>\n\n\n\n Although S<\/em>-nitrosylation is a non-enzymatic reaction (except prokaryotes), it is a highly selective modification and is dependent on different factors^{\u200b3,5\u200b<\/sup><\/span>. Target cysteine residues must be in close proximity of the NO source, within a I\/L-X-C-X2-D\/E motif as well as within a highly hydrophobic region formed by tertiary protein structure or membranes. In addition, the environment is decisive whether a protein is S<\/em>-nitrosylated or not. Since a thiolate is required for S<\/em>-nitrosylation, the reaction is strongly dependent on the neighbouring amino acids, as these strongly influence the pKa of cysteine. Furthermore, S<\/em>-nitrosylation is hindered by bulky amino acid residues such as phenylalanine, tyrosine, arginine and leucine. Over 3000 proteins with potential S<\/em>-nitrosylation sites have been identified^{\u200b2,3\u200b<\/sup><\/span>. S<\/em>-Nitrosylation results in a molecular mass increase of 29 Da^{\u200b2\u200b<\/sup><\/span>. Furthermore, the nitroso group causes an additional absorption in the range between 274 – 442 nm^{\u200b6\u200b<\/sup><\/span>, the maximum being at 336 nm^{\u200b7\u200b<\/sup><\/span>. The influence of the nitroso group on the absorbance was determined by the difference of the UV spectra of glutathione and S-nitrosoglutathione.<\/p>\n\n\n\n}}}}} References<\/h3> \n 1. <\/div> Iwakiri Y, Satoh A, Chatterjee S, et al. Nitric oxide synthase generates nitric oxide locally to regulate compartmentalized protein S-nitrosylation and protein trafficking. Proceedings of the National Academy of Sciences<\/i>. 2006;103:19777 LP \u2013 19782. doi:10.1073\/pnas.0605907103<\/a><\/div>\n <\/div>\n<\/li> \n 2. <\/div> Lamotte O, Bertoldo JB, Besson-Bard A, et al. Protein S-nitrosylation: specificity and identification strategies in plants. Frontiers in chemistry<\/i>. 2014;2:114. doi:10.3389\/fchem.2014.00114<\/a><\/div>\n <\/div>\n<\/li> \n 3. <\/div> Fernando V, Zheng X, Walia Y, Sharma V, Letson J, Furuta S. S-Nitrosylation: An Emerging Paradigm of Redox Signaling. Antioxidants (Basel, Switzerland)<\/i>. 2019;8. doi:10.3390\/antiox8090404<\/a><\/div>\n <\/div>\n<\/li> \n 4. <\/div> Ehrenfeld P, Cordova F, Duran WN, Sanchez FA. S-nitrosylation and its role in breast cancer angiogenesis and metastasis. Nitric Oxide<\/i>. 2019;87:52\u201359. doi:https:\/\/doi.org\/10.1016\/j.niox.2019.03.002<\/a><\/div>\n <\/div>\n<\/li> \n 5. <\/div> Nakamura T, Prikhodko OA, Pirie E, et al. Aberrant protein S-nitrosylation contributes to the pathophysiology of neurodegenerative diseases. Neurobiology of disease<\/i>. 2015;84:99\u2013108. doi:10.1016\/j.nbd.2015.03.017<\/a><\/div>\n <\/div>\n<\/li> \n 6. <\/div> Hwang S, Meyerhoff ME. Organoditelluride-mediated catalytic S-nitrosothiol decomposition. Journal of Materials Chemistry<\/i>. 2007;17:1462\u20131465. doi:10.1039\/B700375G<\/a><\/div>\n <\/div>\n<\/li> \n 7. <\/div> Gordon JL, Reynolds MM, Brown MA. Nitric Oxide as a Potential Adjuvant Therapeutic for Neuroblastoma: Effects of NO on Murine N2a Cells. Veterinary Sciences<\/i>. Published online April 23, 2020:51. doi:10.3390\/vetsci7020051<\/a><\/div>\n <\/div>\n<\/li><\/ol><\/section>\n","protected":false},"excerpt":{"rendered":" Overview S-Nitrosylation is a post-translational modification in which a nitric oxide molecule is bound via a reactive thiol group of a cysteine residue. S-nitrosylation has various regulatory roles in bacteria, yeasts, plants and mammalian cells. pKa NC Loss Gain Deltamass H AA UV-Spec Pattern – No H NO Av: 28.9982M: 28.9902 – C Yes – […]<\/p>\n","protected":false},"author":11,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[26],"tags":[53,57],"class_list":["post-390","post","type-post","status-publish","format-standard","hentry","category-bioinformatics","tag-no-signaling","tag-post-translational-modification"],"jetpack_featured_media_url":"","_links":{"self":[{"href":"https:\/\/www.protpi.ch\/blog\/wp-json\/wp\/v2\/posts\/390","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.protpi.ch\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.protpi.ch\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.protpi.ch\/blog\/wp-json\/wp\/v2\/users\/11"}],"replies":[{"embeddable":true,"href":"https:\/\/www.protpi.ch\/blog\/wp-json\/wp\/v2\/comments?post=390"}],"version-history":[{"count":16,"href":"https:\/\/www.protpi.ch\/blog\/wp-json\/wp\/v2\/posts\/390\/revisions"}],"predecessor-version":[{"id":534,"href":"https:\/\/www.protpi.ch\/blog\/wp-json\/wp\/v2\/posts\/390\/revisions\/534"}],"wp:attachment":[{"href":"https:\/\/www.protpi.ch\/blog\/wp-json\/wp\/v2\/media?parent=390"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.protpi.ch\/blog\/wp-json\/wp\/v2\/categories?post=390"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.protpi.ch\/blog\/wp-json\/wp\/v2\/tags?post=390"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}