:S-Nitrosylation

{{short description|Biochemical reaction; attachment of –NO to cysteine in a protein}}

{{DISPLAYTITLE:S-Nitrosylation}}

In biochemistry, S-nitrosylation is the covalent attachment of a nitric oxide group ({{chem2|\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.{{cite journal | vauthors = Anand P, Stamler JS | title = Enzymatic mechanisms regulating protein S-nitrosylation: implications in health and disease | journal = Journal of Molecular Medicine | volume = 90 | issue = 3 | pages = 233–244 | date = March 2012 | pmid = 22361849 | pmc = 3379879 | doi = 10.1007/s00109-012-0878-z }} 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,{{cite journal | vauthors = Sun J, Xin C, Eu JP, Stamler JS, Meissner G | title = Cysteine-3635 is responsible for skeletal muscle ryanodine receptor modulation by NO | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 20 | pages = 11158–11162 | date = September 2001 | pmid = 11562475 | pmc = 58700 | doi = 10.1073/pnas.201289098 | doi-access = free | bibcode = 2001PNAS...9811158S }} reversible,{{cite journal | vauthors = Padgett CM, Whorton AR | title = S-nitrosoglutathione reversibly inhibits GAPDH by S-nitrosylation | journal = The American Journal of Physiology | volume = 269 | issue = 3 Pt 1 | pages = C739–C749 | date = September 1995 | pmid = 7573405 | doi = 10.1152/ajpcell.1995.269.3.C739 }} spatiotemporally restricted{{cite journal | vauthors = Fang M, Jaffrey SR, Sawa A, Ye K, Luo X, Snyder SH | title = Dexras1: a G protein specifically coupled to neuronal nitric oxide synthase via CAPON | journal = Neuron | volume = 28 | issue = 1 | pages = 183–193 | date = October 2000 | pmid = 11086993 | doi = 10.1016/s0896-6273(00)00095-7 | s2cid = 10533464 | doi-access = free }}{{cite journal | vauthors = Iwakiri Y, Satoh A, Chatterjee S, Toomre DK, Chalouni CM, Fulton D, Groszmann RJ, Shah VH, Sessa WC | display-authors = 6 | title = Nitric oxide synthase generates nitric oxide locally to regulate compartmentalized protein S-nitrosylation and protein trafficking | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 52 | pages = 19777–19782 | date = December 2006 | pmid = 17170139 | pmc = 1750883 | doi = 10.1073/pnas.0605907103 | doi-access = free | bibcode = 2006PNAS..10319777I }} and necessary for a wide range of cellular responses,{{cite journal | vauthors = Hess DT, Matsumoto A, Kim SO, Marshall HE, Stamler JS | title = Protein S-nitrosylation: purview and parameters | journal = Nature Reviews. Molecular Cell Biology | volume = 6 | issue = 2 | pages = 150–166 | date = February 2005 | pmid = 15688001 | doi = 10.1038/nrm1569 | s2cid = 11676184 }} including the prototypic example of red blood cell mediated autoregulation of blood flow that is essential for vertebrate life.{{cite journal | vauthors = Zhang R, Hess DT, Qian Z, Hausladen A, Fonseca F, Chaube R, Reynolds JD, Stamler JS | display-authors = 6 | title = Hemoglobin βCys93 is essential for cardiovascular function and integrated response to hypoxia | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 20 | pages = 6425–6430 | date = May 2015 | pmid = 25810253 | pmc = 4443356 | doi = 10.1073/pnas.1502285112 | doi-access = free | bibcode = 2015PNAS..112.6425Z }} 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.{{cite journal | vauthors = Seth D, Hess DT, Hausladen A, Wang L, Wang YJ, Stamler JS | title = A Multiplex Enzymatic Machinery for Cellular Protein S-nitrosylation | journal = Molecular Cell | volume = 69 | issue = 3 | pages = 451–464.e6 | date = February 2018 | pmid = 29358078 | pmc = 5999318 | doi = 10.1016/j.molcel.2017.12.025 }} 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.{{cite journal | vauthors = Stamler JS, Simon DI, Osborne JA, Mullins ME, Jaraki O, Michel T, Singel DJ, Loscalzo J | display-authors = 6 | title = S-nitrosylation of proteins with nitric oxide: synthesis and characterization of biologically active compounds | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 1 | pages = 444–448 | date = January 1992 | pmid = 1346070 | pmc = 48254 | doi = 10.1073/pnas.89.1.444 | doi-access = free | bibcode = 1992PNAS...89..444S }}{{cite journal | vauthors = Stamler JS, Simon DI, Jaraki O, Osborne JA, Francis S, Mullins M, Singel D, Loscalzo J | display-authors = 6 | title = S-nitrosylation of tissue-type plasminogen activator confers vasodilatory and antiplatelet properties on the enzyme | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 17 | pages = 8087–8091 | date = September 1992 | pmid = 1325644 | pmc = 49861 | doi = 10.1073/pnas.89.17.8087 | doi-access = free | bibcode = 1992PNAS...89.8087S }}{{cite book | vauthors = Stamler JS, Simon DI, Osborne JA, Mullins M, Jaraki O, Michel T, Singel D, Loscalzo J | veditors = Moncada S, Marletta MA, Hibbs JB | chapter = Comparison of properties of nitric oxide | title = The biology of nitric oxide: proceedings of the 2nd International Meeting on the Biology of Nitric Oxide, London | publisher = Portland Press | location = London | pages = 20–23 | date = 1992 | oclc = 29356699 }} The redox-based chemical mechanisms for S-nitrosylation in biological systems were also described concomitantly.{{cite journal | vauthors = Stamler JS, Singel DJ, Loscalzo J | title = Biochemistry of nitric oxide and its redox-activated forms | journal = Science | volume = 258 | issue = 5090 | pages = 1898–1902 | date = December 1992 | pmid = 1281928 | doi = 10.1126/science.1281928 | bibcode = 1992Sci...258.1898S }} Important examples of proteins whose activities were subsequently shown to be regulated by S-nitrosylation include the NMDA-type glutamate receptor in the brain.{{cite journal | vauthors = Lei SZ, Pan ZH, Aggarwal SK, Chen HS, Hartman J, Sucher NJ, Lipton SA | title = Effect of nitric oxide production on the redox modulatory site of the NMDA receptor-channel complex | journal = Neuron | volume = 8 | issue = 6 | pages = 1087–1099 | date = June 1992 | pmid = 1376999 | doi = 10.1016/0896-6273(92)90130-6 | s2cid = 24701634 }}{{cite journal | vauthors = Lipton SA, Choi YB, Pan ZH, Lei SZ, Chen HS, Sucher NJ, Loscalzo J, Singel DJ, Stamler JS | display-authors = 6 | title = A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds | journal = Nature | volume = 364 | issue = 6438 | pages = 626–632 | date = August 1993 | pmid = 8394509 | doi = 10.1038/364626a0 | s2cid = 4355073 | bibcode = 1993Natur.364..626L }} 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.{{cite journal | vauthors = Nakamura T, Prikhodko OA, Pirie E, Nagar S, Akhtar MW, Oh CK, McKercher SR, Ambasudhan R, Okamoto S, Lipton SA | display-authors = 6 | title = Aberrant protein S-nitrosylation contributes to the pathophysiology of neurodegenerative diseases | journal = Neurobiology of Disease | volume = 84 | issue = | pages = 99–108 | date = December 2015 | pmid = 25796565 | pmc = 4575233 | doi = 10.1016/j.nbd.2015.03.017 }} 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.{{cite journal | vauthors = Stamler JS, Sun QA, Hess DT | title = A SNO storm in skeletal muscle | journal = Cell | volume = 133 | issue = 1 | pages = 33–35 | date = April 2008 | pmid = 18394987 | doi = 10.1016/j.cell.2008.03.013 | s2cid = 15149572 | doi-access = free }}{{cite journal | vauthors = Foster MW, Hess DT, Stamler JS | title = Protein S-nitrosylation in health and disease: a current perspective | journal = Trends in Molecular Medicine | volume = 15 | issue = 9 | pages = 391–404 | date = September 2009 | pmid = 19726230 | pmc = 3106339 | doi = 10.1016/j.molmed.2009.06.007 }}{{cite journal | vauthors = Beuve A, Wu C, Cui C, Liu T, Jain MR, Huang C, Yan L, Kholodovych V, Li H | display-authors = 6 | title = Identification of novel S-nitrosation sites in soluble guanylyl cyclase, the nitric oxide receptor | journal = Journal of Proteomics | volume = 138 | pages = 40–47 | date = April 2016 | pmid = 26917471 | pmc = 5066868 | doi = 10.1016/j.jprot.2016.02.009 }} It is estimated that ~70% of the proteome is subject to S-nitrosylation and the majority of those sites are conserved.{{cite journal | vauthors = Stomberski CT, Hess DT, Stamler JS | title = Protein S-Nitrosylation: Determinants of Specificity and Enzymatic Regulation of S-Nitrosothiol-Based Signaling | journal = Antioxidants & Redox Signaling | volume = 30 | issue = 10 | pages = 1331–1351 | date = April 2019 | pmid = 29130312 | pmc = 6391618 | doi = 10.1089/ars.2017.7403 }} S-Nitrosylation is also known to show up in mediating pathogenicity in Parkinson's disease systems.{{cite journal | vauthors = Sircar E, Rai SR, Wilson MA, Schlossmacher MG, Sengupta R | title = Neurodegeneration: Impact of S-nitrosylated Parkin, DJ-1 and PINK1 on the pathogenesis of Parkinson's disease | journal = Archives of Biochemistry and Biophysics | volume = 704 | pages = 108869 | date = June 2021 | pmid = 33819447 | doi = 10.1016/j.abb.2021.108869 | s2cid = 233036980 }} S-Nitrosylation is thus established as ubiquitous in biology, having been demonstrated to occur in all phylogenetic kingdoms{{cite journal | vauthors = Seth D, Hausladen A, Wang YJ, Stamler JS | title = Endogenous protein S-Nitrosylation in E. coli: regulation by OxyR | journal = Science | volume = 336 | issue = 6080 | pages = 470–473 | date = April 2012 | pmid = 22539721 | pmc = 3837355 | doi = 10.1126/science.1215643 | bibcode = 2012Sci...336..470S }} and has been described as the prototypic redox-based signalling mechanism,{{cite journal | vauthors = Derakhshan B, Hao G, Gross SS | title = Balancing reactivity against selectivity: the evolution of protein S-nitrosylation as an effector of cell signaling by nitric oxide | journal = Cardiovascular Research | volume = 75 | issue = 2 | pages = 210–219 | date = July 2007 | pmid = 17524376 | pmc = 1994943 | doi = 10.1016/j.cardiores.2007.04.023 }}