Methionine oxidation and reduction in proteins
Open accessAbstract
Background Cysteine and methionine are the two sulfur containing amino acids in proteins. While the roles of protein-bound cysteinyl residues as endogenous antioxidants are well appreciated, those of methionine remain largely unexplored. Scope We summarize the key roles of methionine residues in proteins. Major conclusion Recent studies establish that cysteine and methionine have remarkably similar functions. General significance Both cysteine and methionine serve as important cellular antioxidants, stabilize the structure of proteins, and can act as regulatory switches through reversible oxidation and reduction. This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn.
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Oxidised methionine residues have been observed in biological samples.
“Although unusual, oxidised methionine residues have been observed in biological samples [32].”
From Discrimination of Methionine Sulfoxide and Sulfone by Human Neutrophil Elastase (2021) · cites this paper as [32]
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Redox-based regulation of signal transduction: principles, pitfalls, and promises
Janssen-Heininger, Y. M. W., Mossman, B. T., Heintz, N. H., Forman, H. J., Kalyanaraman, B., Finkel, T., Stamler, J. S., Rhee, S. G., & van der Vliet, A. (2008) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2008.03.011 · Cited by 784 · see citing works
Moskovitz, J., Rahman, M. A., Strassman, J., Yancey, S. O., Kushner, S. R., Brot, N., & Weissbach, H. (1995) · Journal of Bacteriology · doi:10.1128/jb.177.3.502-507.1995 · Cited by 294 · see citing works
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Research works printed but not linked: 63
- [2]Arner ES Holmgren A Physiological functions of thioredoxin and thioredoxin reductase European journal of biochemistry / FEBS 267 2000 6102 6109 11012661
- [3]Brot N Weissbach H Biochemistry and physiological role of methionine sulfoxide reductase in proteins Arch Biochem Biophys 223 1983 271 281 6859861
- [4]Zhang XH Weissbach H Origin and evolution of the protein-repairing enzymes methionine sulphoxide reductases Biol Rev Camb Philos Soc 83 2008 249 257 18557976
- [5]Grimaud R Ezraty B Mitchell JK Lafitte D Briand C Derrick PJ Barras F Repair of oxidized proteins. Identification of a new methionine sulfoxide reductase J Biol Chem 276 2001 48915 48920 11677230
- [6]Moskovitz J Bar-Noy S Williams WM Requena J Berlett BS Stadtman ER Methionine sulfoxide reductase (MsrA) is a regulator of antioxidant defense and lifespan in mammals Proc Natl Acad Sci USA 98 2001 12920 12925 11606777 PMC60800
- [7]Moskovitz J Berlett BS Poston JM Stadtman ER The yeast peptide-methionine sulfoxide reductase functions as an antioxidant in vivo Proc Natl Acad Sci USA 94 1997 9585 9589 9275166 PMC23225
- [9]Douglas T Daniel DS Parida BK Jagannath C Dhandayuthapani S Methionine sulfoxide reductase A (MsrA) deficiency affects the survival of Mycobacterium smegmatis within macrophages J Bacteriol 186 2004 3590 3598 15150247 PMC415777
- [10]St John G Brot N Ruan J Erdjument-Bromage H Tempst P Weissbach H Nathan C Peptide methionine sulfoxide reductase from Escherichia coli and Mycobacterium tuberculosis protects bacteria against oxidative damage from reactive nitrogen intermediates Proc Natl Acad Sci USA 98 2001 9901 9906 11481433 PMC55550
- [11]Ruan H Tang XD Chen ML Joiner ML Sun G Brot N Weissbach H Heinemann SH Iverson L Wu CF Hoshi T Chen ML Joiner MA Heinemann SH High-quality life extension by the enzyme peptide methionine sulfoxide reductase Proc Natl Acad Sci USA 99 2002 2748 2753 11867705 PMC122419
- [12]Moskovitz J Flescher E Berlett BS Azare J Poston JM Stadtman ER Overexpression of peptide-methionine sulfoxide reductase in Saccharomyces cerevisiae and human T cells provides them with high resistance to oxidative stress Proc Natl Acad Sci USA 95 1998 14071 14075 9826655 PMC24328
- [13]Romero HM Berlett BS Jensen PJ Pell EJ Tien M Investigations into the role of the plastidial peptide methionine sulfoxide reductase in response to oxidative stress in Arabidopsis Plant Physiol 136 2004 3784 3794 15516509 PMC527175
- [14]Yermolaieva O Xu R Schinstock C Brot N Weissbach H Heinemann SH Hoshi T Methionine sulfoxide reductase A protects neuronal cells against brief hypoxia/reoxygenation Proc Natl Acad Sci USA 101 2004 1159 1164 14745014 PMC337023
- [15]Lavine TF The formation, resolution, and optical properties of the diasteriomeric sulfoxides derived from L-methionine J Biol Chem 169 1947 477 491 20259080
- [16]Vogt W Oxidation of methionine residues in proteins: Tools, targets, and reversal Free Rad Biol Med 18 1995 93 105 7896176
- [17]Wood PM The redox potential for dimethyl sulphoxide reduction to dimethyl sulphide: evaluation and biochemical implications FEBS Lett 124 1981 11 14 7215550
- [18]Jocelyn PC The Standard Redox Potential of Cysteine-Cystine from the Thiol-Disulphide Exchange Reaction with Glutathione and Lipoic Acid Eur J Biochem 2 1967 327 331 4865316
- [20]Peskin AV Winterbourn CC Kinetics of the reactions of hypochlorous acid and amino acid chloramines with thiols, methionine, and ascorbate Free Radic Biol Med 30 2001 572 579 11182528
- [21]Winterbourn CC Comparative reactivities of various biological compounds with myeloperoxidase-hydrogen peroxide-chloride, and similarity of the oxidant to hypochlorite Biochim Biophys Acta 1985 6 18 840 204 210 2986713
- [22]Richardson DE Regino CA Yao H Johnson JV Methionine oxidation by peroxymonocarbonate, a reactive oxygen species formed from CO2/bicarbonate and hydrogen peroxide Free Radic Biol Med 35 2003 1538 1550 14680677
- [23]Sottrup-Jensen L Alpha-macroglobulins: structure, shape, and mechanism of proteinase complex formation J Biol Chem 264 1989 11539 11542 2473064
- [24]Travis J Salvesen GS Human plasma proteinase inhibitors Annu Rev Biochem 52 1983 655 709 6193754
- [25]Barrett AJ Starkey PM The interaction of alpha 2-macroglobulin with proteinases. Characteristics and specificity of the reaction, and a hypothesis concerning its molecular mechanism Biochem J 133 1973 709 724 4201304 PMC1177761
- [26]Reddy VY Desrochers PE Pizzo SV Gonias SL Sahakian JA Levine RL Weiss SJ Oxidative dissociation of human α2macroglobulin tetramers into dysfunctional dimers J Biol Chem 269 1994 4683 4691 7508448
- [27]Levine RL Mosoni L Berlett BS Stadtman ER Methionine residues as endogenous antioxidants in proteins Proc Natl Acad Sci USA 93 1996 15036 15040 8986759 PMC26351
- [28]Levine RL Berlett BS Moskovitz J Mosoni L Stadtman ER Methionine residues may protect proteins from critical oxidative damage Mech Ageing Dev 107 1999 323 332 10360685
- [29]Marrero A Duquerroy S Trapani S Goulas T Guevara T Andersen GR Navaza J Sottrup-Jensen L Gomis-Ruth FX The crystal structure of human alpha2-macroglobulin reveals a unique molecular cage Angew Chem Int Ed Engl 51 2012 3340 3344 22290936
- [30]Kolodziej SJ Wagenknecht T Strickland DK Stoops JK The three-dimensional structure of the human alpha 2-macroglobulin dimer reveals its structural organization in the tetrameric native and chymotrypsin alpha 2-macroglobulin complexes J Biol Chem 277 2002 28031 28037 12015318
- [31]Van Leuven F Cassiman JJ Van den Berghe H Functional modifications of alpha 2-macroglobulin by primary amines. I. Characterization of alpha 2 M after derivatization by methylamine and by factor XIII J Biol Chem 256 1981 9016 9022 6167585
- [32]Almassy RJ Janson CA Hamlin R Xuong NH Eisenberg D Novel subunit-subunit interactions in the structure of glutamine synthetase Nature 323 1986 304 309 2876389
- [33]Yamashita MM Almassy RJ Janson CA Cascio D Eisenberg D Refined atomic model of glutamine synthetase at 3.5 A resolution J Biol Chem 264 1989 17681 17690 2572586
- [34]Liaw SH Eisenberg D Structural model for the reaction mechanism of glutamine synthetase, based on five crystal structures of enzyme-substrate complexes Biochemistry 33 1994 675 681 7904828
- [35]Rapoport S Hartel B Hausdorf G Methionine sulfoxide formation: the cause of self-inactivation of reticulocyte lipoxygenase Eur J Biochem 139 1984 573 576 6421581
- [36]Gan QF Witkop GL Sloane DL Straub KM Sigal E Identification of a specific methionine in mammalian 15- lipoxygenase which is oxygenated by the enzyme product 13-HPODE: dissociation of sulfoxide formation from self-inactivation Biochemistry 34 1995 7069 7079 7766617
- [37]Garner B Waldeck AR Witting PK Rye KA Stocker R Oxidation of high density lipoproteins. II. Evidence for direct reduction of lipid hydroperoxides by methionine residues of apolipoproteins AI and AII J Biol Chem 273 1998 6088 6095 9497326
- [38]Sigalov AB Stern LJ Enzymatic repair of oxidative damage to human apolipoprotein AI FEBS Lett 433 1998 196 200 9744793
- [39]Lim JC Gruschus JM Ghesquiere B Kim G Piszczek G Tjandra N Levine RL Characterization and solution structure of mouse myristoylated methionine sulfoxide reductase A J Biol Chem 287 2012 25589 25595 22661718 PMC3408158
- [40]Bender A Hajieva P Moosmann B Adaptive antioxidant methionine accumulation in respiratory chain complexes explains the use of a deviant genetic code in mitochondria Proc Natl Acad Sci USA 105 2008 16496 16501 18946048 PMC2575448
- [41]Cowie DB Cohen GN Bolton ET De Robichon-Szulmajster H Amino acid analog incorporation into bacterial proteins Biochim Biophys Acta 34 1959 39 46 13812494
- [42]Luo S Levine RL Methionine in proteins defends against oxidative stress FASEB J 23 2009 464 472 18845767 PMC2630790
- [43]Valley CC Cembran A Perlmutter JD Lewis AK Labello NP Gao J Sachs JN The Methionine-aromatic Motif Plays a Unique Role in Stabilizing Protein Structure J Biol Chem 287 2012 34979 34991 22859300 PMC3471747
- [45]Chao CC Ma YS Stadtman ER Modification of protein surface hydrophobicity and methionine oxidation by oxidative systems Proc Natl Acad Sci USA 94 1997 2969 2974 9096330 PMC20306
- [46]Wehr NB Levine RL Wanted and wanting: antibody against methionine sulfoxide Free Radic Biol Med 53 2012 1222 1225 22771451 PMC3437004
- [47]Ghesquiere B Jonckheere V Colaert N Van Durme J Timmerman E Goethals M Schymkowitz J Rousseau F Vandekerckhove J Gevaert K Redox proteomics of protein-bound methionine oxidation Mol Cell Proteomics 10 2011 10.1074/mcp.M1110.006866-006861-006812 PMC3098596 21406390 · DOI
- [48]Johnson D Travis J The oxidative inactivation of human alpha-1-proteinase inhibitor. Further evidence for methionine at the reactive center JBiol Chem 254 1979 4022 4026 312289
- [49]Carp H Miller F Hoidal JR Janoff A Potential mechanism of emphysema: alpha 1-proteinase inhibitor recovered from lungs of cigarette smokers contains oxidized methionine and has decreased elastase inhibitory capacity Proc Natl Acad Sci USA 79 1982 2041 2045 6979049 PMC346118
- [50]McGuire WW Spragg RG Cohen AB Cochrane CG Studies on the pathogenesis of the adult respiratory distress syndrome J Clin Invest 69 1982 543 553 7037851 PMC371010
- [51]Ogden BE Murphy SA Saunders GC Pathak D Johnson JD Neonatal lung neutrophils and elastase/proteinase inhibitor imbalance Am Rev Respir Dis 130 1984 817 821 6333839
- [52]Vanacore R Ham AJ Voehler M Sanders CR Conrads TP Veenstra TD Sharpless KB Dawson PE Hudson BG A sulfilimine bond identified in collagen IV Science 325 2009 1230 1234 19729652 PMC2876822
- [53]Bhave G Cummings CF Vanacore RM Kumagai-Cresse C Ero-Tolliver IA Rafi M Kang JS Pedchenko V Fessler LI Fessler JH Hudson BG Peroxidasin forms sulfilimine chemical bonds using hypohalous acids in tissue genesis Nat Chem Biol 8 2012 784 790 22842973 PMC4128002
- [54]Hoshi T Heinemann S Regulation of cell function by methionine oxidation and reduction J Physiol 531 2001 1 11 11179387 PMC2278441
- [55]Bigelow DJ Squier TC Redox modulation of cellular signaling and metabolism through reversible oxidation of methionine sensors in calcium regulatory proteins Biochim Biophys Acta 1703 2005 121 134 15680220
- [56]Ciorba MA Heinemann SH Weissbach H Brot N Hoshi T Regulation of voltage-dependent K+ channels by methionine oxidation: effect of nitric oxide and vitamin C FEBS Lett 442 1999 48 52 9923602
- [57]Sroussi HY Berline J Palefsky JM Oxidation of methionine 63 and 83 regulates the effect of S100A9 on the migration of neutrophils in vitro J Leukoc Biol 81 2007 818 824 17138858
- [58]Erickson JR Joiner ML Guan X Kutschke W Yang J Oddis CV Bartlett RK Lowe JS O’Donnell SE Aykin-Burns N Zimmerman MC Zimmerman K Ham AJ Weiss RM Spitz DR Shea MA Colbran RJ Mohler PJ Anderson ME A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation Cell 133 2008 462 474 18455987 PMC2435269
- [59]Godoy LC Munoz-Pinedo C Castro L Cardaci S Schonhoff CM King M Tortora V Marin M Miao Q Jiang JF Kapralov A Jemmerson R Silkstone GG Patel JN Evans JE Wilson MT Green DR Kagan VE Radi R Mannick JB Disruption of the M80-Fe ligation stimulates the translocation of cytochrome c to the cytoplasm and nucleus in nonapoptotic cells Proc Natl Acad Sci USA 106 2009 2653 2658 19196960 PMC2650321
- [60]Hardin SC Larue CT Oh MH Jain V Huber SC Coupling oxidative signals to protein phosphorylation via methionine oxidation in Arabidopsis Biochem J 422 2009 305 312 19527223 PMC2782308
- [61]Fu X Chen J Gallagher R Zheng Y Chung DW Lopez JA Shear stress-induced unfolding of VWF accelerates oxidation of key methionine residues in the A1A2A3 region Blood 118 2011 5283 5291 21917758 PMC3217410
- [62]Hung RJ Pak CW Terman JR Direct redox regulation of F-actin assembly and disassembly by Mical Science 334 2011 1710 1713 22116028 PMC3612955
- [63]Lim JC You Z Kim G Levine RL Methionine sulfoxide reductase A is a stereospecific methionine oxidase Proc Natl Acad Sci USA 108 2011 10472 10477 21670260 PMC3127874
- [64]Lim JC Gruschus JM Kim G Berlett BS Tjandra N Levine RL A Low pKa cysteine at the active site of mouse methionine sulfoxide reductase A J Biol Chem 275 2012 25596 25601 22661719 PMC3408155
- [65]Shapiro BM Stadtman ER The regulation of glutamine synthesis in microorganisms Annu Rev Microbiol 24 1970 501 524 4927139
- [66]Anderson WB Hennig SB Ginsburg A Stadtman ER Association of ATP: glutamine synthetase adenylyltransferase activity with the P1 component of the glutamine synthetase deadenylylation system Proc Natl Acad Sci USA 67 1970 1417 1424 4249662 PMC283368
- [67]Styskal J Nwagwu FA Watkins YN Liang H Richardson A Musi N Salmon AB Methionine sulfoxide reductase A affects insulin resistance by protecting insulin receptor function Free Radic Biol Med 56 2013 123 132 23089224 PMC3578155
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“Although unusual, oxidised methionine residues have been observed in biological samples [32].”
Background
- Authors
- Kim, G., Weiss, S. J., & Levine, R. L.
- Affiliations
- National Heart, Lung, and Blood Institute (US)
- University of Michigan (US)
- Corresponding author
- Levine, Rodney L.
- Venue
- Biochimica et Biophysica Acta (BBA) - General Subjects
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 1840
- Issue
- 2
- Pages
- 901-905
- ISSN
- 0304-4165 (ISSN-L)
- PMC
- PMC3766491
- OpenAlex
- W2044036144
- Cited by
- 311
- References
- 2
- Citations by year
- 2026: 20 · 2025: 28 · 2024: 34 · 2023: 25 · 2022: 24 · 2021: 37 · 2020: 30 · 2019: 30 · 2018: 30 · 2017: 16 · 2016: 13 · 2015: 15 · 2014: 7 · 2013: 1
- FWCI
- 1.13
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochimica et Biophysica Acta (BBA) - General Subjects (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (ZIAHL000225)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK020572)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Keywords
- methionine oxidation, protein oxidation, cysteine, sulfur-containing amino acids, redox regulation, reactive oxygen species
- MeSH terms
- Animals, Humans, Methionine, Oxidation-Reduction, Proteins
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