Austin J Pharmacol Ther. 2014; 2 (3). 1021
Methionine Sulfoxide Reductase System in Health and Disease
Department of Pharmacology and Toxicology, University of Kansas, USA
*Corresponding author: : Jackob Moskovitz, Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, 66045, USA
Received: April 23, 2014; Accepted: April 24, 2014; Published: April 24, 2014
Methionine (Met) is highly susceptible to oxidation in vivo, particularly under conditions of oxidative stress that are exacerbated at older age. Oxidation of Met to methionine sulfoxide (MetO)is reversible and the reverse reaction is catalyzed by the methionine sulfoxidereductase (Msr) system, comprising methionine S-sulfoxidereductase (MsrA) and methionine R–sulfoxidereductase (MsrB), which reduce the S and R enantiomers of the sulfoxide group, respectively [1,2]. Thus, unlike other consequences of oxidative damage, such as protein carbonylation or nitration, Met oxidation to MetO is reversible and the Msr system provides an efficient protection against oxidative stress by scavenging reactive oxygen species through the recycling of Met . Nonetheless, under consistent oxidative stress conditions, a combination between a compromised Msr system and elevated protein oxidation levels may lead to changes in protein structure and dysfunction of sulfoxidized proteins. All or some of these abnormalities may eventually lead to a permanent cell damage , disease, and death . In recent years, more evidence have emerged supporting the importance of the Msr system in the development of oxidative–stress associated diseases of the brain (e.g. neurodegenerative diseases and disorders), cystic fibrosis (CF), and hearing loss [3–10]. In most of these diseases, reduction of MetO residues by the Msr system has shown to have a protective effect against oxidative damage and related diseases. An exception to this trend is the association between lower MsrA activity and lower chances of developing CF in individuals and in CF mouse models carrying the CF–linked genetic mutations . Accordingly, identifying a specific inhibitor to MsrA activity may prompt the use of this inhibitoras a potential therapy treatment to children having CF. The physiological role of MetO is yet to be completely determined. So far, methionine oxidation has been shown to be involved in controlling protein phosphorylation [11–13], as well as yet to be discovered signal transduction pathway/s leading to an enhanced expression of Msr proteins . In contrast, lack of Msr enzymes causes cells to be more vulnerable to oxidative stress and posttranslational modifications [15–23]. Given the protective role of the Msr system against oxidative damage, induction of Msr activity seems to be beneficiary to support cell survival. For example, over expression of MsrA (by genetic manipulation)in yeast and human cell cultures has been shown to protect these cells from enhanced MetO accumulations while increasing their survival rates under oxidative stress conditions . In addition, several compounds have demonstrated an ability to induce Msr activity in neuronal cell cultures . This observation supports the identification and development of novel compounds that may serve as therapy treatments against neurodegenerative diseases. Another possible approach to reduce the toxic effects of accumulated MetO–proteins is by enhancing their clearance from an organism. Supportive evidence for the importance of the Msr system in protein degradation is demonstrated by the fact that lack of MsrA contributes to the resistant of proteins to degradation. This phenomenon may be explained by the possible interference of MetO residues to phosphorylation–linked degradation processes. For example, over expression of a–synuclein in msrAnull mutant yeast cells inhibits its phosphorylation and degradation in comparison with wild–type (WT) yeast cells . Accordingly, under degenerative disease conditions (like in the case of neurodegenerative diseases) removal of oxidized proteins from brain may be beneficiary to halt the progression of the disease. One approach that has been used to achieve this goal was carried out by immunization of mice models of Alzheimer’s disease (AD) with a MetO–rich protein antigen. Apparently, this treatment reduced mouse brain plaque burden in the hippocampal region of the treated mice compared with non–treated mice . It is speculated that the resulting anti–MetO antibodies , produced through this antigen immunization, interacted with MetO–proteins (including MetO–beta amyloid protein) and cleared them from brain (presumably through enhancing these proteins’ degradation). The overall importance of the Msr system to promote survival under physiological and enhanced oxidative stress conditions has been manifested in several organisms, from prokaryotes to eukaryotes including mammals. So far, methionine oxidation has been shown to affect many proteins’ activities . In mammals, examples of proteins in which their MetO can be also reduced by the Msr system include: the potassium channel of the brain , an isoform of the inhibitory protein B [27–29], calmodulin [30,31], calcium/calmodulin–dependent protein kinase II , and D2–dopamine receptor . Examples of such proteins in lower eukaryotes (not mammals) include: transcription regulator for head box O (FOXO) in fruit fly , and prion–like protein (Sup35) in yeast . These findings suggest a key role for MsrA in regulating MetO reduction in proteins, including major survival regulator transcription factors like FOXO . Genomic analysis of brain of MsrA knockout mouse revealed that lack of the MsrAgene in mouse causes a strong and significant up regulation of genes that are involved in redox homeostasis and transcription regulation . These data strongly suggest that MetO formation and reduction by the Msr system play a major role in the cellular adaptation to oxidative stress conditions, which is mediated by expression regulation of specific transcription factors. However, up–to–date not much is known about the signaling events that are leading to the transcriptional regulation of the Msr proteins themselves. It is suggested that a compounds that can mimic MetO or alternatively contain methyl sulfoxide group can cause an up regulation of at least the MsrA protein . At least in yeast, the MsrA up regulation process may involve thioredoxin and a homologue of elongation factor 1 gamma factor [36,37]. More research is required to identify the components that participated in the Msr signal transduction pathway in order to expand the current understanding of the Msr system. Furthermore, development of specific compounds that can affect signaling molecules of the Msr system will enable the application of novel Msr–based therapeutic approaches.
- Moskovitz J, Singh VK, Requena J, Wilkinson BJ, Jayaswal RK, Stadtman ER. Puriication and characterization of methionine sulfoxide reductases from mouse and Staphylococcus aureus and their substrate stereospeciicity. Biochem Biophys Res Commun. 2002; 290: 62-65.
- Oien DB, Moskovitz J. Substrates of the methionine sulfoxide reductase system and their physiological relevance. Curr Top Dev Biol. 2008; 80: 93- 133.
- Henderson LB, Doshi VK, Blackman SM, Naughton KM, Pace RG, Moskovitz J, et al. Variation in MSRA modiies risk of neonatal intestinal obstruction in cystic ibrosis. PLoS Genet. 2012; 8: e1002580.
- Ahmed ZM, Yousaf R, Lee BC, Khan SN, Lee S, Lee K, et al. Functional null mutations of MSRB3 encoding methionine sulfoxide reductase are associated with human deafness DFNB74. Am J Hum Genet. 2011; 88: 19-29.
- Kwon TJ, Cho HJ, Kim UK, Lee E, Oh SK, Bok J, et al. Methionine sulfoxide reductase B3 deiciency causes hearing loss due to stereocilia degeneration and apoptotic cell death in cochlear hair cells. Hum Mol Genet. 2014; 23: 1591-1601.
- Moskovitz J. Methionine sulfoxide reductases: ubiquitous enzymes involved in antioxidant defense, protein regulation, and prevention of aging-associated diseases. BiochimBiophysActa. 2005; 1703: 213- 219.
- Pal R, Oien DB, Ersen FY, Moskovitz J. Elevated levels of brain-pathologies associated with neurodegenerative diseases in the methionine sulfoxide reductase A knockout mouse. Exp Brain Res. 2007; 180: 765-774.
- Oien DB, Osterhaus GL, Latif SA, Pinkston JW, Fulks J, Johnson M, et al. MsrA knockout mouse exhibits abnormal behavior and brain dopamine levels. Free RadicBiol Med. 2008; 45: 193-200.
- Gabbita SP, Aksenov MY, Lovell MA, Markesbery WR. Decrease in peptide methionine sulfoxide reductase in Alzheimer’s disease brain. J Neurochem.1999; 73: 1660-1666.
- Oien DB, Ortiz AN, Rittel AG, Dobrowsky RT, Johnson MA, Levant B, et al. Dopamine D(2) receptor function is compromised in the brain of the methionine sulfoxide reductase A knockout mouse. J Neurochem. 2010; 114: 51-61.
- Oien DB, Shinogle HE, Moore DS, Moskovitz J. Clearance and phosphorylation of alpha-synuclein are inhibited in methionine sulfoxide reductase a null yeast cells. J MolNeurosci. 2009; 39: 323-332.
- Oien DB, Carrasco GA, Moskovitz J. Decreased Phosphorylation and Increased Methionine Oxidation of a-Synuclein in the Methionine Sulfoxide Reductase A Knockout Mouse. J. Amino Acids. 2011; 2012: 415713.
- Hardin SC, Larue CT, Oh MH, Jain V, Huber SC. Coupling oxidative signals to protein phosphorylation via methionine oxidation in Arabidopsis. Biochem J. 2009; 422: 305-312.
- Moskovitz J, Maiti P, Lopes DH, Oien DB, Attar A, Liu T, et al. Induction of methionine-sulfoxidereductases protects neurons from amyloid ß-protein insults in vitro and in vivo. Biochemistry. 2011; 50: 10687-10697.
- Oien D, Moskovitz J. Protein-carbonyl accumulation in the non-replicative senescence of the methionine sulfoxidereductaseA (msrA) knockout yeast strain. Amino Acids. 2007; 32: 603-606.
- Moskovitz J. Prolonged selenium-deicient diet in MsrA knockout mice causes enhanced oxidative modiication to proteins and affects the levels of antioxidant enzymes in a tissue-speciic manner. Free Rad. Res. 2007; 41: 162-171.
- Moskovitz J, Bar-Noy S, Williams WM, Requena J, Berlett BS, Stadtman ER. Methionine sulfoxidereductase (MsrA) is a regulator of antioxidant defense and lifespan in mammals. Proc Natl Acad Sci USA. 2001; 98: 12920-12925.
- Oien DB, Osterhaus GL, Lundquist BL, Fowler SC, Moskovitz J. Caloric restriction alleviates abnormal locomotor activity and dopamine levels in the brain of the methionine sulfoxide reductase A knockout mouse. Neurosci Lett. 2010; 468: 38-41.
- Oien DB, Canello T, Gabizon R, Gasset M, Lundquist BL, Burns, JM, et al. Detection of oxidized methionine in selected proteins, cellular extracts, and blood serums by novel anti-methionine sulfoxide antibodies. Arch. Biochem. Biophys. 2009; 485: 35-40.
- Moskovitz J, Rahman MA, Strassman J, Yancey SO, Kushner SR, Brot N, et al. Escherichia coli peptide methionine sulfoxide reductase gene: regulation of expression and role in protecting against oxidative damage. J Bacteriol. 1995; 177: 502-507.
- Moskovitz J, Oien DB. Protein carbonyl and the methionine sulfoxide reductase system.Antioxid Redox Signal. 2010; 12: 405-415.
- Rodrigo MJ, Moskovitz J, Salamini F, Bartels D. Reverse genetic approaches in plants and yeast suggest a role for novel, evolutionarily conserved, selenoprotein-related genes in oxidative stress defense. Mol Genet Genomics. 2002; 267: 613-621.
- 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. 1997; 94: 9585-9589.
- Moskovitz J, Flescher E, Berlett BS, Azare J, Poston JM, Stadtman ER. Over expression of peptide-methionine sulfoxidereductase in Saccharomyces cerevisiae and human T cells provides them with high resistance to oxidative stress. Proc Natl Acad Sci USA. 1998; 95: 14071-14075.
- Franklin JM, Carrasco GA, Moskovitz J. Induction of methionine sulfoxide reductase activity by pergolide, pergolide sulfoxide, and S-adenosyl- methionine in neuronal cells. Neurosci Lett. 2013; 533: 86-89.
- Ciorba MA, Heinemann SH, Weissbach H, Brot N, Hoshi T. Modulation of potassium channel function by methionine oxidation and reduction. Proc Natl Acad Sci USA. 1997; 94: 9932-9937.
- Kanayama A, Inoue J, Sugita-Konishi Y, Shimizu M, Miyamoto Y. Oxidation of Ikappa Balpha at methionine 45 is one cause of taurine chloramine-induced inhibition of NF-kappa B activation. J Biol Chem. 2002; 277: 24049-24056.
- Mohri M, Reinach PS, Kanayama A, Shimizu M, Moskovitz J, Hisatsune T et al. Suppression of the TNFalpha-induced increase in IL-1alpha expression by hypochlorite in human corneal epithelial cells. Invest Ophthalmol Vis Sci. 2002; 43: 3190-3195.
- Midwinter RG, Cheah FC, Moskovitz J, Vissers MC, Winterbourn CC. IkappaB is a sensitive target for oxidation by cell-permeable chloramines: inhibition of NF-kappaB activity by glycine chloramine through methionine oxidation. Biochem J. 2006; 396: 71-78.
- Sun H, Gao J, Ferrington DA, Biesiada H, Williams TD, Squier TC. Repair of oxidized calmodulin by methionine sulfoxide reductase restores ability to activate the plasma membrane Ca-ATPase. Biochemistry. 1999; 38: 105- 112.
- Carruthers NJ, Stemmer PM. Methionine oxidation in the calmodulin-binding domain of calcineurin disrupts calmodulin binding and calcineurin activation. Biochemistry. 2008; 47: 3085-3095.
- Erickson JR, Joiner ML, Guan X, Kutschke W, Yang J, Oddis CV. A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation. Cell. 2008; 133: 462-474.
- Chung H, Kim AK, Jung SA, Kim SW, Yu K, Lee JH. The Drosophila homolog of methionine sulfoxide reductase A extends lifespan and increases nuclear localization of FOXO. FEBS Lett. 2010; 584: 3609-3614.
- Sideri TC, Koloteva-Levine N, Tuite MF, Grant CM. Methionine oxidation of Sup35 protein induces formation of the [PSI+] prion in a yeast peroxiredoxin mutant. J Biol Chem. 2011; 286: 38924-38931.
- Oien DB, WangX, Moskovitz J. Genomic and proteomic analyses of the methionine sulfoxide reductase A knockout mouse. Curr. Proteom. 2008; 5: 96-103.
- Hanbauer I, Moskovitz J. The yeast cytosolic thioredoxins are involved in the regulation of methionine sulfoxide reductase A. Free Radic Biol Med. 2006; 40: 1391-1396.
- Hanbauer I, Boja ES, Moskovitz J. A homologue of elongation factor 1 gamma regulates methionine sulfoxide reductase A gene expression in Saccharomyces cerevisiae. Proc Natl Acad Sci USA. 2003; 100: 8199-8204.