MSRA (gene) explained

Peptide methionine sulfoxide reductase (Msr) is a family of enzymes that in humans is encoded by the MSRA gene.^{[1] [2]}

Function

Msr is ubiquitous and highly conserved. Human and animal studies have shown the highest levels of expression in kidney and liver. It carries out the enzymatic reduction of methionine sulfoxide (MetO), the oxidized form of the amino acid methionine (Met), back to methionine, using thioredoxin to catalyze the enzymatic reduction and repair of oxidized methionine residues.^[3] Its proposed function is thus the repair of oxidative damage to proteins to restore biological activity.^[2] Oxidation of methionine residues in tissue proteins can cause them to misfold or otherwise render them dysfunctional.^[3]

Clinical significance

MetO increases with age in body tissues, which is believed by some to contribute to biological ageing.^{[3] [4]} Moreover, levels of methionine sulfoxide reductase A (MsrA) decline in aging tissues in mice and in association with age-related disease in humans.^[3] There is thus a rationale for thinking that by maintaining the structureincreased levels or activity of MsrA might retard the rate of aging.

Indeed, transgenic Drosophila (fruit flies) that overexpress methionine sulfoxide reductase show extended lifespan.^[5] However, the effects of MsrA overexpression in mice were ambiguous.^[6] MsrA is found in both the cytosol and the energy-producing mitochondria, where most of the body's endogenous free radicals are produced. Transgenically increasing the levels of MsrA in either the cytosol or the mitochondria had no significant effect on lifespan assessed by most standard statistical tests, and may possibly have led to early deaths in the cytosol-specific mice, although the survival curves appeared to suggest a slight increase in maximum (90%) survivorship, as did analysis using Boschloo's test, a binomial test designed to test greater extreme variation.^[6]

Deletion of this gene has been associated with insulin resistance in mice,^[7] while overexpression reduces insulin resistance in old mice.^[6]

See also

• MSRB2
• Methionine oxidation
• SEPX1

Further reading

• Hansel A, Heinemann SH, Hoshi T . Heterogeneity and function of mammalian MSRs: enzymes for repair, protection and regulation. . Biochim. Biophys. Acta . 1703 . 2 . 239–47 . 2005 . 15680232 . 10.1016/j.bbapap.2004.09.010 .
• Moskovitz J, Jenkins NA, Gilbert DJ, etal . Chromosomal localization of the mammalian peptide-methionine sulfoxide reductase gene and its differential expression in various tissues. . Proc. Natl. Acad. Sci. U.S.A. . 93 . 8 . 3205–8 . 1996 . 8622914 . 10.1073/pnas.93.8.3205 . 39583 . 1996PNAS...93.3205M . free .
• Hansel A, Kuschel L, Hehl S, etal . Mitochondrial targeting of the human peptide methionine sulfoxide reductase (MSRA), an enzyme involved in the repair of oxidized proteins. . FASEB J. . 16 . 8 . 911–3 . 2002 . 12039877 . 10.1096/fj.01-0737fje . free . 20786793 .
• Strausberg RL, Feingold EA, Grouse LH, etal . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . free .
• Vougier S, Mary J, Friguet B . Subcellular localization of methionine sulphoxide reductase A (MsrA): evidence for mitochondrial and cytosolic isoforms in rat liver cells. . Biochem. J. . 373 . Pt 2 . 531–7 . 2003 . 12693988 . 10.1042/BJ20030443 . 1223498 .
• Picot CR, Perichon M, Cintrat JC, etal . The peptide methionine sulfoxide reductases, MsrA and MsrB (hCBS-1), are downregulated during replicative senescence of human WI-38 fibroblasts. . FEBS Lett. . 558 . 1–3 . 74–8 . 2004 . 14759519 . 10.1016/S0014-5793(03)01530-8 . 32573388 .
• Kantorow M, Hawse JR, Cowell TL, etal . Methionine sulfoxide reductase A is important for lens cell viability and resistance to oxidative stress. . Proc. Natl. Acad. Sci. U.S.A. . 101 . 26 . 9654–9 . 2004 . 15199188 . 10.1073/pnas.0403532101 . 470730 . 2004PNAS..101.9654K . free .
• Gerhard DS, Wagner L, Feingold EA, etal . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 .
• De Luca A, Sacchetta P, Di Ilio C, Favaloro B . Identification and analysis of the promoter region of the human methionine sulphoxide reductase A gene. . Biochem. J. . 393 . Pt 1 . 321–9 . 2006 . 16162094 . 10.1042/BJ20050973 . 1383691 .
• Picot CR, Petropoulos I, Perichon M, etal . Overexpression of MsrA protects WI-38 SV40 human fibroblasts against H2O2-mediated oxidative stress. . Free Radic. Biol. Med. . 39 . 10 . 1332–41 . 2006 . 16257642 . 10.1016/j.freeradbiomed.2005.06.017 .
• Lee JW, Gordiyenko NV, Marchetti M, etal . Gene structure, localization and role in oxidative stress of methionine sulfoxide reductase A (MSRA) in the monkey retina. . Exp. Eye Res. . 82 . 5 . 816–27 . 2006 . 16364291 . 10.1016/j.exer.2005.10.003 . 2825745 .
• Schallreuter KU, Rübsam K, Chavan B, etal . Functioning methionine sulfoxide reductases A and B are present in human epidermal melanocytes in the cytosol and in the nucleus. . Biochem. Biophys. Res. Commun. . 342 . 1 . 145–52 . 2006 . 16480945 . 10.1016/j.bbrc.2006.01.124 .
• Lei KF, Wang YF, Zhu XQ, etal . Identification of MSRA gene on chromosome 8p as a candidate metastasis suppressor for human hepatitis B virus-positive hepatocellular carcinoma. . BMC Cancer . 7 . 172 . 2007 . 17784942 . 10.1186/1471-2407-7-172 . 2000900 . free .

Notes and References

1. Kuschel L, Hansel A, Schonherr R, Weissbach H, Brot N, Hoshi T, Heinemann SH . Molecular cloning and functional expression of a human peptide methionine sulfoxide reductase (hMsrA) . FEBS Lett . 456 . 1 . 17–21 . Sep 1999 . 10452521 . 10.1016/S0014-5793(99)00917-5 . 19104671 . free .
2. Web site: Entrez Gene: MSRA methionine sulfoxide reductase A.
3. Stadtman ER, Van Remmen H, Richardson A, Wehr NB, Levine RL . Methionine oxidation and aging . Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics . 1703 . 2 . 2005 . 135–140 . 15680221 . 10.1016/j.bbapap.2004.08.010.
4. Shringarpure R, Davies KJ . Protein turnover by the proteasome in aging and disease . Free Radical Biology & Medicine . 32 . 11 . 2002 . 1084–1089 . 12031893 . 10.1016/S0891-5849(02)00824-9.
5. Ruan H, Tang XD, Chen ML, Joiner ML, Sun G, Brot N, Weissbach H, Heinemann SH, Iverson L, Wu CF, Hoshi T . High-quality life extension by the enzyme peptide methionine sulfoxide reductase . . 99 . 5 . 2002 . 2748–2753 . 11867705 . 10.1073/pnas.032671199 . 122419. 2002PNAS...99.2748R . free .
6. Salmon AB, Kim G, Liu C, Wren JD, Georgescu C, Richardson A, Levine RL. Effects of transgenic methionine sulfoxide reductase A (MsrA) expression on lifespan and age-dependent changes in metabolic function in mice. Redox Biol. December 2016. 10. 251–256. 10.1016/j.redox.2016.10.012. 27821326. 5099276.
7. Styskal JL, 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. 123–32. October 2012 . 23089224 . 10.1016/j.freeradbiomed.2012.10.544 . 3578155.