MSRA (gene)

Peptide methionine sulfoxide reductase (Msr) is a family of enzymes that in humans is encoded by the MSRA gene.[5][6]

MSRA
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2L90
Identifiers
Aliases	MSRA, PMSR, methionine sulfoxide reductase A
External IDs	OMIM: 601250 MGI: 106916 HomoloGene: 5812 GeneCards: MSRA
Gene location (Human) Chr. Chromosome 8 (human)[1] Band 8p23.1 Start 10,054,292 bp[1] End 10,428,891 bp[1]
Gene location (Mouse) Chr. Chromosome 14 (mouse)[2] Band 14 D1|14 33.36 cM Start 64,122,625 bp[2] End 64,455,903 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • oxidoreductase activity • peptide-methionine (S)-S-oxide reductase activity • L-methionine-(S)-S-oxide reductase activity Cellular component • extracellular exosome • cell nucleus • membrane • nucleoplasm • actin cytoskeleton • mitochondrion • cytoplasm • cytosol Biological process • methionine metabolic process • cellular protein modification process • oxidation-reduction process • response to oxidative stress • protein repair • cellular response to oxidative stress Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	4482	110265
Ensembl	ENSG00000175806 ENSG00000285250	ENSMUSG00000054733
UniProt	Q9UJ68	Q9D6Y7
RefSeq (mRNA)	NM_001135670 NM_001135671 NM_001199729 NM_012331	NM_001253712 NM_001253714 NM_001253715 NM_001253716 NM_026322 NM_001347639
RefSeq (protein)	NP_001129142 NP_001129143 NP_001186658 NP_036463	NP_001240641 NP_001240643 NP_001240644 NP_001240645 NP_001334568 NP_080598
Location (UCSC)	Chr 8: 10.05 – 10.43 Mb	Chr 14: 64.12 – 64.46 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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.[7] Its proposed function is thus the repair of oxidative damage to proteins to restore biological activity.[6] Oxidation of methionine residues in tissue proteins can cause them to misfold or otherwise render them dysfunctional.[7]

Clinical significance

MetO increases with age in body tissues, which is believed by some to contribute to biological ageing.[7][8] Moreover, levels of methionine sulfoxide reductase A (MsrA) decline in aging tissues in mice and in association with age-related disease in humans.[7] 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.[9] However, the effects of MsrA overexpression in mice were ambiguous.[10] 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.[10]

Deletion of this gene has been associated with insulin resistance in mice,[11] while overexpression reduces insulin resistance in old mice.[10]

See also

• MSRB2
• Methionine oxidation
• SEPX1

References

1. ENSG00000285250 GRCh38: Ensembl release 89: ENSG00000175806, ENSG00000285250 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000054733 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Kuschel L, Hansel A, Schonherr R, Weissbach H, Brot N, Hoshi T, Heinemann SH (Sep 1999). "Molecular cloning and functional expression of a human peptide methionine sulfoxide reductase (hMsrA)". FEBS Lett. 456 (1): 17–21. doi:10.1016/S0014-5793(99)00917-5. PMID 10452521.
6. "Entrez Gene: MSRA methionine sulfoxide reductase A".
7. Stadtman ER, Van Remmen H, Richardson A, Wehr NB, Levine RL (2005). "Methionine oxidation and aging". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1703 (2): 135–140. doi:10.1016/j.bbapap.2004.08.010. PMID 15680221.
8. Shringarpure R, Davies KJ (2002). "Protein turnover by the proteasome in aging and disease". Free Radical Biology & Medicine. 32 (11): 1084–1089. doi:10.1016/S0891-5849(02)00824-9. PMID 12031893.
9. Ruan H, Tang XD, Chen ML, Joiner ML, Sun G, Brot N, Weissbach H, Heinemann SH, Iverson L, Wu CF, Hoshi T (2002). "High-quality life extension by the enzyme peptide methionine sulfoxide reductase". Proceedings of the National Academy of Sciences of the United States of America. 99 (5): 2748–2753. doi:10.1073/pnas.032671199. PMC 122419. PMID 11867705.
10. Salmon AB, Kim G, Liu C, Wren JD, Georgescu C, Richardson A, Levine RL (December 2016). "Effects of transgenic methionine sulfoxide reductase A (MsrA) expression on lifespan and age-dependent changes in metabolic function in mice". Redox Biol. 10: 251–256. doi:10.1016/j.redox.2016.10.012. PMC 5099276. PMID 27821326.
11. Styskal JL, Nwagwu FA, Watkins YN, Liang H, Richardson A, Musi N, Salmon AB (October 2012). "Methionine sulfoxide reductase a affects insulin resistance by protecting insulin receptor function". Free Radic. Biol. Med. 56: 123–32. doi:10.1016/j.freeradbiomed.2012.10.544. PMC 3578155. PMID 23089224.

Further reading

• Hansel A, Heinemann SH, Hoshi T (2005). "Heterogeneity and function of mammalian MSRs: enzymes for repair, protection and regulation". Biochim. Biophys. Acta. 1703 (2): 239–47. doi:10.1016/j.bbapap.2004.09.010. PMID 15680232.
• Moskovitz J, Jenkins NA, Gilbert DJ, et al. (1996). "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. doi:10.1073/pnas.93.8.3205. PMC 39583. PMID 8622914.
• Hansel A, Kuschel L, Hehl S, et al. (2002). "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. doi:10.1096/fj.01-0737fje. PMID 12039877.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "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. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Vougier S, Mary J, Friguet B (2003). "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. doi:10.1042/BJ20030443. PMC 1223498. PMID 12693988.
• Picot CR, Perichon M, Cintrat JC, et al. (2004). "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. doi:10.1016/S0014-5793(03)01530-8. PMID 14759519.
• Kantorow M, Hawse JR, Cowell TL, et al. (2004). "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. doi:10.1073/pnas.0403532101. PMC 470730. PMID 15199188.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
• De Luca A, Sacchetta P, Di Ilio C, Favaloro B (2006). "Identification and analysis of the promoter region of the human methionine sulphoxide reductase A gene". Biochem. J. 393 (Pt 1): 321–9. doi:10.1042/BJ20050973. PMC 1383691. PMID 16162094.
• Picot CR, Petropoulos I, Perichon M, et al. (2006). "Overexpression of MsrA protects WI-38 SV40 human fibroblasts against H2O2-mediated oxidative stress". Free Radic. Biol. Med. 39 (10): 1332–41. doi:10.1016/j.freeradbiomed.2005.06.017. PMID 16257642.
• Lee JW, Gordiyenko NV, Marchetti M, et al. (2006). "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. doi:10.1016/j.exer.2005.10.003. PMC 2825745. PMID 16364291.
• Schallreuter KU, Rübsam K, Chavan B, et al. (2006). "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. doi:10.1016/j.bbrc.2006.01.124. PMID 16480945.
• Lei KF, Wang YF, Zhu XQ, et al. (2007). "Identification of MSRA gene on chromosome 8p as a candidate metastasis suppressor for human hepatitis B virus-positive hepatocellular carcinoma". BMC Cancer. 7: 172. doi:10.1186/1471-2407-7-172. PMC 2000900. PMID 17784942.