Summary of the probe development effort to identify inhibitors of Methionine sulfoxide reductase A (MSRA)
Name: Summary of the probe development effort to identify inhibitors of Methionine sulfoxide reductase A (MSRA). ..more
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center (SRIMSC)
Affiliation: The Scripps Research Institute, TSRI
Assay Provider: Herbert Weissbach, Florida Atlantic University
Network: Molecular Library Probe Production Centers Network (MLPCN)
Grant Proposal Number: 1R03DA032473-01
Grant Proposal PI: Herbert Weissbach, Florida Atlantic University
External Assay ID: MSRA_INH_SUMMARY
Name: Summary of the probe development effort to identify inhibitors of Methionine sulfoxide reductase A (MSRA).
Oxidative damage, resulting from the production of reactive oxygen species (ROS) within cells, is believed to be a major factor in age-related diseases and the aging process. One of the mechanisms by which this damage occurs is via oxidation of methionine residues to methionine sulfoxide (Met(O)) derivatives in cellular proteins, which can lead to protein inactivation (1). These Met(O) species can be repaired/reduced by the thioredoxin (Trx)-dependent (2, 3) action of Methionine sulfoxide reductase A (MSRA) (4, 5). MSRA can reduce both free and protein-bound Met(O), and is highly expressed in oxidant-sensitive tissues such as kidney (6), neurons (7), liver(8), retinal epithelial cells (9), and macrophages (10). Each round of methionine oxidation and reduction by the MSRA system destroys one equivalent of ROS (11). Importantly, the action of MSRA has been shown to prevent irreversible oxidative protein damage and extend life span of both flies and yeast (12-14). As a result, the identification of compounds that modulate MSRA activity could have therapeutic value for cardiovascular (15, 16), neurodegenerative, lung (17), and eye diseases (18) involving oxidative damage. Similarly, because MSRA is found in virtually all species (19), and the catalytic mechanism has been elucidated (1, 20, 21), the identification of chemical tools that modulate MSRA would help elucidate its function and activation in cells, and may lead to useful tools to extend lifespan and reduce aging-related diseases (11).
Summary of Probe Development Effort:
This probe development effort is focused on the identification of inhibitors of Methionine sulfoxide reductase A (MSRA). All AIDs that contain results associated with this project can be found in the "Related Bioassays" section of this Summary AID.
1. Lowther, W.T., N. Brot, H. Weissbach, and B.W. Matthews, Structure and mechanism of peptide methionine sulfoxide reductase, an "anti-oxidation" enzyme. Biochemistry, 2000. 39(44): p. 13307-12.
2. Lowther, W.T., N. Brot, H. Weissbach, J.F. Honek, and B.W. Matthews, Thiol-disulfide exchange is involved in the catalytic mechanism of peptide methionine sulfoxide reductase. Proc Natl Acad Sci U S A, 2000. 97(12): p. 6463-8.
3. Sagher, D., D. Brunell, J.F. Hejtmancik, M. Kantorow, N. Brot, and H. Weissbach, Thionein can serve as a reducing agent for the methionine sulfoxide reductases. Proc Natl Acad Sci U S A, 2006. 103(23): p. 8656-61.
4. Weissbach, H., L. Resnick, and N. Brot, Methionine sulfoxide reductases: history and cellular role in protecting against oxidative damage. Biochim Biophys Acta, 2005. 1703(2): p. 203-12.
5. Weissbach, H., F. Etienne, T. Hoshi, S.H. Heinemann, W.T. Lowther, B. Matthews, G. St John, C. Nathan, and N. Brot, Peptide methionine sulfoxide reductase: structure, mechanism of action, and biological function. Arch Biochem Biophys, 2002. 397(2): p. 172-8.
6. Moskovitz, J., H. Weissbach, and N. Brot, Cloning the expression of a mammalian gene involved in the reduction of methionine sulfoxide residues in proteins. Proc Natl Acad Sci U S A, 1996. 93(5): p. 2095-9.
7. Yermolaieva, O., R. Xu, C. Schinstock, N. Brot, H. Weissbach, S.H. Heinemann, and T. Hoshi, Methionine sulfoxide reductase A protects neuronal cells against brief hypoxia/reoxygenation. Proc Natl Acad Sci U S A, 2004. 101(5): p. 1159-64.
8. Vougier, S., J. Mary, and B. Friguet, Subcellular localization of methionine sulphoxide reductase A (MsrA): evidence for mitochondrial and cytosolic isoforms in rat liver cells. Biochem J, 2003. 373(Pt 2): p. 531-7.
9. Marchetti, M.A., G.O. Pizarro, D. Sagher, C. Deamicis, N. Brot, J.F. Hejtmancik, H. Weissbach, and M. Kantorow, Methionine sulfoxide reductases B1, B2, and B3 are present in the human lens and confer oxidative stress resistance to lens cells. Invest Ophthalmol Vis Sci, 2005. 46(6): p. 2107-12.
10. Moskovitz, J., N.A. Jenkins, D.J. Gilbert, N.G. Copeland, F. Jursky, H. Weissbach, and N. Brot, Chromosomal localization of the mammalian peptide-methionine sulfoxide reductase gene and its differential expression in various tissues. Proc Natl Acad Sci U S A, 1996. 93(8): p. 3205-8.
11. Brunell, D., H. Weissbach, P. Hodder, and N. Brot, A high-throughput screening compatible assay for activators and inhibitors of methionine sulfoxide reductase A. Assay Drug Dev Technol, 2010. 8(5): p. 615-20.
12. Moskovitz, J., E. Flescher, B.S. Berlett, J. Azare, J.M. Poston, and E.R. Stadtman, 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 U S A, 1998. 95(24): p. 14071-5.
13. Moskovitz, J., B.S. Berlett, J.M. Poston, and E.R. Stadtman, The yeast peptide-methionine sulfoxide reductase functions as an antioxidant in vivo. Proc Natl Acad Sci U S A, 1997. 94(18): p. 9585-9.
14. Ruan, H., X.D. Tang, M.L. Chen, M.L. Joiner, G. Sun, N. Brot, H. Weissbach, S.H. Heinemann, L. Iverson, C.F. Wu, and T. Hoshi, High-quality life extension by the enzyme peptide methionine sulfoxide reductase. Proc Natl Acad Sci U S A, 2002. 99(5): p. 2748-53.
15. Haenold, R., R. Wassef, N. Brot, S. Neugebauer, E. Leipold, S.H. Heinemann, and T. Hoshi, Protection of vascular smooth muscle cells by over-expressed methionine sulphoxide reductase A: role of intracellular localization and substrate availability. Free Radic Res, 2008. 42(11-12): p. 978-88.
16. Shao, B., G. Cavigiolio, N. Brot, M.N. Oda, and J.W. Heinecke, Methionine oxidation impairs reverse cholesterol transport by apolipoprotein A-I. Proc Natl Acad Sci U S A, 2008. 105(34): p. 12224-9.
17. Ogawa, F., K. Shimizu, T. Hara, E. Muroi, K. Komura, M. Takenaka, M. Hasegawa, M. Fujimoto, K. Takehara, and S. Sato, Autoantibody against one of the antioxidant repair enzymes, methionine sulfoxide reductase A, in systemic sclerosis: association with pulmonary fibrosis and vascular damage. Arch Dermatol Res, 2010. 302(1): p. 27-35.
18. Brennan, L.A., W. Lee, T. Cowell, F. Giblin, and M. Kantorow, Deletion of mouse MsrA results in HBO-induced cataract: MsrA repairs mitochondrial cytochrome c. Mol Vis, 2009. 15: p. 985-99.
19. Delaye, L., A. Becerra, L. Orgel, and A. Lazcano, Molecular evolution of peptide methionine sulfoxide reductases (MsrA and MsrB): on the early development of a mechanism that protects against oxidative damage. J Mol Evol, 2007. 64(1): p. 15-32.
20. Boschi-Muller, S., S. Azza, S. Sanglier-Cianferani, F. Talfournier, A. Van Dorsselear, and G. Branlant, A sulfenic acid enzyme intermediate is involved in the catalytic mechanism of peptide methionine sulfoxide reductase from Escherichia coli. J Biol Chem, 2000. 275(46): p. 35908-13.
21. Taylor, A.B., D.M. Benglis, Jr., S. Dhandayuthapani, and P.J. Hart, Structure of Mycobacterium tuberculosis methionine sulfoxide reductase A in complex with protein-bound methionine. J Bacteriol, 2003. 185(14): p. 4119-26.
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