One of the known post-translation modifications of proteins is the oxidation of methionine residues to methionine sulfoxide [Met (O)]. An enzyme, peptide-methionine sulfoxide reductase (MsrA), which has been detected in virtually all organisms examined, catalyzes the reduction of free and protein-bound methionine sulfoxide residues to methionine. By its function, the enzyme can repair, to some extent, proteins damaged by reactive oxygen species (ROS). We have created a """"""""knock-out"""""""" mouse lacking the MsrA protein by disruption of the second exon of the msrA gene in which the putative active site resides. The homozygote mice (MT) are viable and do not show an obvious phenotype in comparison to the wild-type (WT) parent mice. However, tissue levels of oxidized proteins in MTs are higher than in WTs and the MTs are more sensitive to killing by 100% oxygen than the WTs, suggesting that the loss of MsrA increased the sensitivity to oxidative stress. Moreover, we have identified a compensatory system for the lack of MsrA activity, which is induced in the MT animals, and characterized its function in various tissues. The fact that such a system exists manifests the importance of the MsrA function. Further experiments are planned to investigate the role of the msrA gene and the alternative back-up system in aging using the MT mice as a study model. So far the oldest animals are only around 12 months old. It is expected with further aging that differences in the viability between the two strains of mice will become more pronounced.
| Moskovitz, J; Poston, J M; Berlett, B S et al. (2000) Identification and characterization of a putative active site for peptide methionine sulfoxide reductase (MsrA) and its substrate stereospecificity. J Biol Chem 275:14167-72 |
| Moskovitz, J; Berlett, B S; Poston, J M et al. (1999) Methionine sulfoxide reductase in antioxidant defense. Methods Enzymol 300:239-44 |
