Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
ReviewMethionine sulfoxide reductases: history and cellular role in protecting against oxidative damage
Section snippets
Early History
An enzyme that could reduce methionine sulfoxide (Met(o)) to methionine (Met) in proteins was discovered almost 25 years ago in studies on the biological activity of the Escherichia coli ribosomal protein, L12 [1]. These initial studies showed that L12 lost its biological activity due to the oxidation of one or more of the three Met residues in the protein to Met(o) [2]. Chemical reduction of the Met(o) residues back to met resulted in the restoration of activity. This protein was known to
Structure and mechanism of action of MsrA
By the early 1990s it became clear that it would be necessary to clone the MsrA gene in order to learn more about the structure of the protein and its possible role in cells. The E. coli MsrA gene was initially cloned and expressed [17] and soon afterwards the bovine MsrA gene was also cloned [18]. It then became possible to obtain large amounts of bacterial and mammalian MsrA to perform structural and genetic studies. The E. coli, bovine and Mycobacterium tuberculosis MsrA proteins have been
Evidence that MsrA can protect cells against oxidative damage
Table 2 summarizes experiments from several laboratories that show the effect of either knocking out the MsrA gene or overexpressing the gene in cells and organisms. The first evidence that MsrA might have an important function in vivo came from studies with an MsrA mutant of E. coli [27]. Although this organism showed no phenotype under normal growth conditions, it was markedly sensitive to hydrogen peroxide using a semiquantitative filter disc assay [27]. These experiments were later
Studies on PilB: identification of MsrB
When it became clear that MsrA specifically reduces the S form of both peptide-bound and free Met(o) [18], [38], it was apparent that there must be another protein(s) that could reduce the R form of Met(o) in proteins, since oxidation of Met in proteins by ROS would be expected to yield an equal mixture of both the R and S forms (See Fig. 1). The identification of MsrB came from studies of the N. gonorrhoeae PilB protein which has a region homologous to MsrA from other species. This protein is
Repair and scavenger function of the Msr system
Initially it was felt that the Msr system was acting as a repair mechanism to reverse damage to proteins whose met residues had been oxidized. This seemed reasonable since a large number of proteins had been shown to have altered biological activity upon Met oxidation, which could be partially restored by incubation with MsrA (Table 1). The possibility that the Msr system could function to destroy ROS was first noted by Levine et al. [46], in studies on glutamine synthetase. They pointed out
Other members of the Msr family
In E. coli it appears that there are at least six members of the Msr family, which differ in their substrate specificity (free Met(o) and/or peptide bound Met(o)), stereospecificity (R or S) and location (soluble or membrane bound). The characteristics of the different E. coli Msr members are summarized in Table 4.
The two Msr members most studied are MsrA, which reduces both free and peptide bound Met-S-(o), and MsrB, which reduces peptide Met-R-(o), but has only very low activity towards free
Msr activity against Sulindac, a drug containing a methyl sulfoxide moiety
Although the primary interest in the Msr system has centered about its potential roles as a repair system for Met(o) in protein and scavenger of ROS, it has been shown that MsrA can reduce methyl sulfoxide groups in a wide variety of compounds [18]. One example is sulindac (sul, Fig. 6A) which is a methyl sulfoxide-containing prodrug that must be reduced to the sulfide (suls, Fig. 6B) to be active as an inhibitor of cyclooxygenases 1 and 2 and exert anti-inflammatory activity [52]. Sul and
Creation of novel catalytic anti-oxidants based on the Msr system
Sul could function both as an anti-inflammatory drug, since it is an inhibitor of COX-1 and COX-2, and as a potential catalytic anti-oxidant, since it is a substrate for MsrA. Each round of sul reduction to suls, followed by oxidation of suls by ROS, would destroy 1 equivalent of ROS. However, the catalytic anti-oxidant ability of sul is limited because it is not a substrate for MsrB. We would like to obtain derivatives of sul and other NSAIDs that would be substrates for both MsrA and MsrB.
Concluding remarks
Cells use two general mechanisms to protect themselves against oxidative damage due to ROS. These damaging species can be destroyed through the activity of enzymes such as catalase, superoxide dismutase and glutathione peroxidase. In addition, cells have repair mechanisms to reverse damage done to macromolecules. The Msr system is unique in that it may function both as a repair system and also as a scavenger of ROS. The concept that met residues in proteins may function as catalytic
Acknowledgements
This contribution is number P200406 from the Center of Excellence in Biomedical and Marine Biotechnology, which funded part of these studies.
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2021, Insect Biochemistry and Molecular BiologyCitation Excerpt :While MsrA and MsrB possess divergent amino acid sequences and are structurally unrelated (Lowther et al., 2002), their active sites show approximate mirror symmetry and both share common catalytic mechanisms at the expense of NADPH through the thioredoxin (Trx) or glutaredoxin (Grx) systems (Lowther et al., 2002; Bigelow and Squier, 2011; Kim, 2012; Lourenço Dos Santos et al., 2018). Like other antioxidant enzymes, Msrs play important roles in protecting against oxidative stress in various organisms ranging from bacteria to mammals (Weissbach et al., 2005; Drazic and Winter 2014). For example, overexpressing MsrA conferred increased resistance to paraquat-induced oxidative stress and a markedly extended lifespan in Drosophila (Ruan et al., 2002).