Current Pharmaceutical Design, 2004, 10, 000-000 1 1381-6128/04 $45.00+.00 © 2004 Bentham Science Publishers Ltd. Roles of Methionine Suldfoxide Reductases in Antioxidant Defense, Protein Regulation and Survival Jackob Moskovitz * The University of Kansas, Department of Pharmacology and Toxicology, School of Pharmacy, Lawrence, KS 66045- 7582, USA Abstract: One of the most oxidation-sensitive amino acids is methionine. Oxidation of methionine to methionine sulfoxide (MetO) could, on the one hand, be an important component of signal transduction pathways and on the other hand, may lower the cellular antioxidant capacity, alter protein function, interfere with signal transduction, and damage proteins. The latter changes could lead to the accumulation and malfunction of various proteins. As a result, enhanced development of certain diseases and signs of aging may occur. So far, two major enzymes that could reduce MetO in proteins have been described, denoted as MsrA and MsrB (Methionine sulfoxide reductases). In general, Msrs have been shown to be important in protecting cells from oxidative stress throughout many species from bacteria to mammals. In addition, the activities of certain enzymes could be restored or controlled following reduction of their MetO residues, through the Msr system. Of all Msrs, MsrA seems to be important in controlling MetO reduction in general and MsrB, thioredoxin reductase (Trr), and the adhesion capabilities of certain bacterial cells in particular. The recently discovered MsrB can reduce specifically the R-MetO enantiomer while MsrA can reduce specifically the S-MetO enantiomer. Another significant difference between MsrA and MsrB is that the latter’s major form in mammalian cells is a selenoprotein. The current review will discuss the major characteristics of methionine sulfoxide reductases as physiological antioxidants, repair systems, and cellular regulating enzymes. Key Words: Methionine oxidation, Methionine sulfoxide reductase, oxidative stress, Alzheimer’s, Parkinson’s, aging, antioxidants, and signal transduction. INTRODUCTION Methionine (Met) can be oxidized to methionine sul- foxide (MetO) by reactive oxygen species (ROS) resulting in two isomers: S-MetO and R-MetO. Most organisms have the potential for the expression of enzymes which can reduce both the S and R forms of MetO (either as free amino acid or as a protein–bound residue). Theses enzymatic reactions area catalyzed by methionine sulfoxide reductases (Msr), thioredoxin (Trx), thioredoxin reductase (Trr), and NADPH [1-3]. The Msr family of enzymes consists of two major Msr proteins: MsrA and MsrB that can reduce S-MetO and R- MetO, respectively [2-7]. Both MsrA and MsrB have been shown to protect bacterial and yeast cells from the cytotoxic effects of ROS and thereby preventing excessive accumu- lation of oxidized proteins and premature death [8-13]. Over- expression of MsrA in cultured human T cells enhanced their resistance to oxidative stress induced by hydrogen peroxide [14]. Likewise, over-expression of MsrA in flies’ brains increased their survival rate, especially under oxidative stress conditions [15]. Furthermore, disruption of the MsrA gene in mice has shortened their life span both under normoxic and hyperoxic conditions [16]. In addition to the ability of Msrs to protect cells/organisms from oxidative stress related damages, it has been shown that Msrs can also regulate protein activity by alternating it between active and non active form depending on a reversal of a specific MetO *Address correspondence to this author at The University of Kansas, Department of Pharmacology and Toxicology, School of Pharmacy, Lawrence, KS 66045-7582, USA; E-mail: moskovij@ku.edu residue to Met. Many proteins’ activities have been affected by their methionine/s residue/s oxidation, in-vitro [17]. However, so far only a few proteins have been monitored for their cellular function following Methionine-residue oxida- tion, in-vivo. For example: the potassium channel of the brain (as it is demonstrated in a semi in-vivo system [18]), α isoform of the inhibitory protein kB (IkBα) [19, 20], and calmodulin [21]. According to the latter examples, it is clear that methionine oxidation / reduction may play an important role in post-translation regulation of protein’s function in various biological systems, either directly or through signal transduction pathways. The major form of the mammalian MsrB enzyme has been found to be a selenoprotein [12, 13, 22] and its expression has been shown to be under the control of MsrA expression and selenium availability [23]. Similar controlling mechanisms have been shown to exist in the case of the selenoprotein-Trr expression, as well [16, 24, 25]. These findings suggest a key role for MsrA in control- ling MetO reduction in general and MsrB and Trr expression in particular, under certain conditions. In addition, the ability of selenium to affect both Trr and MsrB expression, suggests that selenium metabolism has a major contribution to the cellular ability of reducing MetO. MsrA and MsrB enzymes can reduce any methyl-sulfoxide compounds whereas free methionine sulfoxide reductases (FMsrs) can reduce only the free amino acid MetO [2, 3, 14, 26]. So far, the identities of these FMsrs proteins still remain unknown. In the current review, the possible roles of the various Msr enzymes as antioxidants, protein-function regulators, and possible means to protect organisms from aging associated diseases will be discussed.