Biochemistry and function of methionine sulfoxide reductase

Reactive oxygen species (ROS) oxidize methionine to a mixture of methionine-S-sulfoxide and methionine-R-sulfoxide. Methionine is also oxidized by various flavin-containing monooxygenases in a partially or fully stereospecific manner. Methionine sulfoxide can be reduced by methionine sulfoxide reductase (Msr) proteins in four different families. Both free and protein-based forms of methionine-S-sulfoxide are reduced by MsrA, whereas protein-based methionine-R-sulfoxide is reduced by MsrB. Among the three known mammalian MsrBs, only MsrB1 is a selenoprotein, containing a selenocysteine residue in place of the catalytic cysteine. Free methionine-R-sulfoxide reductase (fRMsr) reduces methionine-R-sulfoxide in the free, but not protein-based state, and is found only in unicellular organisms, whereas MsrA and MsrB are present in organisms in all three kingdoms of life. MsrP reduces both methionine-S-sulfoxide and methionine-R-sulfoxide, particularly in membrane-embedded proteins, with assistance from MsrQ, which is involved in electron transport in the mitochondrial respiratory chain. MsrP cannot utilize thioredoxin as a reducing agent. Msrs are oxidoreductases that protect against the effects of oxidative stress by increasing oxidative stress resistance and repairing damaged proteins via cyclic methionine oxidation/reduction. In addition to its two main functions, MsrB1 reversibly regulates actin assembly in conjunction with Mical, making methionine oxidation similar to other reversible posttranslational modifications. This finding highlights a new era in the understanding of Msr function and should facilitate further studies of the physiological role of Msrs.