Methionine oxidation, methionine sulfoxide reductases and the regulation of disease

Oxidative stress has been shown to be a major contributory factor in the etiology of many different diseases and perhaps even the aging process itself. While oxidative stress can affect all cellular macromolecules, oxidation of proteins may have the most dramatic effect. Oxidation of proteins can lead to aberrant or reduced function that, in turn, might directly cause cell, tissue, or organ dysfunction. Sulfur containing amino acids, like cysteine and methionine, are particularly prone to oxidation due to their structure. Methionine in particular can be readily oxidized to the reversible methionine sulfoxide moiety; methionine sulfoxide can be further oxidized to the non-reversible methionine sulfone. The antioxidant defense system has evolved to diminish oxidative stress and thereby reduce protein oxidation; in general however, antioxidants cannot repair oxidative damage. Methionine sulfoxide reductases (Msr) have evolved as a repair mechanism specifically for methionine residues, and hence, specifically can protect proteins from oxidative damage. Msr catalytically convert methionine sulfoxides back to the reduced methionine moiety in a NADPH-dependent reaction. Msr have also been implicated as powerful regulators of the progression of several different diseases and pathologies including neurodegeneration, obesity/diabetes, cardiac dysfunction and even the aging process itself. The goal of this review is to highlight the importance of Msr and methionine oxidation in disease in both the classical and most recent literature, and to point out the potential of Msr as a therapeutic for multiple disease states.