While the roles of cysteine as an antioxidant and in cell signaling are widely appreciated, only recently has it been recognized that methionine, like cysteine, functions as an antioxidant and as a key component of a system for regulation of cellular metabolism. The efficiency of methionine as an antioxidant or as a component of signaling systems depends on its ready interconversion between the reduced form (methionine) and the oxidized form (methionine sulfoxide). Methionine sulfoxide reductase catalyzes the reduction of methionine sulfoxide back to methionine. Our studies of methionine sulfoxide reductase A have established: One gene encodes the protein, targeting it to both the cytosol and the mitochondria through two protein initiation sites. The cytosolic form of the reductase is myristoylated, an unexpected covalent modification. The myristoylated protein does not translocate to the membrane, suggesting a new function for myristoylation. Solving the solution structure of the myristoylated enzyme revealed a novel binding pocket for the myristoyl group, the myristoyl nest. We showed that it serves to promote protein-protein interaction. The enzyme was known to be a stereospecific methionine sulfoxide reductase, but a partner oxidase which could form a signaling system had been elusive. We showed that the reductase is bifunctional;it is also a stereospecific oxidase. Overexpression of cytosolic, myristoylated reductase protects the heart from ischemia-perfusion mediated damage. The mechanism of protection has not yet been elucidated.

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National Heart, Lung, and Blood Institute
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Kim, Geumsoo; Levine, Rodney L (2016) A Methionine Residue Promotes Hyperoxidation of the Catalytic Cysteine of Mouse Methionine Sulfoxide Reductase A. Biochemistry 55:3586-93
Werner-Allen, Jon W; DuMond, Jenna F; Levine, Rodney L et al. (2016) Toxic Dopamine Metabolite DOPAL Forms an Unexpected Dicatechol Pyrrole Adduct with Lysines of α-Synuclein. Angew Chem Int Ed Engl 55:7374-8
Uehara, Hiroshi; Luo, Shen; Aryal, Baikuntha et al. (2016) Distinct oxidative cleavage and modification of bovine [Cu- Zn]-SOD by an ascorbic acid/Cu(II) system: Identification of novel copper binding site on SOD molecule. Free Radic Biol Med 94:161-73
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Kim, Geumsoo; Weiss, Stephen J; Levine, Rodney L (2014) Methionine oxidation and reduction in proteins. Biochim Biophys Acta 1840:901-5
Maltsev, Alexander S; Chen, Jue; Levine, Rodney L et al. (2013) Site-specific interaction between ýý-synuclein and membranes probed by NMR-observed methionine oxidation rates. J Am Chem Soc 135:2943-6
Liu, Xiong; Lee, Duck-Yeon; Cai, Shutao et al. (2013) Regulation of the actin-activated MgATPase activity of Acanthamoeba myosin II by phosphorylation of serine 639 in motor domain loop 2. Proc Natl Acad Sci U S A 110:E23-32
Zhao, Hang; Kim, Geumsoo; Levine, Rodney L (2012) Methionine sulfoxide reductase contributes to meeting dietary methionine requirements. Arch Biochem Biophys 522:37-43
Wehr, Nancy B; Levine, Rodney L (2012) Wanted and wanting: antibody against methionine sulfoxide. Free Radic Biol Med 53:1222-5

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