Methionine sulfoxide reductases (MsrA and MsrB) are repair enzymes that reduce methionine sulfoxide (Met(O)) residues in proteins to methionine (Met) in a stereospecific manner. These enzymes protect cells from oxidative stress and have been implicated in delaying the aging process and progression of neurodegenerative diseases. Mammals possess one MsrA and three MsrBs. The major mammalian MsrB, MsrB1, is a selenocysteine-containing protein, whose expression and activity can be regulated by dietary selenium. Little is known about Met oxidation and repair in vivo and about identities of molecular targets of methionine sulfoxide reductases. We propose to address deficiencies in our understanding of Met(O) formation and reduction and its relevance to aging by functionally characterizing MsrA and MsrB and determining their potential for extending lifespan in animals.
Specific Aim 1 is to characterize the pathway of Met(O) formation and reduction and biological functions of MsrA and MsrBs. We will determine spatial and temporal characteristics of Met oxidation and repair, identify proteins and Met residues in these proteins that are oxidized by reactive oxygen species and repaired by MsrA and MsrBs, and determine the contributions of MsrA and MsrBs to providing Met for mammalian cells. For this purpose, we will prepare new molecular tools to monitor Met(O) and will utilize them in cellular and organismal systems with altered MsrA and MsrB levels, selenium status, susceptibility to oxidative stress, and with different age of animals.
Specific Aim 2 is to characterize the roles of methionine sulfoxide reductases in aging. Using fruit flies, we will determine which MsrB forms can extend lifespan and which factors are responsible for MsrB-dependent lifespan extension. In addition, we will examine a possibility that a combination of calorie restriction and selenium supplementation increases lifespan in mice. Our previous data and preliminary results suggest feasibility of these studies.
Oxidative damage to proteins is considered to be one of the major factors that lead to or accompany aging. This damage results from the oxidation of certain amino acid residues, among which methionine is notable because of its abundance and susceptibility to oxidation and reductive repair. Methionine sulfoxide reductases, MsrA and MsrB, are thioredoxin-dependent oxidoreductases that reduce the oxidized forms of methionine, methionine sulfoxides, to methionine in a stereospecific manner. These enzymes protect cells from oxidative stress and have been implicated in delaying the aging process and progression of neurodegenerative diseases. Mammals have one MsrA and three MsrBs, including MsrB1, a highly active selenocysteine- containing enzyme, whose expression and activity can be regulated by dietary selenium. We propose to address critical deficiencies in our understanding of methionine sulfoxide formation and reduction and its relevance to aging by functionally characterizing MsrA and MsrB and determining their potential for extending lifespan in animals.
|Podolskiy, Dmitriy I; Gladyshev, Vadim N (2016) Intrinsic Versus Extrinsic Cancer Risk Factors and Aging. Trends Mol Med 22:833-834|
|Lee, Byung Cheon; Kaya, Alaattin; Gladyshev, Vadim N (2016) Methionine restriction and life-span control. Ann N Y Acad Sci 1363:116-24|
|PÃ©terfi, ZalÃ¡n; Tarrago, Lionel; Gladyshev, Vadim N (2016) Practical guide for dynamic monitoring of protein oxidation using genetically encoded ratiometric fluorescent biosensors of methionine sulfoxide. Methods 109:149-157|
|Tian, Xiao; Azpurua, Jorge; Ke, Zhonghe et al. (2015) INK4 locus of the tumor-resistant rodent, the naked mole rat, expresses a functional p15/p16 hybrid isoform. Proc Natl Acad Sci U S A 112:1053-8|
|Ma, Siming; Yim, Sun Hee; Lee, Sang-Goo et al. (2015) Organization of the Mammalian Metabolome according to Organ Function, Lineage Specialization, and Longevity. Cell Metab 22:332-43|
|Kaya, Alaattin; Lee, Byung Cheon; Gladyshev, Vadim N (2015) Regulation of protein function by reversible methionine oxidation and the role of selenoprotein MsrB1. Antioxid Redox Signal 23:814-22|
|Ma, Siming; Lee, Sang-Goo; Kim, Eun Bae et al. (2015) Organization of the Mammalian Ionome According to Organ Origin, Lineage Specialization, and Longevity. Cell Rep 13:1319-26|
|Kaya, Alaattin; Ma, Siming; Wasko, Brian et al. (2015) Defining Molecular Basis for Longevity Traits in Natural Yeast Isolates. NPJ Aging Mech Dis 1:|
|Tarrago, Lionel; PÃ©terfi, ZalÃ¡n; Lee, Byung Cheon et al. (2015) Monitoring methionine sulfoxide with stereospecific mechanism-based fluorescent sensors. Nat Chem Biol 11:332-8|
|Hine, Christopher; Harputlugil, Eylul; Zhang, Yue et al. (2015) Endogenous hydrogen sulfide production is essential for dietary restriction benefits. Cell 160:132-44|
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