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BBA - Proteins and Proteomics (v.1703, #2)
The oxidative environment and protein damage by Michael J. Davies (pp. 93-109).
Proteins are a major target for oxidants as a result of their abundance in biological systems, and their high rate constants for reaction. Kinetic data for a number of radicals and non-radical oxidants (e.g. singlet oxygen and hypochlorous acid) are consistent with proteins consuming the majority of these species generated within cells. Oxidation can occur at both the protein backbone and on the amino acid side-chains, with the ratio of attack dependent on a number of factors. With some oxidants, damage is limited and specific to certain residues, whereas other species, such as the hydroxyl radical, give rise to widespread, relatively non-specific damage. Some of the major oxidation pathways, and products formed, are reviewed. The latter include reactive species, such as peroxides, which can induce further oxidation and chain reactions (within proteins, and via damage transfer to other molecules) and stable products. Particular emphasis is given to the oxidation of methionine residues, as this species is readily oxidised by a wide range of oxidants. Some side-chain oxidation products, including methionine sulfoxide, can be employed as sensitive, specific, markers of oxidative damage. The product profile can, in some cases, provide valuable information on the species involved; selected examples of this approach are discussed. Most protein damage is non-repairable, and has deleterious consequences on protein structure and function; methionine sulfoxide formation can however be reversed in some circumstances. The major fate of oxidised proteins is catabolism by proteosomal and lysosomal pathways, but some materials appear to be poorly degraded and accumulate within cells. The accumulation of such damaged material may contribute to a range of human pathologies.
Keywords: Protein oxidation; Free radical; Oxidant; Fragmentation; Cross-linking; Methionine; Methionine sulfoxide
Methionine oxidation by reactive oxygen species: reaction mechanisms and relevance to Alzheimer's disease by Christian Schöneich (pp. 111-119).
The oxidation of methionine plays an important role in vivo, during biological conditions of oxidative stress, as well as for protein stability in vitro. Depending on the nature of the oxidizing species, methionine may undergo a two-electron oxidation to methionine sulfoxide or one-electron oxidation to methionine radical cations. Both reaction mechanisms derive catalytic support from neighboring groups, which stabilize electron-deficient reaction centers. In vivo, methionine sulfoxide is subject to reduction by the methionine sulfoxide reductase (Msr) system, suggesting that some methionine sulfoxide residues may only be transiently involved in the deactivation of proteins through reactive oxygen species (ROS). Other methionine sulfoxide residues may accumulate, depending on the accessibility to Msr. Moreover, methionine sulfoxide levels may increase as a result of a lower abundance of active Msr and/or the required cofactors as a consequence of pathologies and biological aging. On the other hand, methionine radical cations will enter predominantly irreversible reaction channels, which ultimately yield carbon-centered and/or peroxyl radicals. These may become starting points for chain reactions of protein oxidation. This review will provide detailed mechanistic schemes for the reactions of various prominent, biologically relevant ROS with methionine and organic model sulfides. Emphasis will be given on the one-electron oxidation pathway, characterizing the physico-chemical parameters, which control this mechanism, and its physiological relevance, specifically for the oxidation and neurotoxicity of the Alzheimer's disease β-amyloid peptide (βAP).
Keywords: Methionine; Methionine sulfoxide; Sulfide radical cation; One-electron oxidation; Hydroxyl radical; β-Amyloid; Alzheimer's disease; Aging
Redox modulation of cellular signaling and metabolism through reversible oxidation of methionine sensors in calcium regulatory proteins by Diana J. Bigelow; Thomas C. Squier (pp. 121-134).
Adaptive responses associated with environmental stressors are critical to cell survival. Under conditions when cellular redox and antioxidant defenses are overwhelmed, the selective oxidation of critical methionines within selected protein sensors functions to down-regulate energy metabolism and the further generation of reactive oxygen species (ROS). Mechanistically, these functional changes within protein sensors take advantage of the helix-breaking character of methionine sulfoxide. The sensitivity of several calcium regulatory proteins to oxidative modification provides cellular sensors that link oxidative stress to cellular response and recovery. Calmodulin (CaM) is one such critical calcium regulatory protein, which is functionally sensitive to methionine oxidation. Helix destabilization resulting from the oxidation of either Met144 or Met145 results in the nonproductive association between CaM and target proteins. The ability of oxidized CaM to stabilize its target proteins in an inhibited state with an affinity similar to that of native (unoxidized) CaM permits this central regulatory protein to function as a cellular rheostat that down-regulates energy metabolism in response to oxidative stress. Likewise, oxidation of a methionine within a critical switch region of the regulatory protein phospholamban is expected to destabilize the phosphorylation-dependent helix formation necessary for the release of enzyme inhibition, resulting in a down-regulation of the Ca-ATPase in response to β-adrenergic signaling in the heart. We suggest that under acute conditions, such as inflammation or ischemia, these types of mechanisms ensure minimal nonspecific cellular damage, allowing for rapid restoration of cellular function through repair of oxidized methionines by methionine sulfoxide reductases and degradation pathways after restoration of normal cellular redox conditions.
Keywords: Methionine oxidation; Calmodulin; Signal transduction; Calcium regulation; Methionine sulfoxide reductase; Cellular metabolism
Methionine oxidation and aging by Earl R. Stadtman; Holly Van Remmen; Arlan Richardson; Nancy B. Wehr; Rodney L. Levine (pp. 135-140).
It is well established that many amino acid residues of proteins are susceptible to oxidation by various forms of reactive oxygen species (ROS), and that oxidatively modified proteins accumulate during aging, oxidative stress, and in a number of age-related diseases. Methionine residues and cysteine residues of proteins are particularly sensitive to oxidation by ROS. However, unlike oxidation of other amino acid residues, the oxidation of these sulfur amino acids is reversible. Oxidation of methionine residues leads to the formation of both R- and S-stereoisomers of methionine sulfoxide (MetO) and most cells contain stereospecific methionine sulfoxide reductases (Msr's) that catalyze the thioredoxin-dependent reduction of MetO residues back to methionine residues. We summarize here results of studies, by many workers, showing that the MetO content of proteins increases with age in a number of different aging models, including replicative senescence and erythrocyte aging, but not in mouse tissues during aging. The change in levels of MetO may reflect alterations in any one or more of many different mechanisms, including (i) an increase in the rate of ROS generation; (ii) a decrease in the antioxidant capacity; (iii) a decrease in proteolytic activities that preferentially degrade oxidized proteins; or (iv) a decrease in the ability to convert MetO residues back to Met residues, due either to a direct loss of Msr enzyme levels or indirectly to a loss in the availability of the reducing equivalents (thioredoxin, thioredoxin reductase, NADPH generation) involved. The importance of Msr activity is highlighted by the fact that aging is associated with a loss of Msr activities in a number of animal tissues, and mutations in mice leading to a decrease in the Msr levels lead to a decrease in the maximum life span, whereas overexpression of Msr leads to a dramatic increase in the maximum life span.
Keywords: Methionine sulfoxide; Methionine; Methionine sulfoxide reductase; Aging
Structural and functional consequences of methionine oxidation in thrombomodulin by Matthew J. Wood; Judith Helena Prieto; Elizabeth A. Komives (pp. 141-147).
Thrombomodulin (TM) is an endothelial cell surface glycoprotein that is responsible for switching the catalytic activity of thrombin away from fibrinogen cleavage (pro-coagulant) and towards protein C cleavage (anticoagulant). Although TM is a large protein, only the fourth and fifth epidermal growth factor-like (EGF-like) domains are required for anticoagulant function. These two domains must work together, and the linker between the two domains contains a single methionine residue, Met 388. Oxidation of Met 388 is deleterious for TM activity. Structural studies, both X-ray and NMR, of wild type and variants at position 388 show that Met 388 provides a key linkage between the two domains. Oxidation of the methionine has consequences for the structure of the fifth domain, which binds to thrombin. Oxidation also appears to disrupt the interdomain contacts resulting in structural and dynamic changes. The functional consequences of oxidation of Met 388 include decreased anticoagulant activity. Oxidative stress from several causes is reflected in lower serum levels of activated protein C and a higher thrombotic tendency, and this is thought to be linked to the oxidation of Met 388 in TM. Thus, TM structure and function are altered in a subtle but functionally critical way upon oxidation of Met 388.
Keywords: Anticoagulant; Protein C; Thrombin; Coagulation; NMR; EGF domain
The critical role of methionine 35 in Alzheimer's amyloid β-peptide (1–42)-induced oxidative stress and neurotoxicity by D. Allan Butterfield; Debra Boyd-Kimball (pp. 149-156).
Amyloid beta-peptide (1–42) [Aβ(1–42)] has been proposed to play a central role in the pathogenesis of Alzheimer's disease, a neurodegenerative disorder associated with cognitive decline and aging. AD brain is under extensive oxidative stress, and Aβ(1–42) has been shown to induce protein oxidation, lipid peroxidation, and reactive oxygen species formation in neurons and synaptosomes, all of which are inhibited by the antioxidant vitamin E. Additional studies have shown that Aβ(1–42) induces oxidative stress when expressed in vivo in Caenorhabditis elegans, but when methionine 35 is replaced by cysteine, the oxidative stress is attenuated. This finding coupled with in vitro studies using mutant peptides have demonstrated a critical role for methionine 35 in the oxidative stress and neurotoxic properties of Aβ(1–42). In this review, we discuss the role of methionine 35 in the oxidative stress and neurotoxicity induced by Aβ(1–42) and the implications of these findings in the pathogenesis of AD.
Keywords: Amyloid beta-peptide; Alzheimer's disease; Oxidative stress; including protein oxidation and lipid peroxidation; Methionine
Methionine oxidation, α-synuclein and Parkinson's disease by Charles B. Glaser; Ghiam Yamin; Vladimir N. Uversky; Anthony L. Fink (pp. 157-169).
The aggregation of normally soluble α-synuclein in the dopaminergic neurons of the substantia nigra is a crucial step in the pathogenesis of Parkinson's disease. Oxidative stress is believed to be a contributing factor in this disorder. Because it lacks Trp and Cys residues, mild oxidation of α-synuclein in vitro with hydrogen peroxide selectively converts all four methionine residues to the corresponding sulfoxides. Both oxidized and non-oxidized α-synucleins have similar unfolded conformations; however, the fibrillation of α-synuclein at physiological pH is completely inhibited by methionine oxidation. The inhibition results from stabilization of soluble oligomers of Met-oxidized α-synuclein. Furthermore, the Met-oxidized protein also inhibits fibrillation of unmodified α-synuclein. The degree of inhibition of fibrillation by Met-oxidized α-synuclein is proportional to the number of oxidized methionines. However, the presence of metals can completely overcome the inhibition of fibrillation of the Met-oxidized α-synuclein. Since oligomers of aggregated α-synuclein may be cytotoxic, these findings indicate that both oxidative stress and environmental metal pollution could play an important role in the aggregation of α-synuclein, and hence possibly Parkinson's disease. In addition, if the level of Met-oxidized α-synuclein was under the control of methionine sulfoxide reductase (Msr), then this could also be factor in the disease.
Keywords: Methionine oxidation; α-Synuclein; Parkinson's disease
Formation of methionine sulfoxide-containing specific forms of oxidized high-density lipoproteins by Ute Panzenböck; Roland Stocker (pp. 171-181).
Atherosclerosis is characterized by the accumulation of both lipoprotein-derived lipids and inflammatory cells in the affected vascular wall that results in a state of heightened oxidative stress and that is reflected by the accumulation of oxidized lipoproteins. Circulating oxidized low-density lipoprotein (oxLDL) is used as a surrogate marker for coronary artery disease, although the ‘escape’ of oxLDL from the vessel wall is hindered by the large size of this lipoprotein and its specific retention by the extracellular matrix. Also, the oxidation of lipoproteins in human atherosclerotic lesions is not limited to LDL. In fact, the lipids of all classes of lipoproteins are oxidized to a comparable extent. Examining the fate of lipid hydroperoxides, the primary lipid peroxidation products, in high-density lipoproteins (HDL) undergoing oxidation, revealed that they become reduced to the corresponding alcohols by specific Met residues of apolipoprotein A-I (apoA-I) and apoA-II. As a consequence, Met residues in apoA-I and apoA-II become selectively and consecutively oxidized to their respective Met sulfoxide (MetO) forms that can be separated by HPLC. This review describes the characterization of specifically oxidized HDL with an emphasis on MetO formation, the structural and functional consequences of such oxidation, and the potential utility of specifically oxidized HDL as a surrogate marker of atherosclerosis.
Keywords: Lipoprotein; Oxidation; Atherosclerosis; Surrogate marker; Protein oxidation
Potential roles of flavin-containing monooxygenases in sulfoxidation reactions ofl-methionine, N-acetyl-l-methionine and peptides containingl-methionine by Adnan A. Elfarra; Renee J. Krause (pp. 183-189).
Flavin-containing monooxygenases (FMOs) are microsomal enzymes that catalyze the NADPH-dependent oxidation of a large number of sulfur-, selenium-, and nitrogen-containing compounds. Five active isoforms (FMO1–5) have been identified and shown to be differently expressed in various mammalian tissues. Previous work from this laboratory has shownl-methionine to be S-oxidized by rat, rabbit and human FMO1–4, with FMO3 exhibiting the highest stereoselectivity for the formation of the d-diastereomer of methionine sulfoxide. In this report, we describe new studies aimed at determining if N-acetyl-l-methionine and peptides containingl-methionine can be substrates for FMOs. Experiments were carried out using either rabbit liver microsomes or human cDNA-expressed FMOs. The results show that while N-acetyl-l-methionine and peptides with a modified methionine amino group may not function as substrates for FMOs, peptides containing a free N-terminal methionine may act as FMO substrates. With human cDNA-expressed FMO1, FMO3, and FMO5, both FMO1 and FMO3 exhibited activity with the active peptides whereas FMO5 was inactive. With FMO3, the activity measured with methionine was similar (1 mM) or higher (5 mM) than the activity measured with H-Met-Val-OH and H-Met-Phe-OH. With FMO1, H-Met-Phe-OH and methionine exhibited similar activities whereas activity with H-Met-Val-OH was much lower. Collectively, the results show that FMOs can oxidize peptides containing a free N-terminal methionine. Thus, the role of FMOs in the oxidation of methionine in larger peptides or proteins warrants further investigation.
Keywords: l; -Methionine; Flavin-containing monooxygenases; l; -Methionine sulfoxide
Conserved methionines in chloroplasts by Cecilia Sundby; Ulrika Härndahl; Niklas Gustavsson; Emma Åhrman; Denis J Murphy (pp. 191-202).
Heat shock proteins counteract heat and oxidative stress. In chloroplasts, a small heat shock protein (Hsp21) contains a set of conserved methionines, which date back to early in the emergence of terrestrial plants. Methionines M49, M52, M55, M59, M62, M67 are located on one side of an amphipathic helix, which may fold back over two other conserved methionines (M97 and M101), to form a binding groove lined with methionines, for sequence-independent recognition of peptides with an overall hydrophobic character. The sHsps protect other proteins from aggregation by binding to their hydrophobic surfaces, which become exposed under stress. Data are presented showing that keeping the conserved methionines in Hsp21 in a reduced form is a prerequisite to maintain such binding. The chloroplast generates reactive oxygen species under both stress and unstressed conditions, but this organelle is also a highly reducing cellular compartment. Chloroplasts contain a specialized isoform of the enzyme, peptide methionine sulfoxide reductase, the expression of which is light-induced. Recombinant proteins were used to measure that this reductase can restore Hsp21 methionines after sulfoxidation. This paper also describes how methionine sulfoxidation–reduction can be directly assessed by mass spectrometry, how methionine-to-leucine substitution affects Hsp21, and discusses the possible role for an Hsp21 methionine sulfoxidation–reduction cycle in quenching reactive oxygen species.
Keywords: Chaperone; Heat stress; Oxidative stress; Photosynthesis; Protein mass spectrometry; Protein–protein interaction
Methionine sulfoxide reductases: history and cellular role in protecting against oxidative damage by Herbert Weissbach; Lionel Resnick; Nathan Brot (pp. 203-212).
An enzyme that can reduce methionine sulfoxide in proteins was first discovered in Escherichia coli about 25 years ago. It is now apparent that there is a family of enzymes, referred to as methionine sulfoxide reductases (Msr), and in recent years there has been considerable interest in one of the members of the Msr family, MsrA. This enzyme has been shown to protect cells against oxidative damage, which suggests a possible role in a large number of age-related diseases. This review summarizes the history of the discovery of MsrA, properties of the enzyme and its role in protecting cells against oxidative damage. Other members of the Msr family that differ in substrate specificity and localization are described as well as a possible role for the Msr system in drug metabolism. The concept that the Msr system can be used to develop novel drugs that could be catalytic anti-oxidants is discussed.
Keywords: Methionine; Methionine sulfoxide; Methionine sulfoxide reductase; Oxidation
Methionine sulfoxide reductases: ubiquitous enzymes involved in antioxidant defense, protein regulation, and prevention of aging-associated diseases by Jackob Moskovitz (pp. 213-219).
Oxidative damage to proteins is considered to be one of the major causes of aging and age-related diseases, and thus mechanisms have evolved to prevent or reverse these modifications. Methionine is one of the major targets of reactive oxygen species (ROS), where it is oxidized to methionine sulfoxide (MetO). Recently, evidence has accumulated suggesting that methionine (Met) oxidation may play an important role in the development and progression of neurodegenerative diseases like Alzheimer's and Parkinson's diseases. Oxidative alteration of Met to Met(O) is reversed by the methionine sulfoxide reductases (consisting of MsrA enzymes that reduce S-MetO and MsrB enzymes that reduce R-MetO, respectively). A major biological role of the Msr system is suggested by the fact that the MsrA null mouse (MT) exhibits a neurological disorder in the form of ataxia (“tip toe walking�), is more sensitive to oxidative stress, and has a shorter life span (by ∼40%) than wild-type (WT) mice. By their action, the Msr enzymes can regulate protein function, be involved in signal-transduction pathways, and prevent cellular accumulation of faulty proteins. Malfunction of the Msr system can lead to cellular changes resulting in compromised antioxidant defense, enhanced age-associated diseases involving neurodegeneration, and shorter life span.In this review, the function and possible roles of the Msr system in prokaryotes and eukaryotes, in general, and in neurodegenerative diseases, in particular, will be discussed.
Keywords: Methionine oxidation; Methionine sulfoxide reductase; Oxidative stress; Alzheimer's disease; Parkinson's disease; Aging; Antioxidants
Methionine sulfoxide reductases in prokaryotes by Benjamin Ezraty; Laurent Aussel; Frédéric Barras (pp. 221-229).
In living organisms, most methionine residues exposed to reactive oxygen species (ROS) are converted to methionine sulfoxides. This reaction can lead to structural modifications and/or inactivation of proteins. Recent years have brought a wealth of new information on methionine sulfoxide reductase A (MsrA) and B (MsrB) which makes methionine oxidation a reversible process. Homologs of msrA and msrB genes have been identified in most living organisms and their evolution throughout different species led to different genetic organization and different copy number per organism. While MsrA and MsrB had been the focus of multiple biochemical investigations, our understanding of their physiological role in vivo remains scarce. Yet, the recent identification of a direct link between protein targeting and MsrA/MsrB repair offers a best illustration of the physiological importance of this pathway. Repeatedly identified as a potential “virulence factor�, contribution of msrA to pathogenicity is also discussed. It remains, however, unclear whether reduced virulence results from overall viability loss or relates to specific oxidized virulence factors left unrepaired. We speculate that a major issue towards assessing the in vivo role of the MsrA/MsrB repair pathway in the next future will be to decipher the interrelations, if any, between MsrA/MsrB-mediated repair and chaperone-assisted folding and/or protease-assisted degradation.
Keywords: Methionine Sulfoxide Reductase; MsrA; MsrB; ROS
The enzymology and biochemistry of methionine sulfoxide reductases by Sandrine Boschi-Muller; Alexandre Olry; Mathias Antoine; Guy Branlant (pp. 231-238).
The methionine sulfoxide reductase (Msr) family is composed of two structurally unrelated classes of monomeric enzymes named MsrA and MsrB, which display opposite stereo-selectivities towards the sulfoxide function. MsrAs and MsrBs, characterized so far, share the same chemical mechanism implying sulfenic acid chemistry. The mechanism includes three steps with (1) formation of a sulfenic acid intermediate with a concomitant release of 1 mol of methionine per mol of enzyme; (2) formation of an intramonomeric disulfide Msr bond followed by; (3) reduction of the oxidized Msr by thioredoxin (Trx). This scheme is in accordance with the kinetic mechanism of both Msrs which is of ping-pong type. For both Msrs, the reductase step is rate-determining in the process leading to the formation of the disulfide bond. The overall rate-limiting step takes place within the thioredoxin-recycling process, likely being associated with oxidized thioredoxin release. The kinetic data support structural recognition between oxidized Msr and reduced thioredoxin. The active sites of both Msrs are adapted for binding protein-bound methionine sulfoxide (MetSO) more efficiently than free MetSO. About 50% of the MsrBs binds a zinc atom, the location of which is in an opposite direction from the active site. Introducing or removing the zinc binding site modulates the catalytic efficiency of MsrB.
Keywords: Abbreviations; MetSO; methionine sulfoxide; MsrA/B; methionine sulfoxide reductase A/B; Trx; thioredoxin; Msr; ox; Msr in the disulfide state; Msr; red; Msr in the reduced state; Trx; ox; Trx in the disulfide state; Trx; red; Trx in the reduced state; TNB; −; 3-carboxy 4-nitrobenzenethiol; DTT; dithiothreitolMsr; Sulfenic acid; Catalytic mechanism; Rate-limiting step; Thioredoxin; Trp fluorescent probe
Heterogeneity and function of mammalian MSRs: enzymes for repair, protection and regulation by Alfred Hansel; Stefan H. Heinemann; Toshinori Hoshi (pp. 239-247).
Methionine sulfoxide, the physiologically relevant oxidation product of methionine, is enzymatically reduced by peptide methionine sulfoxide reductases (MSRs). Two distinct classes of these enzymes, MSRA and MSRB, which selectively reduce the two methionine sulfoxide epimers, methionine-S-sulfoxide and methionine-R-sulfoxide, respectively, are found in virtually all organisms. Mammals typically possess only one gene encoding MSRA, but at least three genes encoding MSRBs. These MSRs show distinct tissue- and subcellular expression patterns and may play specific functional roles. Susceptibility of some ion channels to reversible methionine oxidation suggests that MSRs have a regulatory role in cellular excitability. Some—if not all—MSRs protect cells and organisms against a variety of oxidative stress episodes, including those by hypoxia and reperfusion, and play a modulatory role in lifespan determination. More MSR-dependent physiological phenomena await to be discovered.
Keywords: Mammalian methionine sulfoxide reductase; Protein oxidation; Oxidative stress; MSRA; MSRB; Reactive oxygen species
The three-dimensional structures of peptide methionine sulfoxide reductases: current knowledge and open questions by Brice Kauffmann; André Aubry; Frédérique Favier (pp. 249-260).
Methionine sulfoxides are easily formed in proteins exposed to reactive oxidative species commonly present in cells. Their reduction back to methionine residues is catalyzed by peptide methionine sulfoxide reductases. Although grouped in a unique family with respect to their biological function, these enzymes are divided in two classes named MsrA and MsrB, depending on the sulfoxide enantiomer of the substrate they reduce. This specificity-based classification differentiates enzymes which display no sequence homology. Several three-dimensional structures of peptide methionine sulfoxide reductases have been determined, so that members of both classes are known to date. These crystal structures are reviewed in this paper. The folds and active sites of MsrAs and MsrBs are discussed in the light of the methionine sulfoxide reductase sequence diversity.
Keywords: MsrA; MsrB; Methionine sulfoxide; Stereospecificity; X-ray structure; Thioredoxin
Protein maintenance in aging and replicative senescence: a role for the peptide methionine sulfoxide reductases by Isabelle Petropoulos; Bertrand Friguet (pp. 261-266).
Cellular aging is characterized by the build-up of oxidatively modified protein that results, at least in part, from impaired redox homeostasis associated with the aging process. Protein degradation and repair are critical for eliminating oxidized proteins from the cell. Oxidized protein degradation is mainly achieved by the proteasomal system and it is now well established that proteasomal function is generally impaired with age. Specific enzymatic systems have been identified which catalyze the regeneration of cysteine and methionine following oxidation within proteins. Protein-bound methionine sulfoxide diastereoisomers S and R are repaired by the combined action of the enzymes MsrA and MsrB that are subsequently regenerated by thioredoxin/thioredoxin reductase. Importantly, the peptide methionine sulfoxide reductase system has been implicated in increased longevity and resistance to oxidative stress in different cell types and model organisms. In a previous study, we reported that peptide methionine sulfoxide reductase activity as well as gene and protein expression of MsrA are decreased in various organs as a function of age. More recently, we have shown that gene expression of both MsrA and MsrB2 (Cbs-1) is decreased during replicative senescence of WI-38 fibroblasts, and this decline is associated with an alteration in catalytic activity and the accumulation of oxidized protein. In this review, we will address the importance of protein maintenance in the aging process as well as in replicative senescence, with a special focus on regulation of the peptide methionine sulfoxide reductase systems.
Keywords: Protein oxidation; Aging; Replicative senescence; Protein maintenance; Proteasome; Peptide methionine sulfoxide reductase