Methionine oxidation and aging

doi:10.1016/j.bbapap.2004.08.010

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

Volume 1703, Issue 2, 17 January 2005, Pages 135-140

https://doi.org/10.1016/j.bbapap.2004.08.010 Get rights and content

Abstract

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.

Section snippets

Role of methionine oxidation in aging

The singular importance of methionine oxidation in aging is highlighted by the following findings: (i) The level of MsrA in various rat tissues declines with age [20], [21] and in some age-related diseases, i.e., Alzheimer's disease [22], emphysema (especially in cigarette smokers) [1], [23], bronchitis [24], and Parkinson's disease [25], [26]. (ii) Mutations leading to a loss of MsrA activity in mice lead to a 40% decrease in the maximum life span [14]. (iii) Overexpression of msrA in flies

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Posttranslational modifications in fibrinogen resulting from induced oxidation or oxidative stress in the organism can have deleterious influence on optimal functioning of fibrinogen, causing a disturbance in assembly and properties of fibrin. The protective mechanism supporting the ability of fibrinogen to function in ROS-generating environment remains completely unexplored. The effects of very low and moderately low HOCl/⁻OCl concentrations on fibrinogen oxidative modifications, the fibrin network structure as well as the kinetics of both fibrinogen-to-fibrin conversion and fibrin hydrolysis have been explored in the current study. As opposed to 25 Μm, HOCl/⁻OCl, 10 μM HOCl/⁻OCl did not affect the functional activity of fibrinogen. It is shown for the first time that a number of Met residues, AαMet476, AαMet517, AαMet584, BβMet367, γMet264, and γMet94, identified in 10 μM HOCl/–OCl fibrinogen by the HPLC-MS/MS method, operate as ROS scavengers, performing an important antioxidant function. In turn, this indicates that the fibrinogen structure is adapted to the detrimental action of ROS. The results obtained in our study provide evidence for a protective mechanism responsible for maintaining the structure and functioning of fibrinogen molecules in the bloodstream under conditions of mild and moderate oxidative stress.
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Oxidation by OH radicals produced by $γ$ -radiolysis of single amino acids proline and glutamic acid accompanied by a series of Met-containing model peptides were investigated by a combined study of tandem mass spectrometry and infrared multiple-photon dissociation spectroscopy in the fingerprint region. The thioether group of methionine has been identified as a common target of OH free radicals leading to a S⁺ radical cation, which made a 2-center-three electron (2c-3e) bond with any atom having having a lone pair of electrons. However, the final fate of these 2c-3e free radicals is still unknown. These studies led to the identification of the final stable products of oxidation and the localization of the modified sites. We show that the final products contain mostly methionine sulfoxide, whatever the structure of the preceding free radical. Although the distance between two Met residues controls the nature of free radicals formed in the peptides, it has no significant effect on the final products of oxidation. These results thus confirm that the final products are not controlled by free radical structure. Also, although no proline free radical was detected previously, we show that proline residue can be oxidized.
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The oxidation of methionine side chain residues in proteins provides a great diversity of possible oxidation mechanisms dictated, among others, by the oxidizing species, solvent properties, and protein structure. The oxidation behavior of a series of short acetylated synthetic peptides, Ac-GMG, Ac-GGMGG and Ac-GGGMGGG, was investigated by differential pulse and square wave voltammetry, in a wide pH range, at glassy carbon electrode. It was found that always the first oxidation step represents the one-electron oxidation of thioether moiety with the formation of a radical cation. Following this, depending on the experimental conditions and side chain position of methionine, the radical is stabilized by the nucleophilic attack of water or by catalytic support of the neighboring carbonyl and amide groups in an intermediate structure, finally converted in methionine sulfoxide which can be further oxidized, at more positive potential, into methionine sulfone. For Ac-GGGMGGG, at pH 8.0, the amino and amide groups are active involved in the oxidation process and the electrode reaction takes place with proton transfer
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Classically activated pro-inflammatory macrophages are generated from naive macrophages by pro-inflammatory cues that dynamically reprogram their fuel metabolism toward glycolysis. This increases their intracellular reactive oxygen species (ROS) levels, which then activate the transcription and release of pro-inflammatory mediators. Our study on mice that lack methionine sulfoxide reductase (Msr)-B1 shows that the resulting partial loss of protein methionine reduction in pro-inflammatory macrophages creates a unique metabolic signature characterized by altered fuel utilization, including glucose and pyruvate. This change also associates with hyper-inflammation that is at least partly due to sustained oxidation of an exposed methionine residue (M44) on glyceraldehyde 3-phosphate dehydrogenase (GAPDH), thereby inducing GAPDH aggregation, inflammasome activation, and subsequent increased interleukin (IL)-1β secretion. Since MsrB1-knockout mice exhibit increased susceptibility to lipopolysaccharide (LPS)-induced sepsis, the MsrB1-GAPDH axis may be a key molecular mechanism by which protein redox homeostasis controls the metabolic profile of macrophages and thereby regulates their functions.
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Published by Elsevier B.V.

Methionine oxidation and aging

Abstract

Section snippets

Role of methionine oxidation in aging

Free Radic. Biol. Med.

Arch. Biochem. Biophys.

FEBS Lett.

Free Radic. Biol. Med.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Mech. Ageing Dev.

Mech. Ageing Dev.

Life Sci.

FEBS Lett.

J. Biol. Chem.

Arch. Biochem. Biophys.

J. Biol. Chem.

One-electron photooxidation of N-methionyl peptides. Mechanism of sulfoxide and azasulfonium diastereomer formation through reaction of sulfide radical cation complexes with oxygen or superoxide

J. Am. Chem. Soc.

The mirrored methionine sulfoxide reductases of Neisseria gonorrhoeae pilB

Nat. Struct. Biol.

Methionine residues as endogenous antioxidants in proteins

Proc. Natl. Acad. Sci. U. S. A.

The yeast peptide-methionine sulfoxide reductase functions as an antioxidant in vivo

Proc. Natl. Acad. Sci. U. S. A.

Escherichia coli peptide methionine sulfoxide reductase gene: regulation of expression and role in protecting against oxidative damage

J. Bacteriol.

Methionine sulfoxide reductase A (MsrA) deficiency affects the survival of Mycobacterium smegmatis within macrophages

J. Bacteriol.

Peptide methionine sulfoxide reductase from Escherichia coli and Mycobacterium tuberculosis protects bacteria against oxidative damage from reactive nitrogen intermediates

Proc. Natl. Acad. Sci. U. S. A.