Review
The physiological role of reversible methionine oxidation

https://doi.org/10.1016/j.bbapap.2014.01.001Get rights and content

Highlights

  • Aerobic conditions and especially oxidative stress cause oxidation of methionines.

  • Oxidation of methionine to methionine sulfoxide usually causes protein inactivation.

  • Yet, some proteins are selectively activated by methionine oxidation.

  • Methionine sulfoxide reductases reduce methionine sulfoxide back to methionine.

  • Reversible methionine oxidation is a novel mode of redox-regulation of proteins.

Abstract

Sulfur-containing amino acids such as cysteine and methionine are particularly vulnerable to oxidation. Oxidation of cysteine and methionine in their free amino acid form renders them unavailable for metabolic processes while their oxidation in the protein-bound state is a common post-translational modification in all organisms and usually alters the function of the protein. In the majority of cases, oxidation causes inactivation of proteins. Yet, an increasing number of examples have been described where reversible cysteine oxidation is part of a sophisticated mechanism to control protein function based on the redox state of the protein. While for methionine the dogma is still that its oxidation inhibits protein function, reversible methionine oxidation is now being recognized as a powerful means of triggering protein activity. This mode of regulation involves oxidation of methionine to methionine sulfoxide leading to activated protein function, and inactivation is accomplished by reduction of methionine sulfoxide back to methionine catalyzed by methionine sulfoxide reductases. Given the similarity to thiol-based redox-regulation of protein function, methionine oxidation is now established as a novel mode of redox-regulation of protein function. This article is part of a Special Issue entitled: Thiol-Based Redox Processes.

Introduction

Reactive oxygen species (ROS) and reactive chlorine species (RCS) are a major source of cysteine (Cys) and methionine (Met) oxidation. Both reactive species are the inevitable consequence of aerobic life style. ROS are produced as by-product of respiration, i.e., when oxygen is reduced to water. Upon incomplete reduction of oxygen, superoxide and hydrogen peroxide (H2O2) are generated, the latter of which can further react with metal ions to form hydroxyl radicals (HOradical dot). Further, ROS are major constituents of the innate immune response. Upon bacterial infection, neutrophils produce H2O2 and chloride ions, and the enzyme myeloperoxidase catalyzes the generation of hypochlorous acid (HOCl) [1], [2]. Thus, H2O2 and HOCl are two potent effector molecules of the immune system responsible for killing invading microorganisms. HOCl is also produced by mucosal barrier epithelia to control bacterial colonization [3]. Its strong bactericidal activity is derived from its high reactivity with macromolecules including DNA, proteins, and lipids. As a consequence, amines may be chlorinated/oxidized generating RCS such as chloramines [4], [5], chromosomal mutations and lipid peroxidation may occur [6], [7], and proteins may be inactivated or aggregated [8], [9], [10] leading to loss of cellular energy [11]. Accumulation of oxidative damage causes a condition called oxidative stress, which is hazardous to all kinds of organisms and may cause killing or apoptosis. Thus, ROS and RCS are ubiquitous sources of oxidation reactions and oxidative stress.

Cys and Met residues are extremely vulnerable to oxidation. While Cys oxidation and its role in redox regulation and cell signaling are well-established and have been extensively studied, Met oxidation and its role in cells are the topics of this review. Groundbreaking work by Weissbach, Brot, Schöneich, Levine, Moskovitz, Stadtman, Squier, Gladyshev and their co-workers unraveled Met oxidation as damage to proteins and the function of methionine sulfoxide reductases (Msrs) in repairing such damage as well as the underlying mechanisms (for reviews see for example the special issue on “Methionine Oxidation and Methionine Sulfoxide Reductases” in Biochim Biophys Acta 2005, volume 1703). Met oxidation and accordingly Msrs play an important role during oxidative stress; they are thus associated with the aging process and several pathophysiological conditions such as neurodegenerative diseases and cancer. In this review we will give an overview about the role of ROS and RCS in Met oxidation to methionine sulfoxide (Met-SO), the function of Msrs in damage repair, and detection methods for reduced and oxidized Met residues. We will shed light on the implications of Met oxidation on microorganisms and higher eukaryotes, focusing on oxidative stress and related effects. Further, we will eventually discuss the consequences of Met oxidation for individual proteins, namely inactivation of proteins as well as activation of protein function. Especially the role of Met oxidation to reversibly trigger the activation of proteins will expand the focus of current reviews in order to establish Met oxidation as a novel mode of redox-regulation of proteins.

Section snippets

Chemical reactions causing methionine oxidation

All nascent polypeptides start with Met as first amino acid, which can be modified, for example by acetylation or formylation, or become processed, e.g. by cleavage from a precursor. On average, about 1.5% of amino acids in a protein are Met residues. In Escherichia coli, the Met content roughly ranges from 1 to 3% (most abundant protein: elongation factor TU: 2.8%; oxidative stress related proteins: KatE (1.3%), HypT (2%), MsrA (3.3%); according to EcoCyc). Similar values were reported for

Methionine sulfoxide reductases — enzymes that reduce Met-SO

Given that Met oxidation occurs unavoidably under aerobic conditions, it is not unexpected that cells have developed sophisticated mechanisms and enzymes to counteract Met oxidation. In contrast to Met sulfone, Met-SO is a reversible post-translational modification. The enzymes catalyzing the reduction of Met-SO back to Met are methionine sulfoxide reductases (Msr). The first Msr was described in E. coli in 1981 [21] and later termed MsrA. MsrA turned out to be specific for the S-epimer of

Detection of reduced and oxidized methionines

Given the high susceptibility of Met to oxidation and their ubiquitous occurrence, detection of Met in the reduced/oxidized state is of great interest. Detection methods include mass spectrometry (MS analysis; [10], [84]), chemical modification of Met or Met-SO residues combined with amino acid analysis [15], radioactivity assays [85], high performance liquid chromatography (HPLC; [84], [86]), and immunological methods using antibodies specific to the Met-oxidized forms [14], [87], [88].

Met as scavenger of oxidants

Under aerobic conditions, up to 6% of protein-bound Met may be oxidized spontaneously (see Section 4). Not all Met residues in a protein are equally sensitive to oxidation, showing that the localization of Met within the protein structure, i.e., whether it is surface exposed or buried, may determine its accessibility to oxidants. Early experiments by Shechter showed that Met residues in peptides and denatured proteins are completely oxidized, whereas in native proteins only exposed Met residues

Conclusions

Met oxidation as an inevitable consequence of aerobic life style regulates the activity of numerous proteins. While proteins are mostly inhibited or inactivated, some recent examples show that Met oxidation also activates protein function. This underscores the relevance of Msrs in the regulation of protein activity. Thus, Met oxidation and Msrs are part of a highly regulated machinery controlling the function of signaling factors under physiological conditions and conditions of oxidative stress.

Acknowledgements

The authors acknowledge financial support by the Elitenetzwerk Bayern to AD and the Emmy-Noether program of the DFG to JW.

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