Methionine Oxidation and Protein Repair Mechanisms

Methionine residues in proteins are particularly susceptible to oxidation by reactive oxygen species, forming methionine sulfoxide and potentially compromising protein structure and function. This reversible post-translational modification can serve as a regulatory switch in redox signalling but may also lead to irreversible damage under excessive oxidative conditions. Cells harness dedicated enzymes known as methionine sulfoxide reductases (MSRAs and MSRBs) to repair oxidised methionine, restoring proteins to their native state. These reductases exhibit stereospecificity towards the S- or R-forms of methionine sulfoxide and rely on electron donors such as thioredoxin or glutaredoxin systems. Beyond repair, reversible methionine oxidation modulates protein–protein interactions, stabilises flexible regions through methionine-aromatic motifs and regulates cell signalling. Imbalance between oxidative stress and repair capacity has been implicated in ageing, neurodegeneration, immune dysfunction and chronic disease. Recent advances have deepened our understanding of substrate specificity, repair kinetics and the broader physiological roles of methionine oxidation in cellular homeostasis and disease pathogenesis, highlighting potential for therapeutic and biomarker development.

Research from Nature Portfolio

Innovative mass spectrometry approaches have quantified methionine sulfoxide in circulating proteins, identifying elevated oxidation at specific albumin residues in patients with metabolic and renal disorders. This work demonstrates high reproducibility of redox quantification from minimal serum volumes and positions methionine sulfoxide levels as potential biomarkers of systemic oxidative stress. By establishing robust analytical workflows, this research has paved the way for non-invasive monitoring of disease progression and response to antioxidant therapies.

Methionine Oxidation and Protein Repair Mechanisms publication trend

The graph below shows the total number of articles in methionine oxidation and protein repair mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Reactive oxygen species (ROS): Highly reactive molecules derived from oxygen that can oxidise amino acid side chains.
Methionine sulfoxide: An oxidised form of the amino acid methionine, containing an additional oxygen atom on the sulphur.
Methionine sulfoxide reductases (MSRs): Enzymes that catalyse the stereospecific reduction of methionine sulfoxide back to methionine, utilising electron donors such as thioredoxin or glutaredoxin.
Stereospecificity: The property of an enzyme to selectively act on one of two mirror-image forms (R- or S-form) of a substrate.
Post-translational modification: Chemical alteration of amino acid residues in proteins after synthesis, affecting function and stability.

References

1. Ndufaf2, a protein in mitochondrial complex I, interacts in vivo with methionine sulfoxide reductases. Redox Report (2023).
2. Methionine Sulfoxide Speciation in Mouse Hippocampus Revealed by Global Proteomics Exhibits Age- and Alzheimer’s Disease-Dependent Changes Targeted to Mitochondrial and Glycolytic Pathways. International Journal of Molecular Sciences (2024).
3. The DmsABC S-oxide reductase is an essential component of a novel, hypochlorite-inducible system of extracellular stress defense in Haemophilus influenzae. Frontiers in Microbiology (2024).
4. Oxidation Resistance of the Sulfur Amino Acids: Methionine and Cysteine. BioMed Research International (2017).
5. The Oxidized Protein Repair Enzymes Methionine Sulfoxide Reductases and Their Roles in Protecting against Oxidative Stress, in Ageing and in Regulating Protein Function. Antioxidants (2018).
6. The Methionine-aromatic Motif Plays a Unique Role in Stabilizing Protein Structure*. Journal of Biological Chemistry (2012).
7. Methionine sulfoxides in serum proteins as potential clinical biomarkers of oxidative stress. Scientific Reports (2016).