The MsrA enzyme plays a role in cellular antioxidant defense by reversing methionine oxidation. Its deficiency is associated with a variety of diseases. Structurally, it contains three cysteines near a conserved active-site motif, which is essential for catalysis. The C-terminal tail is elongated and flexible, allowing the formation of disulfide bonds that are important for the enzyme’s conformation and catalytic mechanism.
Function
Reactive oxygen species (ROS) and nitrogen intermediates can cause cellular damage. Cells have developed several mechanisms to eliminate these reactive molecules or repair the damage. Among proteins, one of the amino acids most easily oxidized is methionine, which is converted into methionine sulfoxide. The enzyme peptide methionine sulfoxide reductase (MsrA) catalyzes the reduction of methionine sulfoxide back to methionine, both in proteins and as free methionine. MsrA plays an important role in protecting the cell against oxidative damage.
Disease
MsrA has the ability to provide protection against oxidative stress in vivo. It also appears to be involved in the attachment of pathogenic microorganisms to eukaryotic and plant cells and in the onset of Alzheimer's disease. Reduction in MsrA activity occurs in very old rats and in the brains of patients with Alzheimer’s disease, which consequently leads to accumulation of carbonyl adducts in proteins.
Bacteria and yeast cells lacking the msrA gene show increased sensitivity to oxidative stress and lower survival rates, with yeast showing accumulation of high levels of both free and protein-bound Met(O).
MsrA deficiency exacerbates ischemia/reperfusion (I/R)-induced acute kidney injury. The absence of MsrA leads to increased oxidative stress and inflammatory responses in the kidneys, since oxidative stress and inflammation are key factors in the progression of renal fibrosis. MsrA plays an important role in protecting kidney function in chronic kidney diseases associated with fibrosis.
Relevance
The oxidation of methionine to methionine sulfoxide, Met(O), has been implicated in a variety of neurodegenerative diseases, emphysema, cataractogenesis, and rheumatoid arthritis. At the same time, the readily oxidizable nature of surface methionines suggests that these may act as an endogenous oxidant defense system. Other studies indicate that Met oxidation and/or reduction is involved in regulating potassium channel function and other cellular signaling mechanisms.
The reduction of Met(O) to Met, both as the free amino acid and when incorporated into proteins, is mediated by peptide methionine sulfoxide reductase (MsrA). This enzyme is a member of the minimal gene set required for life and is found in all mammalian tissues, with the highest levels in the cerebellum and kidney. The sequences of the presumed catalytic domains of the MsrAs are highly conserved [e.g., human, Escherichia coli, and yeast MsrAs are 88, 60, and 34% identical to bovine MsrA (bMsrA), respectively]. MsrA has the ability to provide protection against oxidative stress in vivo.
Structural highlights
| Total Structure Weight:
| Resolution:
| Method:
| Sequence Length
|
| 48.07 kDa
| 1.70 Å
| X-RAY DIFFRACTION
| 217
|
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is formed by Alpha helix, Beta sheet and loop. In the protein, you can see and in different colors.
MsrAs contain within their presumed a conserved Gly-Cys-Phe-Trp-Gly motif. Mutation of the Cys residue in either bovine or yeast MsrA results in a complete loss of activity. Catalysis is presumed to occur through a series of thiol−disulfide exchange steps, although an alternative mechanism utilizing a sulfenic acid intermediate has been proposed.
There are three cysteine residues, , located in the .
As a tertiary structure, the protein features disulfide bonds, that occur preferentially between or alternatively between .
The terminal tail is quite elongated and makes little contact with the rest of the protein, appearing as a surface-exposed loop in this crystalline form. Conformational changes in a tail appear to allow the three thiols to come together, leading to the formation of disulfide bonds and enabling their participation in catalysis. The reduction of Met(O) requires an electron donor mediated by Cys — that is, dithiothreitol (DTT) in vitro or a thioredoxin regeneration system in vivo. However, it has been suggested that one or more Cys residues are involved in the catalytic process.
