Peroxiredoxins are proteins conserved across all domains of life that protect cells against the threat of reactive oxygen species. Researchers have recently characterized the evolutionary history of an essential peroxiredoxin gene from a common livestock pathogen.
Reactive oxygen species (ROS), such as those found in the common disinfectant hydrogen peroxide, are very effective antimicrobial agents.
ROS occur naturally wherever oxygen is present, and most commonly form when an oxygen molecule (O2) gains a single free electron. This new molecule is highly reactive because of its new unpaired electron, causing it to “attack” the chemical bonds around it.
When the surrounding chemical bonds happen to make up the proteins and DNA of a living cell, the results can be deadly.
To combat this process of “oxidative stress”, organisms have evolved a wide range of defenses to protect themselves from destruction by ROS.
One such defense, an enzyme called peroxiredoxin, is found ubiquitously across all domains of life. Peroxiredoxin is a protein with antioxidant properties that works by converting ROS into water or a harmless alcohol.
Defenses such as peroxiredoxins help cope with ROS stress produced by everyday activities, such as metabolism, but they can also assist in bacterial pathogenicity by allowing invaders to elude mammalian immune system mechanisms that use directed ROS attack.
One important group of pathogens that use peroxiredoxins to their advantage are the mycoplasmas. Bacteria in this group cause diseases such as pneumonia and tuberculosis in humans and other animals and typically have very small genomes, encoding one or just a few ROS defense genes.
Though the genes may not be numerous, they are essential for bacterial survival during infection.
Therefore, understanding the evolution of peroxiredoxins in mycoplasmas will allow us to characterize important genetic causes of disease and may even help determine its potential as a drug target against pathogens.
To this end, researchers recently studied the evolutionary history of the peroxiredoxin enzyme in Mycoplasma hyopneumoniae, which cause respiratory infections in pigs and is an important and widespread livestock pathogen.
The authors found that peroxiredoxins in mycoplasma form two distinct groups: one which contains two cysteines (one of the 20 amino acid building-blocks of proteins) that work together to dismantle ROS, and another that contains only one cysteine but performs the same job.
Interestingly, when the authors examined the evolutionary relationship between these two peroxiredoxin groups they found that the one- and two-cysteine versions diverged very recently, likely from a two-cysteine ancestor.
The researchers then attempted to reconstruct the ancestral protein by artificially reintroducing the lost cysteine back into the one-cysteine peroxiredoxin.
They found that at high concentrations, the mutant peroxiredoxin (the one-cysteine version with an extra cysteine added back in) exhibited the same ability to curb ROS damage compared to the normal, unaltered one-cysteine version.
However, at low concentrations, the mutant peroxiredoxin had significantly lower ROS activity, failing to reduce oxidative damage as well as the unaltered version.
How and why did natural selection split up the cysteine duo?
The authors speculate that the one-cysteine version of peroxiredoxin likely recently arose in mycoplasma due to the selective pressure of a low free-cysteine environment or by a concentration-related mechanism, as demonstrated by the experiments reintroducing the lost cysteine.
In all, these findings suggest that peroxiredoxins – or indeed antioxidant and ROS defense enzymes in general – are likely not suitable targets for antimicrobial drugs because of their demonstrated ability to quickly evolve in response to recent environmental pressure.
And in the case of the mycoplasma bacteria themselves, this study provides another example in the long list of pathogens that have evolved to use different means to the same end.