Some bacteria, including those that cause strep throat and pneumonia, use a certain type of enzyme to replicate their DNA without the usually required metal ions, according to new research.
This process may allow infectious bacteria to replicate even when the host’s immune system sequesters iron and manganese ions in an attempt to slow pathogen replication.
The findings could drive the development of new, more effective antibiotics.
A little RNR
“Every organism uses ribonucleotide reductase (RNR) enzymes to make the nucleotide building blocks needed for DNA replication and repair,” says lead author Amie Boal, an assistant professor of chemistry and of biochemistry and molecular biology at Penn State.
“Because RNRs are essential, they are validated drug targets for some cancers and viral infections, but they have not yet been exploited as drug targets in pathogenic bacteria. One of the goals of our work is to better understand the cofactors required by RNRs to function, which will hopefully inspire the creation of new, potent antimicrobial drugs that can inhibit the enzyme,” she says.
RNRs perform complex chemistry to convert ribonucleotides—the building blocks of RNA, which are present in the cell—into deoxyribonucleotides—the building blocks of DNA. All known RNRs used during aerobic metabolism require a metal ion cofactor, which acts as a powerful oxidizing agent to drive the conversion.
In the new study, researchers have now identified and described a new subclass of RNR that is capable of performing this process without the aid of a metal ion in the bacterial pathogens that cause strep throat, pneumonia, rheumatic fever, and other diseases.
“Requiring a trace-metal cofactor is the Achilles heel of an RNR, especially in pathogenic bacteria,” says coauthor Gavin Palowitch, a PhD candidate in biochemistry, microbiology, and molecular biology.
“When a pathogen invades your body, one of the things that your immune system can do is try to deprive it of iron and manganese ions in an attempt to slow reproduction. If you have a way to make DNA that doesn’t rely as much on a metal cofactor, that’s a novel tactic for evading the immune response,” he says.
The researchers showed that this new subclass of RNR is able to use a modified amino acid instead of a metal ion as the oxidizing agent that drives the creation of DNA nucleotides. It remains unknown whether a metal is required for initial synthesis of the modified amino acid and then lost. But the study establishes that the modification does require a separate protein for its installation.
“The need for another activating protein is critical for thinking about inhibiting this enzyme with antibiotic drugs,” Boal says. “Protein-protein interactions are really attractive targets for disruption by small molecule therapeutics.”
The research appears in the Proceedings of the National Academy of Sciences.
Additional researchers are from Penn State, the University of Pennsylvania, and Massachusetts Institute of Technology. The Searle Scholars Program and the National Institutes of Health funded the study. Additional support came from the Penn State Huck Institutes of the Life Sciences.
Source: Penn State