Researchers at the Chinese University of Hong Kong (CUHK) have uncovered how Helicobacter pylori safely handles toxic nickel ions while surviving in the stomach’s highly acidic environment, potentially opening a new avenue for non-antibiotic treatments.
H. pylori is a bacterium that is a major cause of peptic ulcers and an important risk factor for gastric cancer.
A team led by Wong Kam-bo, professor at CUHK’s School of Life Sciences, revealed the molecular mechanism by which the bacterium transfers nickel between two key chaperone proteins without allowing the metal to accumulate at toxic levels.
To colonize the stomach, H. pylori relies on an enzyme called urease, which breaks down urea into ammonia and helps neutralize gastric acid.
However, urease requires nickel ions to function, while free nickel can be toxic to the bacterium. H. pylori must therefore transport the metal in a tightly controlled manner to activate the enzyme without damaging its own cells.
The researchers identified how two specialized proteins, UreE and UreG, work together during this process.
Using X-ray crystallography and biochemical analysis, the team determined the structures of the proteins while they were bound together and mapped the nickel-transfer process at the atomic level.
The study also found that guanosine triphosphate, or GTP, an energy-carrying molecule, plays an essential role in controlling the transfer.
When GTP binds to UreG, the protein changes shape, bringing its nickel-binding site into alignment with that of UreE and allowing the metal ion to pass from one protein to the other.
After receiving the nickel, UreG undergoes another structural change and separates from the complex before delivering the metal to urease.
The process enables H. pylori to supply nickel to the enzyme it needs for survival while minimizing the risk of toxic metal leakage inside the bacterium.
The findings were published in the journal Proceedings of the National Academy of Sciences (PNAS).
Current treatment for H. pylori infection relies largely on combinations of antibiotics and acid-suppressing drugs, but rising antibiotic resistance has made some infections increasingly difficult to eradicate.
By identifying a molecular step that is critical to the bacterium’s ability to activate urease, the CUHK study points to a possible new target for drug development.
Future treatments could potentially be designed to disrupt the transfer of nickel between UreE and UreG. Without an adequate supply of nickel, urease would be unable to function properly, potentially making H. pylori less able to withstand the stomach’s acidic conditions.
Such an approach could provide a basis for developing therapies that do not rely solely on conventional antibiotics, although further research would be needed to determine whether the mechanism can be safely and effectively targeted in patients.
