The ulcer-causing bacterium Helicobacter pylori thrives where most other living things get chemically minced into bits–the acidic environment of the human stomach. Scientists are divided on exactly how H. pylori combats acid, but they agree on one thing: The enzyme urease has a lot to do with it.
Now, Byung-Ha Oh of Pohang University in Korea and his colleagues have brought into the debate the three-dimensional structure of the H. pylori urease. Their results, they say, bolster a previously proposed mechanism in which urease that coats the bacterial surface acts as an acid-neutralizing shield.
Scientists have known for years that inside cells, this enzyme converts urea, a waste compound, into acid-neutralizing ammonia. H. pylori is packed with urease. As the bacteria age, they can burst and release urease into the acidic stomach and onto the surface of neighboring H. pylori.
Researchers would like to know if this bacterial urease continues to function outside the cells, or if all the ammonia coating the bacteria simply diffuses from inside the cells.
In the June Nature Structural Biology, Oh’s group describes a mechanism that could help settle the question. Using X-ray crystallography, the team revealed that H. pylori’s urease consists of 12 identical parts that interlock to form a sphere. Twelve ammonia-producing regions, or active sites, cluster underneath the sphere’s protective surface. The H. pylori urease has more active sites than other ureases–and can pump out more ammonia per enzyme. That output, says Oh, quickly coats each enzyme molecule with a neutralizing layer that enables it to survive in acid. In support of the enzyme’s acid resistance, Oh showed that the urease can survive in acidities as strong as pH 3.0.
Oh says his group’s finding suggests that the enzyme could in fact function outside the bacteria. “The enzyme exists in a small, little spacesuit of ammonia,” concurs Bruce Dunn, a microbiologist at the Medical College of Wisconsin in Milwaukee. Others aren’t convinced.
“The facts speak against their deductions,” says H. pylori researcher George Sachs of the University of Los Angeles. In particular, he notes that stomach pH can dip far below 3.0–the enzyme’s functional limit determined by Oh. He also contends that the bacteria survived in Oh’s experiments only because the scientists permitted acid concentrations to decrease as the urease did its work. In the stomach, however, the acidity is maintained at a stable level. Sachs says that in his own experiments, which better replicate stomach conditions, the enzyme is incapacitated.
Sachs contends, therefore, that ammonia from the interior of the bacteria is sufficient to neutralize acid. Ammonia simply diffuses to the liquid layer between the microbe’s two membranes, he says.
Harry Mobley, a microbiologist at the University of Maryland in Baltimore, also is unconvinced that urease is acid resistant. Even so, he says, the new data will help researchers interested in designing antiulcer drugs or vaccines targeted against urease, “It’s very exciting. I’m delighted,” says Mobley.