|Helicobacter Pylori. Image credit: Steadyhealth.com|
The notion that a bacteria could live and thrive in the stomach took some getting used to among scientists and doctors. The environment in the human stomach is extremely harsh and acidic, making it inhospitable to many micro-organisms. H. Pylori has adapted by cleverly developing a way to neutralize the stomach's acidity by secreting an enzyme which breaks down urea, a naturally occurring waste product in human fluids. The enzyme, urease, chops up urea into its component parts, ammonia and carbon dioxide. Ammonia, which is basic, then neutralizes the acid in the stomach.
H. Pylori is shaped like a corkscrew and possesses a long whip-like tail, or flagella. These properties are exploited to allow it move efficiently through the liquid environment in the stomach aided by the flagella and to burrow into the lining of the stomach as a corkscrew would spiral into a wine cork. After settling into the stomach lining, H. Pylori infection may be asymptomatic in some individuals or may contribute to the development of ulcers or gastric cancer. It is not yet clear why the bacteria is pathogenic in some individuals and harmless in others. To test for the bacteria, a simple blood test for antibodies against H. Pylori or testing for urease in patients' breath is often sufficient to diagnose H. Pylori infection.
|H. Pylori in stomach tissue retrieved during a gastric biopsy. Image credit: Wikipedia|
After infection has been confirmed, infected individuals are typically given a round of antibiotics to fight off the bacteria. Researchers at the DOE's SLAC National Accelerator Laboratory at Stanford University wanted to find a new, more efficient way of eliminating the ulcer- and cancer-causing bacteria. They managed to find a chink in the microbe's armor- by disabling the mechanism which permits neutralization of stomach acid, they realized, the microbes would then become vulnerable to and unable to survive the extreme acidity of the stomach.
H. Pylori takes in urea from its environment through small channels and chops it up before releasing neutralizing ammonia and carbon dioxide, the byproducts of this activity. A team of researchers led by Hartmut Luecke reported in a paper which was published online in Nature on Dec. 9th that they had managed to solve the structure of these channels by x-ray crystallography.
The first step in solving a protein structure by x-ray crystallography is to actually getting the protein of interest to crystallize in a neat, well-ordered pattern- a task which is notoriously difficult with membrane proteins. Proteins are finicky enough as it is, and even slight changes in pH, salinity, temperature, and other variables can cause a protein to change or lose its shape. Membrane proteins are especially problematic because they need to be carefully extracted from the membrane in a way that won't disrupt the actual shape of the protein; after removal from the membrane, moreover, certain parts of the protein that are normally hidden from water and tucked away within the membrane may be exposed, causing the protein to change shape. All told, experimenting with 'growing' conditions for protein crystal samples is often time and labor intensive.
Luecke and his team stated in a press release that they screened thousands of crystals before finding the right one for their experiment. Once they had the urea channels crystallized, they determined its structure by x-ray crystallography, bouncing x-rays off of the protein and measuring the scatter of the rays to create a 3D map of the protein (I know that explanation isn't really doing the process any justice, so imagine tossing thousands of tennis balls at a statue and carefully recording and measuring the angles and directions they bounce back in...then, from that mountain of data, figuring out where they must have initially struck and bounced back from to reproduce the image of the statue- in other words, its complicated).
Understanding the structure of these channels makes it easier to identify potential drug targets or therapeutic ways of interfering with these channels activity. Disrupting the movement of urea into the cell would compromise the microbe's ability to neutralize its environment, rendering the bacterium unable to survive in the extremely acidic human stomach. Instead of relying on antibiotics as a catch-all treatment for H. Pylori infection, which may sometimes harm the 'good' bacteria in our gut, solving the structure of the microbe's membrane urea channels may permit for the design of a more specific and reliable way of targeting the bacterium in the stomach.