Neutron analysis at the Department of Energy's Oak Ridge National Laboratory is helping researchers better understand a key enzyme found in a bacterium known to cause stomach cancer.
Understanding the details of this enzyme, and thus the Helicobacter pylori bacteria's metabolism and biological pathways, could be central to developing drugs that act against H. pylori, but that do not attack the stomach's useful bacteria.
"Most drugs, including common antibiotics, use a generalized mechanism to bind to their targets, which, in turn, eliminates the good bacteria you need to stay healthy, as well as the bad bacteria," said Andrey Kovalevsky, one of the instrument scientists at the ORNL High Flux Isotope Reactor and coauthor of this research published in the Proceedings of the National Academy of Sciences.
"By understanding how this enzyme functions, we can get clues about how to fine-tune a drug to recognize only a specific target, which would eliminate some of the side effects that cause so many problems for people when a more generalized approach to kill bacteria is used."
Kovalevsky was part of a team led by Donald Ronning at the University of Toledo who used HFIR's IMAGINE instrument to study the metabolism of a bacterial enzyme known as H. pylori 5'-methylthioadenosine nucleosidase, or HpMTAN, which plays a key function in H. pylori. This bacterium garnered international attention in 2005 when a team of researchers was awarded the Nobel Prize in Medicine for determining its role as a "bacterial culprit" in the development of gastric conditions, including ulcers, chronic gastritis and cancer.
Ronning's team focused on H. pylori's use of a unique biosynthetic pathway to synthesize vitamin K2, which aids in the electron transfer processes, or chemical reactions, of all organisms. HpMTAN is one specific enzyme that functionbs within this unique pathway and provides the promising specific target or point of attack for new medications. Vitamin K2 acts to expedite the HpMTAN enzyme's interaction with other macromolecules, including the very bacterium that causes an array of gastric health issues.
Neutron crystallography at HFIR's IMAGINE instrument allowed researchers to accurately visualize the positions and predict the movements of hydrogen atoms in HpMTAN, especially those involved in the critical stages when the enzyme binds to its substrate and then proceeds with the catalytic reaction.
For a comprehensive view on the interatomic interactions, Ronning's team examined four different HpMTAN neutron structures to observe how ligands, or molecules that bind via noncovalent bonding, interacted with their respective enzyme sites.
"This knowledge will inform future drug design efforts by taking advantage of the known orientation of the nucleophilic water molecule and its intimate interactions with the neighboring components of the enzyme," Ronning said.
While Ronning qualified that the development of a new drug to treat gastric issues will take several years and continued study of the enzyme's behavior, he said that his team's research confirms HpMTAN's potential for use and this knowledge could, in fact, speed up the creation of such a medicine.
This research was partially funded through the National Institute of Health's National Institute of Allergy and Infectious Disease and a cooperative agreement with the National Aeronautics and Space Administration's Center for the Advancement of Science in Space. The work was conducted in part at the Heinz Maier-Leibnitz Research Neutron Source with the Technical University of Munich, both in Munich, Germany, and at ORNL's High Flux Isotope Reactor, a DOE Office of Science User Facility.
UT-Battelle manages ORNL for the DOE's Office of Science. The Office of Science is the single largest supporter of basic research in the physical sciences in the United States, and is working to address some of the most pressing challenges of our time. For more information, please visit http://science.
Katie Bethea | EurekAlert!
NIH scientists describe potential antibody treatment for multidrug-resistant K. pneumoniae
14.03.2018 | NIH/National Institute of Allergy and Infectious Diseases
Researchers identify key step in viral replication
13.03.2018 | University of Pittsburgh Schools of the Health Sciences
Animal photoreceptors capture light with photopigments. Researchers from the University of Göttingen have now discovered that these photopigments fulfill an...
On 15 March, the AWI research aeroplane Polar 5 will depart for Greenland. Concentrating on the furthest northeast region of the island, an international team...
The world’s second-largest ice shelf was the destination for a Polarstern expedition that ended in Punta Arenas, Chile on 14th March 2018. Oceanographers from...
At the 2018 ILA Berlin Air Show from April 25–29, the Fraunhofer Institute for Laser Technology ILT is showcasing extreme high-speed Laser Material Deposition (EHLA): A video documents how for metal components that are highly loaded, EHLA has already proved itself as an alternative to hard chrome plating, which is now allowed only under special conditions.
When the EU restricted the use of hexavalent chromium compounds to special applications requiring authorization, the move prompted a rethink in the surface...
At the ILA Berlin, hall 4, booth 202, Fraunhofer FHR will present two radar sensors for navigation support of drones. The sensors are valuable components in the implementation of autonomous flying drones: they function as obstacle detectors to prevent collisions. Radar sensors also operate reliably in restricted visibility, e.g. in foggy or dusty conditions. Due to their ability to measure distances with high precision, the radar sensors can also be used as altimeters when other sources of information such as barometers or GPS are not available or cannot operate optimally.
Drones play an increasingly important role in the area of logistics and services. Well-known logistic companies place great hope in these compact, aerial...
16.03.2018 | Event News
13.03.2018 | Event News
08.03.2018 | Event News
16.03.2018 | Earth Sciences
16.03.2018 | Physics and Astronomy
16.03.2018 | Life Sciences