Chemists at the University of Illinois and collaborators in Taiwan studied a type of enzyme found in humans, plants, fungi, parasites, and many bacteria that begins the synthesis of triterpenes – one of the most abundant and most ancient classes of molecules. Triterpenes are precursors to steroids such as cholesterol.
“These enzymes are important drug targets,” said chemistry professor Eric Oldfield, who co-led the study. “Blocking their activity can lead to new cholesterol-lowering drugs, antibiotics that cure staph infections, and drugs that target the parasites that cause tropical maladies such as Chagas disease – a leading cause of sudden death in Latin America.”
For the study, the team picked a representative enzyme, dehydrosqualene synthase (CrtM), from the Staphylococcus aureus bacterium. Staph is one of the most common, yet notoriously hard to kill, bacterial infections. A key reason for staph’s resilience is a golden-colored coating called staphyloxanthin that protects it from the body’s immune system. CrtM catalyzes the first reaction in making staphyloxanthin, so inhibiting it would strip the bacteria of their protective coats and leave them vulnerable to attack by white blood cells.
The researchers already knew what CrtM looked like and its end product, but they didn’t know how the enzyme did its job. Uncovering the mechanism of action would enable scientists to design better inhibitors, and even tailor them to other targets.
The team crystallized the enzyme and soaked it with intermediates and inhibitors. They then studied the complex structures by X-ray crystallography using the synchrotron at the Advanced Photon Source at Argonne National Laboratory.
They found that CrtM performs a two-step reaction, individually removing two diphosphate groups from the substrate. The substrate switches between two active sites within the enzyme as the reaction progresses. The most effective inhibitors bind to both sites, blocking the enzyme from any action.
“The leads that people have been developing for treating these diseases really haven’t had any structural basis,” said Oldfield, also a professor of biophysics. “But now that we can see how the protein works, we’re in a much better position to design molecules that will be much more effective against staph infections and parasitic diseases, and potentially, in cholesterol-lowering.”
The researchers’ inhibitor technologies have been licensed to AuricX Pharmaceuticals, which recently received a grant from the Texas Emerging Technology Fund for preclinical testing in staph infections.
The team published its work in the Proceedings of the National Academy of Sciences. The work was sponsored by the National Institutes of Health and the National Science Council. Co-authors were U. of I. graduate students Fu-Yang Lin and Yi-Liang Liu, research scientists Rong Cao and Yonghui Zhang, and postdoctoral associate Ke Wang. Taiwan collaborators included Chia-I Liu, Wen-Yih Jeng, Tzu-Ping Ko and Andrew H. Wang.
Liz Ahlberg | University of Illinois
Don't Give the Slightest Chance to Toxic Elements in Medicinal Products
23.03.2018 | Physikalisch-Technische Bundesanstalt (PTB)
North and South Cooperation to Combat Tuberculosis
22.03.2018 | Universität Zürich
Satellites in near-Earth orbit are at risk due to the steady increase in space debris. But their mission in the areas of telecommunications, navigation or weather forecasts is essential for society. Fraunhofer FHR therefore develops radar-based systems which allow the detection, tracking and cataloging of even the smallest particles of debris. Satellite operators who have access to our data are in a better position to plan evasive maneuvers and prevent destructive collisions. From April, 25-29 2018, Fraunhofer FHR and its partners will exhibit the complementary radar systems TIRA and GESTRA as well as the latest radar techniques for space observation across three stands at the ILA Berlin.
The "traffic situation" in space is very tense: the Earth is currently being orbited not only by countless satellites but also by a large volume of space...
An international team of researchers has discovered a new anti-cancer protein. The protein, called LHPP, prevents the uncontrolled proliferation of cancer cells in the liver. The researchers led by Prof. Michael N. Hall from the Biozentrum, University of Basel, report in “Nature” that LHPP can also serve as a biomarker for the diagnosis and prognosis of liver cancer.
The incidence of liver cancer, also known as hepatocellular carcinoma, is steadily increasing. In the last twenty years, the number of cases has almost doubled...
In just a few weeks from now, the Chinese space station Tiangong-1 will re-enter the Earth's atmosphere where it will to a large extent burn up. It is possible that some debris will reach the Earth's surface. Tiangong-1 is orbiting the Earth uncontrolled at a speed of approx. 29,000 km/h.Currently the prognosis relating to the time of impact currently lies within a window of several days. The scientists at Fraunhofer FHR have already been monitoring Tiangong-1 for a number of weeks with their TIRA system, one of the most powerful space observation radars in the world, with a view to supporting the German Space Situational Awareness Center and the ESA with their re-entry forecasts.
Following the loss of radio contact with Tiangong-1 in 2016 and due to the low orbital height, it is now inevitable that the Chinese space station will...
Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, provider of research and development services for OLED lighting solutions, announces the founding of the “OLED Licht Forum” and presents latest OLED design and lighting solutions during light+building, from March 18th – 23rd, 2018 in Frankfurt a.M./Germany, at booth no. F91 in Hall 4.0.
They are united in their passion for OLED (organic light emitting diodes) lighting with all of its unique facets and application possibilities. Thus experts in...
A new scenario seeking to explain how Mars' putative oceans came and went over the last 4 billion years implies that the oceans formed several hundred million...
23.03.2018 | Event News
19.03.2018 | Event News
16.03.2018 | Event News
23.03.2018 | Materials Sciences
23.03.2018 | Agricultural and Forestry Science
23.03.2018 | Physics and Astronomy