The findings appear in the Proceedings of the National Academy of Sciences.
"There is an urgent need for new drugs to combat malaria and bacterial diseases such as tuberculosis that are becoming resistant to existing treatments," said chemistry professor Eric Oldfield, who led the study. "Millions of people have tuberculosis, for example, and some of the bacterial strains that cause TB are completely drug resistant," he said. The parasites that cause malaria also have become resistant to quinine, chloroquine and now, artemisinin, three common treatments for the disease.
The new study focuses on an essential chemical pathway that occurs in malaria parasites and in most bacteria but not in humans or other animals, making it an ideal drug target. Several teams of researchers have spent nearly a decade trying to understand an important player in this cascade of chemical reactions, an enzyme known as IspH. This enzyme promotes the synthesis of a class of compounds, called isoprenoids, which are essential to life.
"Isoprenoids are the largest class of compounds on the planet," Oldfield said. "There are over 60,000 of them. Cholesterol is an isoprenoid. The orange beta-carotene in carrots is an isoprenoid. And bacterial cell walls are made using isoprenoids."
IspH (rhymes with "lisp, H") is a reductase. It acts on a cellular compound, HMBPP, "reducing" it by adding two electrons and two protons to it in an early stage of isoprenoid biosynthesis. Understanding the structure and function of IspH, researchers hope, will allow them to find a way to block it and shut down production of isoprenoids in the disease-causing bugs.
Oldfield and his colleagues already had discovered the structure of IspH, which has a cube-like cluster of iron and sulfur atoms at its core. They determined that the core contained four iron and four sulfur atoms, a finding they published in the Journal of the American Chemical Society in 2008. (Other researchers later maintained that there were only three iron atoms in IspH, but recently amended their proposed structure to include four iron atoms.)
In the search for possible compounds that would inhibit IspH, Oldfield and his colleagues, including graduate student Weixue Wang, turned to a powerful technique, called electron paramagnetic resonance (EPR), which allows researchers to determine molecular structure.
"We thought we could use this EPR technique to see how inhibitors bind to IspH," Oldfield said. "But some of the early EPR spectra that Weixue got were really unusual."
To make sense of what he was seeing, Wang reviewed other studies and discovered that the unusual spectra closely resembled those seen with another enzyme, nitrogenase, which also has a metal-sulfur core and also acts as a reductase. His EPR spectra, along with data obtained using computational methods, convinced the researchers that during the chemical reaction, IspH and the compound that it reduces, HMBPP, form an intermediate that involves a highly unusual iron-carbon bond.
"People have been studying iron-sulfur clusters for 40 or 50 years," Wang said. "But they never discovered such interactions between iron and carbon in four-iron, four-sulphur proteins."
The researchers noted that a chemical compound, acetylene, blocks the activity of nitrogenase. They reasoned that this compound – or a similar one – might also inhibit IspH.
They made derivatives of acetylene and engineered a compound, which they call PPP, to test against IspH. Laboratory tests revealed that PPP is in fact a powerful inhibitor of IspH.
"It's one thousand times more potent than previous inhibitors," Oldfield said.
PPP has not yet been tested in cells, and much work remains to be done to develop anti-malarial or antibacterial drugs based on the new findings, Oldfield said.
"We're really at the initial, key stage, which is understanding structure and function and getting clues for inhibitors – drug leads," he said. "But there are a finite number of proteins unique to bacteria and malaria parasites that can be targeted for the development of new drugs. And everyone agrees that this enzyme, IspH, is a tremendous target."
"The Oldfield group has uncovered completely unexpected behavior for iron-sulfur clusters," said U. of I. chemistry professor Thomas B. Rauchfuss, who was not involved in the study. "We can expect that their discovery will lead to intense follow-up studies because the results have obvious implications for both biomedicine and organometallic catalysis. Iron-sulfur clusters are found in all forms of life, so when a new function is discovered, it is big news to a wide community."
The National Institute of General Medical Sciences at the National Institutes of Health funded this research.
Editor's note: To reach Eric Oldfield, call 217- 333-3374; e-mail email@example.com.
The paper, "Bioorganometallic mechanism of action, and inhibition, of IspH," is available from the University of Illinois News Bureau. See contact information, above.
Diana Yates | EurekAlert!
Monitoring biodiversity with sound: how machines can enrich our knowledge
18.06.2019 | Georg-August-Universität Göttingen
Uncovering hidden protein structures
18.06.2019 | Universität Konstanz
The well-known representation of chemical elements is just one example of how objects can be arranged and classified
The periodic table of elements that most chemistry books depict is only one special case. This tabular overview of the chemical elements, which goes back to...
Light can be used not only to measure materials’ properties, but also to change them. Especially interesting are those cases in which the function of a material can be modified, such as its ability to conduct electricity or to store information in its magnetic state. A team led by Andrea Cavalleri from the Max Planck Institute for the Structure and Dynamics of Matter in Hamburg used terahertz frequency light pulses to transform a non-ferroelectric material into a ferroelectric one.
Ferroelectricity is a state in which the constituent lattice “looks” in one specific direction, forming a macroscopic electrical polarisation. The ability to...
Researchers at TU Graz calculate the most accurate gravity field determination of the Earth using 1.16 billion satellite measurements. This yields valuable knowledge for climate research.
The Earth’s gravity fluctuates from place to place. Geodesists use this phenomenon to observe geodynamic and climatological processes. Using...
Discovery by Brazilian and US researchers could change the classification of two species, which appear more akin to jellyfish than was thought.
The tube anemone Isarachnanthus nocturnus is only 15 cm long but has the largest mitochondrial genome of any animal sequenced to date, with 80,923 base pairs....
Researchers at Chalmers University of Technology, Sweden, have discovered a completely new way of capturing, amplifying and linking light to matter at the nanolevel. Using a tiny box, built from stacked atomically thin material, they have succeeded in creating a type of feedback loop in which light and matter become one. The discovery, which was recently published in Nature Nanotechnology, opens up new possibilities in the world of nanophotonics.
Photonics is concerned with various means of using light. Fibre-optic communication is an example of photonics, as is the technology behind photodetectors and...
29.04.2019 | Event News
17.04.2019 | Event News
15.04.2019 | Event News
18.06.2019 | Life Sciences
18.06.2019 | Life Sciences
18.06.2019 | Life Sciences