The new study focused 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.
IspH 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.
In the search for possible compounds that would inhibit IspH, researchers, 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," lead author Eric Oldfield said. "But some of the early EPR spectra...were really unusual."
Researchers 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. The 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.
The team 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.
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."
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