The iron-sulfur protein IspH plays a central role in the terpene metabolism of several pathogens. The mechanism of the reaction provides an approach for developing new antibiotics, particularly against malaria and tuberculosis. While researching this enzyme, biochemists at the Technische Universität München (TUM) discovered a previously unknown reaction: IspH accepts two completely different classes of molecules as partners. This surprising insight, published in Nature Communications, opens up new perspectives in combating infectious diseases.
Terpenes constitute one of the largest and most versatile classes of natural compounds – familiar examples are cholesterol and estrogen. In all organisms the biosynthesis of terpenes starts from the two building blocks isopentenyl-diphosphate (IPP) and dimethylallyl diphosphate (DMAPP); however, mammals and bacteria use different biosynthetic pathways to do this. In bacteria and pathogenic microorganisms the enzyme IspH catalyzes the last step in the production of IPP and DMAPP. Thus for several years scientists have recognized the potential of IspH as a point of attack in developing drugs against malaria and tuberculosis.
Now Prof. Michael Groll and Dr. Ingrid Span at the TUM Chair of Biochemistry have made a significant breakthrough in this area. They have been working with Prof. Eric Oldfield and his group at the University of Illinois to characterize certain acetylene compounds that inhibit the IspH enzyme. With the aid of X-ray crystallography, they discovered that the enzyme not only binds several of these molecules to its active site but also modifies them: Through the additionof water to the acetylene groups (hydrocarbons with triple bonds), the compounds are converted to aldehydes or ketones. “In general enzymes react with only one specific substrate,” explains Ingrid Span. “So we were surprised to find that IspH, in contrast, accepts two completely different classes of molecules."