Insights into the biosynthesis of isoprenoid precursors and their potential in semisynthetic strategies

• Applicant: Professor Dr. Michael Groll
• Subject Area: Structural Biology
• Term: from 2011 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 195109706

Isoprenoids (terpenes) are the largest group of known natural products (at least 35,000) [1]. Whereas animals biosynthesize isoprenoids via the mevalonate pathway, it is now established that many pathogenic bacteria and the apicomplexan subgroup of pathogenic protozoa use the more recently discovered nonmevalonate pathway for that purpose. The enzymes of the non-mevalonate pathway are essential in these pathogens. They are promising targets for the development of novel antiinfective drugs which should be exempt from target-related toxicity, due to the absence of the pathway in the human host. The final steps of the non-mevalonate pathway affording the universal isoprenoid precursors IPP and DMAPP are catalyzed by two iron-sulfur proteins specified by the ispG and ispH genes. Recently, we have determined the crystal structures of IspG and IspH protein. This work will serve as basis for the further elucidation of the reaction mechanisms of these proteins, using X-ray crystallography, enzyme kinetics, NMR and as well as sitedirected mutagenesis. These methods will also be applied to study the mode of action of IspG and IspH inhibitors.

• DFG Programme: Research Grants
• International Connection: USA
• Cooperation Partner: Professor Eric Oldfield, Ph.D.