Biosynthesis of isoprenoids : iron-sulfur enzymes as therapeutic targets

The functional importance of iron-sulfur proteins makes them, under certain conditions, potential therapeutic targets of great interest. This concept is illustrated here with the case of the biosynthesis of the isoprenoid precursors isopentenylpyrophosphate (IPP) and dimethyallypyrophosphate (DMAPP). Isoprenoids are a group of natural molecules that play essential roles in biology (ubiquinone, vitamin E, cholesterol, carotene, etc.). It was recently discovered that the biosynthesis of IPP and DMAPP uses different pathways in humans (the mevalonate pathway) and in certain pathogenic bacteria (the methyl-erythritolphosphate pathway), making it possible to envisage highly selective antibacterial approaches, specifically targeting the second pathway. In this lecture, we show how two iron-sulfur enzymes, IspG and IspH, involved in this biosynthetic pathway, are studied in great depth from the point of view of their structure and reactivity, in order to develop selective and effective inhibitor molecules. Recent results offer hope for future applications in antibacterial therapy, based on molecules developed using this approach.