The Reductive Dehydroxylation Catalyzed by IspH, a Source of Inspiration for the Development of Novel Anti-Infectives

International audienceThe non-mevalonate or also called MEP pathway is an essential route for the biosynthesis of isoprenoid precursors in most bacteria and in microorganisms belonging to the Apicomplexa phylum, such as the parasite responsible for malaria. The absence of this pathway in mammalians makes it an interesting target for the discovery of novel anti-infectives. As last enzyme of this pathway, IspH is an oxygen sensitive [4Fe-4S] metalloenzyme that catalyzes 2H+/2e- reductions and a water elimination by involving non-conventional bioinorganic and bioorganometallic intermediates. After a detailed description of the discovery of the [4Fe-4S] cluster of IspH, this review focuses on the IspH mechanism discussing the results that have been obtained in the last decades using an approach combining chemistry, enzymology, crystallography, spectroscopies, and docking calculations. Considering the interesting druggability of this enzyme, a section about the inhibitors of IspH discovered up to now is reported as well. The presented results constitute a useful and rational help to inaugurate the design and development of new potential chemotherapeutics against pathogenic organisms

Synthesis and kinetic evaluation of analogs of (E)-4-amino-3-methylbut-2-en-1-yl diphosphate, a potent inhibitor of the IspH metalloenzyme

International audienceOur previous research revealed that (E)-4-amino-3-methylbut-2-en-1-yl diphosphate (AMBPP) is one of the best inhibitors of IspH, a [4Fe-4S]-dependent enzyme involved in the methylerythritol phosphate pathway that is a valuable target for the discovery of new antibacterial and antiparasitic drugs as it is absent in humans. AMBPP has substantial limitations for drug development due to its poor metabolic stability. Here, we investigate the replacement of the diphosphate moiety of AMBPP by more stable mimics: sulfonate, phosphonate or phosphinophosphonate. After synthesis of the derivatives, enzymatic assays demonstrated that none of these AMBPP analogs is an efficient IspH inhibitor