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

Abstract

The 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.

Computer-Based Identification of Potential Druggable Targets in Multidrug-Resistant Acinetobacter baumannii: A Combined In Silico, In Vitro and In Vivo Study

“…Previous studies have reported identifying potential drug targets in A. baumannii by the subtractive proteomics approach [ 20 , 21 , 22 , 49 ]. Some of the 68 shortlisted drug targets in the current study have been reported in previous studies [ 20 , 21 , 22 , 50 , 51 , 52 , 53 ]. However, it is worth mentioning that our study is the first one to proceed with further in vitro and in vivo validation.…”

Biomimetic Radical Chemistry and Applications

“…An overview of reductive dihydroxylation catalyzed by IspH, an enzyme involved in the biosynthesis of isoprenoids, has been reviewed [ 27 ]. IspH is an oxygen sensitive [4Fe-4S] metalloenzyme that catalyzes 2H + /2e − reductions and water elimination by involving non-conventional bioinorganic and bioorganometallic intermediates.…”

Carbohydrate-Templated Syntheses of Trifluoromethyl-Substituted MEP Analogues for the Study of the Methylerythritol Phosphate Pathway

“…Therefore, the seven enzymes involved in the MEP pathway (steps i to vii, Figure ) have been the subject of a number of studies with the ultimate goal to identify new drugs with unprecedented modes of action . Regarding mechanistic aspects, the seven reactions include examples of complex enzyme-catalyzed transformations, which culminate in final reductive ring opening and hydroxy-group elimination via iron–sulfur clusters-mediated electron transfers . Strategies based on FABS have been used in the study of some of the enzymes of the MEP pathway, as exemplified in Figure .…”