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.
Highlights
Isoprenoids are present in all living organisms and are involved in numerous important biological processes
The group of Jomaa reported that an E. coli mutant harboring a deletion of the lytB gene and engineered for the utilization of exogenous mevalonate, accumulates an immunogenic compound stimulating the proliferation of Vγ9/Vδ2 T cells
When lytB was absent in the construction, the mutant accumulated [U-13C6]HMBPP from [U-13C6]DX [22]. These results indicate that the lytB gene product, further called LytB or IspH, catalyzes the conversion of HMBPP into IPP and DMAPP in a mixture of 5:1
Summary
IspH as an enzyme of the MEP pathway occurs in most bacteria, plant chloroplasts, green algae, and apicomplexan but is absent in humans [7]. The group of Jomaa reported that an E. coli mutant harboring a deletion of the lytB gene and engineered for the utilization of exogenous mevalonate (to rescue the cells and allow the synthesis of crucial isoprenoids when the endogenous MEP pathway is disrupted), accumulates an immunogenic compound stimulating the proliferation of Vγ9/Vδ2 T cells. This compound was identified as HMBPP 19 after its isolation followed by a complete characterization using NMR spectroscopy and mass spectrometry, affording the first evidence that HMBPP was the substrate of the lytB gene product [20]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
