ArticleJournal of the American Chemical Society2013
Inhibition of IspH, a [4Fe-4S]2+ enzyme involved in the biosynthesis of isoprenoids via the methylerythritol phosphate pathway.
Article in Journal of the American Chemical Society, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 41 citations in OpenAlex.
- Mössbauer spectroscopy in drug discovery: revealing Fe- and Fe-S cluster dependent targets.Expert opinion on drug discovery · 2026Review
- Unconventional T cells in urological cancers: catch them if you can.Nature reviews. Urology · 2026Review
- MEP Pathway: First-Synthesized IspH-Directed Prodrugs with Potent Antimycobacterial Activity.Microorganisms · 2026Article
- Resonance Raman Spectroscopic Study of the Unusual [4Fe-4S]Chembiochem : a European journal of chemical biology · 2025Article
- Flavonoids as Promising Natural Compounds for Combating Bacterial Infections.International journal of molecular sciences · 2025Review
- Studying Target-Engagement of Anti-Infectives by Solvent-Induced Protein Precipitation and Quantitative Mass Spectrometry.ACS infectious diseases · 2024Article
- Enantioselective Synthesis of Sealutomicin C.Journal of the American Chemical Society · 2024Article
- The Multifaceted MEP Pathway: Towards New Therapeutic Perspectives.Molecules (Basel, Switzerland) · 2023Review
- The Reductive Dehydroxylation Catalyzed by IspH, a Source of Inspiration for the Development of Novel Anti-Infectives.Molecules (Basel, Switzerland) · 2022Review
- Microbial (Frontiers in bioengineering and biotechnology · 2022Review
- Article
- Synthesis and Bioactivity of the Alanyl Phosphonamidate Stereoisomers Derived from a Butyrophilin Ligand.ACS medicinal chemistry letters · 2019Article
- Mixed Aryl Phosphonate Prodrugs of a Butyrophilin Ligand.ACS medicinal chemistry letters · 2017Article
- Spectroscopic and Computational Investigations of Ligand Binding to IspH: Discovery of Non-diphosphate Inhibitors.Chembiochem : a European journal of chemical biology · 2017Article
- Structure and Function of Four Classes of the 4Fe-4S Protein, IspH.Biochemistry · 2016Article
- New Insight into Isoprenoids Biosynthesis Process and Future Prospects for Drug Designing in Plasmodium.Frontiers in microbiology · 2016Review
- Isoprenoid Biosynthesis in Pathogenic Bacteria: Nuclear Resonance Vibrational Spectroscopy Provides Insight into the Unusual [4Fe-4S] Cluster of the E. coli LytB/IspH Protein.Angewandte Chemie (International ed. in English) · 2015Article
- Mechanistic insights into the reductive dehydroxylation pathway for the biosynthesis of isoprenoids promoted by the IspH enzyme.Chemical science · 2015Article
- Broken-Symmetry DFT Computations for the Reaction Pathway of IspH, an Iron-Sulfur Enzyme in Pathogenic Bacteria.Inorganic chemistry · 2015Article
- Synthesis of methylerythritol phosphate analogues and their evaluation as alternate substrates for IspDF and IspE from Agrobacterium tumefaciens.The Journal of organic chemistry · 2014Article
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
The MEP pathway, which is absent in animals but present in most pathogenic bacteria, in the parasite responsible for malaria and in plant plastids, is a target for the development of antimicrobial drugs. IspH, an oxygen-sensitive [4Fe-4S] enzyme, catalyzes the last step of this pathway and converts (E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate (HMBPP) into the two isoprenoid precursors: isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). A crucial step in the mechanism of this enzyme is the binding of the C4 hydroxyl of HMBPP to the unique fourth iron site in the [4Fe-4S](2+) moiety. Here, we report the synthesis and the kinetic investigations of two new extremely potent inhibitors of E. coli IspH where the OH group of HMBPP is replaced by an amino and a thiol group. (E)-4-Mercapto-3-methylbut-2-en-1-yl diphosphate is a reversible tight-binding inhibitor of IspH with K(i) = 20 ± 2 nM. A detailed kinetic analysis revealed that (E)-4-amino-3-methylbut-2-en-1-yl diphosphate is a reversible slow-binding inhibitor of IspH with K(i) = 54 ± 19 nM. The slow binding behavior of this inhibitor is best described by a one-step mechanism with the slow step consisting of the formation of the enzyme-inhibitor (EI) complex.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.