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IspG (also called GcpE) is an oxygen‐sensitive [4Fe‐4S] enzyme catalyzing the penultimate step of the methylerythritol phosphate (MEP) pathway, a validated target for drug development. It converts 2‐C‐methyl‐d‐erythritol‐2,4‐cyclo‐diphosphate (MEcPP) into (E)‐4‐hydroxy‐3‐methyl‐but‐2‐enyl‐1‐diphosphate (HMBPP). The reaction, assimilated to a reductive dehydration, involves redox partners responsible for the formal transfer of two electrons to substrate MEcPP. The 2‐vinyl analogue of MEcPP was designed to generate conjugated species during enzyme catalysis, with the aim of providing new reactive centers to be covalently trapped by neighboring amino acid residues. The synthesized substrate analogue displayed irreversible inhibition towards IspG. Furthermore, we have shown that electron transfer occurs prior to inhibition; this might designate conjugated intermediates as probable affinity tags through covalent interaction at the catalytic site. This is the first report of an irreversible inhibitor of the IspG metalloenzyme. [ABSTRACT FROM AUTHOR]

[4Fe-4S] enzymes, fraudulent substrates, irreversible inhibition, IspG (GcpE), MEP pathway Cover Feature: Irreversible Inhibition of IspG, a Target for the Development of New Antimicrobials, by a 2-Vinyl Analogue of its MEcPP Substrate (Chem. Eur. J. 30/2022) Keywords: [4Fe-4S] enzymes; fraudulent substrates; irreversible inhibition; IspG (GcpE); MEP pathway EN [4Fe-4S] enzymes fraudulent substrates irreversible inhibition IspG (GcpE) MEP pathway 1 1 1 05/27/22 20220525 NES 220525 B The rational design b of a substrate analogue has afforded the first irreversible inhibitor of an IspG enzyme, a target for the development of new drugs to fight antimicrobial resistance. [Extracted from the article]