Irreversible Inhibition of IspG, a Target for the Development of New Antimicrobials, by a 2‐Vinyl Analogue of its MEcPP Substrate

Vivien Herrscher (1) , Clea Witjaksono (2) , Marie Buchotte (1) , Claire Ferret (2) , Fabien Massicot (1) , Jean-Luc Vasse (1) , Franck Borel (3) , Jean-Bernard Behr (1) , Myriam Seemann (2)

1 ICMR - Institut de Chimie Moléculaire de Reims - UMR 7312
2 Institut de Chimie de Strasbourg
3 IBS - UMR 5075 - Institut de biologie structurale

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.

Mots clés: [4Fe-4S] enzymes; fraudulent substrates; irreversible inhibition; IspG (GcpE); MEP pathway

Domaines: Chimie; Chimie organique; Sciences du Vivant [q-bio]

Vivien Herrscher, Clea Witjaksono, Marie Buchotte, Claire Ferret, Fabien Massicot, et al.. Irreversible Inhibition of IspG, a Target for the Development of New Antimicrobials, by a 2‐Vinyl Analogue of its MEcPP Substrate. Chemistry - A European Journal, 2022, 28 (30), pp.e202200241. ⟨10.1002/chem.202200241⟩. ⟨hal-03845648⟩