Work

Substitution of CH 3 by CH 2 F in 2‐Methylerythritol Cyclodiphosphate Triggers Potent Inhibition of IspG with Concomitant Fluoride Ion Expulsion

Year: 2025

Type: article

Abstract: IspG (also known as GcpE) is a key [4Fe‐4S] metalloenzyme that catalyzes the penultimate step of the methylerythritol phosphate (MEP) pathway, a well‐established target for the development of new antimicrobials. This oxygen‐sensitive enzyme mediates the reductive dehydroxylation of 2‐ C ‐methyl‐ d ‐erythritol 2,4‐cyclodiphosphate (MEcPP) to ( E )‐4‐hydroxy‐3‐methylbut‐2‐en‐1‐yl diphosphate (HMBPP), requiring electron transfer proteins to deliver two electrons needed for catalysis. To probe the mechanism of IspG and access new mechanism‐based inhibitors, we synthesized a substrate analogue, monofluoromethyl‐ d ‐erythritol cyclodiphosphate, in which the natural methyl group of MEcPP is replaced by a CH 2 F group. This analogue proved to be a potent inhibitor of IspG. This study also demonstrates that electron capture is a prerequisite for inhibition and that the inhibitor leads to fluoride release in the IspG‐catalyzed reaction. Together, these results provide further support for the involvement of a carbanionic intermediate in the IspG mechanism.

Source: Chemistry - A European Journal

DOI: 10.1002/chem.202502471