Substitution of CH₃ by CH₂F in 2-Methylerythritol Cyclodiphosphate Triggers Potent Inhibition of IspG with Concomitant Fluoride Ion Expulsion.

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 CH₂F group. This analogue proved to be a potent inhibitor of IspG. This study also demonst

SUBMITTER: Witjaksono C 

PROVIDER: S-EPMC12648460 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature