2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase (IspF) (IspF)

2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase (IspF) is a key enzyme in the non-mevalonate (MEP) pathway, which is responsible for the biosynthesis of essential isoprenoid precursors in many bacteria and protozoan parasites [1, 5, 6]. This pathway is essential for the survival of pathogens such as Mycobacterium tuberculosis and Plasmodium falciparum but is entirely absent in humans, making IspF an attractive target for selective antimicrobial and antimalarial drug development [3, 6, 15, 19]. The enzyme catalyzes the conversion of 4-diphosphocytidyl-2-C-methyl-D-erythritol 2-phosphate (CDP-ME2P) into 2-C-methyl-D-erythritol 2,4-cyclodiphosphate (MEcPP) and cytidine monophosphate (CMP) [1, 6]. Structurally, IspF typically exists as a homotrimer with active sites located at the subunit interfaces, requiring divalent metal ions like zinc or magnesium for activity [1, 5, 21]. Various small-molecule inhibitors have been explored, including thiazolopyrimidines, aryl bis-sulfonamides, and cytidine analogs, which target the enzyme's lipophilic active site [18, 20, 23, 27]. Although no IspF-targeted drugs have reached clinical approval, the enzyme remains a high-priority target for addressing drug-resistant infections due to its unique role in microbial metabolism [19, 21, 32].

Other names

mecSygbBMEcPP synthase2-methylerythritol 2,4-cyclodiphosphate synthase

Inhibition of 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase activity, which disrupts the production of isoprenoid precursors (isopentenyl diphosphate and dimethylallyl diphosphate) via the non-mevalonate (MEP) pathway [1, 5, 6].