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

2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase (IspF) is a critical enzyme in the non-mevalonate (MEP) pathway, which is the primary route for isoprenoid biosynthesis in many pathogenic bacteria and apicomplexan parasites [1, 11]. It catalyzes the conversion of 4-diphosphocytidyl-2-C-methyl-D-erythritol 2-phosphate into 2-C-methyl-D-erythritol 2,4-cyclodiphosphate and cytidine monophosphate [2, 11]. This enzyme is essential for the survival of major human pathogens, including Mycobacterium tuberculosis and Plasmodium falciparum, the causative agents of tuberculosis and malaria, respectively [4, 7, 9]. Because the MEP pathway is absent in humans, who instead utilize the mevalonate pathway, IspF represents a highly selective target for antimicrobial and antiparasitic drug development [1, 5, 17]. Structurally, the enzyme functions as a homotrimer with active sites that require divalent metal ions, such as zinc and magnesium, for catalysis [1, 4, 12]. Although no IspF inhibitors have yet reached clinical approval, several classes of experimental compounds, including thiazolopyrimidines and cytosine analogs, have demonstrated potent inhibitory activity in vitro [3, 7, 8]. The primary challenge in targeting IspF involves optimizing the drug-like properties and cellular permeability of inhibitors to effectively reach the enzyme within the pathogen [3, 5]. Overall, IspF remains a promising candidate for the development of next-generation anti-infective therapies with minimal risk of host toxicity [5, 17].

Other names

IspFMECDP synthaseMECP synthaseygbB2-C-methyl-D-erythritol 2,4-cyclopyrophosphate synthaseMDS

Inhibition of the IspF enzyme, leading to the disruption of the MEP pathway and depletion of essential isoprenoid precursors.