4-diphosphocytidyl-2-C-methyl-D-erythritol kinase (IspE)

4-diphosphocytidyl-2-C-methyl-D-erythritol kinase (IspE) is an essential enzyme in the non-mevalonate (MEP) pathway, which is the primary route for isoprenoid biosynthesis in many bacteria and apicomplexan parasites [1, 2]. It catalyzes the ATP-dependent phosphorylation of 4-diphosphocytidyl-2-C-methyl-D-erythritol (CDP-ME) at the 2-hydroxy position to form 4-diphosphocytidyl-2-C-methyl-D-erythritol 2-phosphate (CDP-MEP) [2, 4]. This enzyme is vital for the survival of pathogens such as Plasmodium falciparum, the causative agent of malaria, and Mycobacterium tuberculosis, the cause of tuberculosis [2, 10]. Because the MEP pathway is absent in humans, who instead utilize the mevalonate pathway, IspE is considered a highly attractive target for the development of selective antimicrobial and antiparasitic agents [1, 2, 4]. Drug discovery efforts have focused on identifying small-molecule inhibitors, including cytidine analogs and benzimidazole derivatives, through high-throughput screening and structure-based design [1, 3]. While several potent in vitro inhibitors have been identified, translating these into effective clinical candidates remains a challenge due to issues with cellular permeability and structural variations among different species [2, 14]. The inhibition of IspE leads to the depletion of essential isoprenoid precursors, ultimately resulting in the death of the target pathogen [2, 4].

Other names

CDP-ME kinase [3, 4]CMK [8]4-(cytidine-5'-diphospho)-2-C-methyl-D-erythritol kinase [8]YchB [7, 8]

Inhibition of 4-diphosphocytidyl-2-C-methyl-D-erythritol kinase activity, which disrupts the methylerythritol phosphate (MEP) pathway and prevents the synthesis of essential isoprenoid precursors [2, 4].