(E)-4-hydroxy-3-methylbut-2-enyl diphosphate reductase (IspH) (IspH)

(E)-4-hydroxy-3-methylbut-2-enyl diphosphate reductase (IspH) is a vital enzyme in the methylerythritol phosphate (MEP) pathway, which is the primary route for isoprenoid biosynthesis in most bacteria and apicomplexan parasites [4, 6]. This pathway is essential for producing precursors like isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), which are necessary for cell wall synthesis, respiration, and membrane stability [8, 12]. Since humans utilize the distinct mevalonate pathway for isoprenoid production, IspH is considered an ideal target for selective antimicrobial and antimalarial drug development [2, 11]. The enzyme is a metalloenzyme containing an oxygen-sensitive [4Fe-4S] cluster that facilitates a complex reductive dehydroxylation reaction [3, 13]. Recent research has highlighted IspH as a target for "dual-acting immuno-antibiotics" (DAIAs), which not only inhibit bacterial growth but also stimulate the human innate immune system [1, 15]. Specifically, inhibition of IspH leads to the accumulation of its substrate, HMBPP, which is a potent activator of human Vγ9Vδ2 T-cells, thereby enhancing the host's ability to clear the infection [9, 14].

Other names

LytBHMBPP reductase(E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate reductaseIsopentenyl-diphosphate:NADP+ oxidoreductase

Inhibition of the MEP pathway by blocking the reductive dehydroxylation of HMBPP, leading to depletion of isoprenoid precursors and accumulation of HMBPP, which activates Vγ9Vδ2 T-cells [8, 9, 14].